U.S. patent application number 16/596741 was filed with the patent office on 2020-02-13 for compositions of obeticholic acid and methods of use.
The applicant listed for this patent is Intercept Pharmaceuticals, Inc., Sumitomo Dainippon Pharma Co., Ltd.. Invention is credited to Jeffrey Edwards, Lise Eliot, Roya Hooshmand-Rad, Masashi Kagihiro, Richard Gail Lancaster, Leigh A. MacConell, Tonya K. Marmon, Mitsuhiro Matono, Kay K. Olmstead, Richard Pencek, Mark Pruzanski, Cathi Sciacca, David Shapiro, Ikuko Taoka.
Application Number | 20200046736 16/596741 |
Document ID | / |
Family ID | 57198868 |
Filed Date | 2020-02-13 |
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United States Patent
Application |
20200046736 |
Kind Code |
A1 |
Lancaster; Richard Gail ; et
al. |
February 13, 2020 |
COMPOSITIONS OF OBETICHOLIC ACID AND METHODS OF USE
Abstract
The disclosure relates to obeticholic acid formulations with
improved stability, dissolution, and/or solubility, methods of
preparing the same for use and methods of treating various diseases
and conditions.
Inventors: |
Lancaster; Richard Gail;
(San Diego, CA) ; Olmstead; Kay K.; (Escondido,
CA) ; Kagihiro; Masashi; (Osaka, JP) ; Matono;
Mitsuhiro; (Osaka, JP) ; Taoka; Ikuko; (Osaka,
JP) ; Pruzanski; Mark; (New York, NY) ;
Shapiro; David; (Rancho Sante Fe, CA) ;
Hooshmand-Rad; Roya; (San Diego, CA) ; Pencek;
Richard; (San Diego, CA) ; Sciacca; Cathi;
(San Diego, CA) ; Eliot; Lise; (San Diego, CA)
; Edwards; Jeffrey; (San Diego, CA) ; MacConell;
Leigh A.; (Encinitas, CA) ; Marmon; Tonya K.;
(San Diego, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Intercept Pharmaceuticals, Inc.
Sumitomo Dainippon Pharma Co., Ltd. |
New York
Osaka |
NY |
US
JP |
|
|
Family ID: |
57198868 |
Appl. No.: |
16/596741 |
Filed: |
October 8, 2019 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16030141 |
Jul 9, 2018 |
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16596741 |
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15139138 |
Apr 26, 2016 |
10052337 |
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16030141 |
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62153040 |
Apr 27, 2015 |
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62317933 |
Apr 4, 2016 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 43/00 20180101;
A61K 9/2054 20130101; C07J 9/005 20130101; A61K 31/575 20130101;
A61K 9/2072 20130101; A61P 1/16 20180101; A61K 9/1617 20130101;
A61K 47/50 20170801; A61K 9/14 20130101; A61P 31/14 20180101; A61K
45/06 20130101; A61K 9/2059 20130101; A61K 31/575 20130101; A61K
2300/00 20130101 |
International
Class: |
A61K 31/575 20060101
A61K031/575; A61K 47/50 20060101 A61K047/50; A61K 9/16 20060101
A61K009/16; A61K 9/14 20060101 A61K009/14; C07J 9/00 20060101
C07J009/00; A61K 9/20 20060101 A61K009/20; A61K 45/06 20060101
A61K045/06 |
Claims
1. A pharmaceutical composition comprising an active pharmaceutical
ingredient, which is obeticholic acid or a pharmaceutically
acceptable salt or amino acid conjugate thereof, and one or more
pharmaceutically acceptable excipients, which provides a peak
plasma concentration (C.sub.max) of obeticholic acid in a subject
at a median time (T.sub.max) of approximately 2 hours after
administration of the pharmaceutical composition to the
subject.
2. The pharmaceutical composition of claim 1, which provides
formation of glyco-obeticholic acid and/or tauro-obeticholic acid
after the administration of the pharmaceutical composition to the
subject and which provides a peak plasma concentration (C.sub.max)
of glyco-obeticholic acid or of tauro-obeticholic acid at a median
time (T.sub.max) of approximately 10 hours after the
administration.
3. The pharmaceutical composition of claim 1, wherein said one or
more pharmaceutically acceptable excipients have a total alcohol
impurity having a primary alcohol group content of less than about
6% (wt/wt).
4. The pharmaceutical composition of claim 3, wherein said one or
more pharmaceutically acceptable excipients having a total alcohol
impurity having a primary alcohol group content of less than about
6% (wt/wt) is sodium starch glycolate.
5. The pharmaceutical composition of claim 1, wherein said one or
more pharmaceutically acceptable excipients includes a viscosity
enhancer.
6. The pharmaceutical composition of claim 5, wherein the viscosity
enhancer is colloidal silicon dioxide.
7. The pharmaceutical composition of claim 1, wherein the active
pharmaceutical ingredient is obeticholic acid.
8. The pharmaceutical composition of claim 7, wherein the
obeticholic acid is present in an amount of 25 mg.
9. The pharmaceutical composition of claim 1, in the form of an
oral dosage form.
10. The pharmaceutical composition of claim 9, wherein the oral
dosage form is a tablet.
11. The pharmaceutical composition of claim 1, wherein the active
pharmaceutical ingredient is the only active pharmaceutical
ingredient in the pharmaceutical composition.
12. A method of treating nonalcoholic steatohepatitis (NASH),
comprising administering to a subject the pharmaceutical
composition of claim 1.
13. The method of claim 12, wherein the active pharmaceutical
ingredient is obeticholic acid.
14. The method of claim 13, wherein the obeticholic acid is present
in an amount of 25 mg.
15. The method of claim 12, wherein the active pharmaceutical
ingredient is the only active pharmaceutical ingredient in the
pharmaceutical composition.
16. A method of treating nonalcoholic steatohepatitis (NASH)
comprising administering to a subject a pharmaceutical composition,
the pharmaceutical composition comprises an active pharmaceutical
ingredient, which is obeticholic acid or a pharmaceutically
acceptable salt or amino acid conjugate thereof, and one or more
pharmaceutically acceptable excipients, which provides a peak
plasma concentration (C.sub.max) of obeticholic acid in a subject
at a median T.sub.max of approximately 1.5 hours after
administration of the pharmaceutical composition to the
subject.
17. The method of claim 16, wherein the active pharmaceutical
ingredient is obeticholic acid.
18. The method of claim 17, wherein the obeticholic acid is present
in an amount of 25 mg.
19. The method of claim 16, wherein the active pharmaceutical
ingredient is the only active pharmaceutical ingredient in the
pharmaceutical composition.
Description
BACKGROUND
[0001] The farnesoid X receptor (FXR), also known as the bile acid
receptor (BAR) or NR1H4, is a member of the nuclear receptor
superfamily of ligand-activated transcription factors. FXR forms
with retinoid X receptor (RXR) a heterodimer receptor crucial for
bile acid homeostasis. FXR is expressed in various tissues
including the liver, kidney, intestine, colon, ovary, and adrenal
gland, and is activated by a variety of naturally occurring bile
acids, including the primary bile acid chenodeoxycholic acid (CDCA)
and its taurine and glycine conjugates. Upon activation, the
FXR-RXR heterodimer binds the promoter region of target genes and
regulates their expression.
[0002] 6-Ethyl-chenodeoxycholic acid (6-ECDCA, or obeticholic acid,
or OCA), a bile acid derivative, shows a potent FXR activating
activity, and accordingly offers great promise for the treatment of
FXR-mediated diseases or conditions. Thus, there is a need to
develop obeticholic acid compositions having desirable dissolution
profile and solubility, and possessing advantageous storage
stability.
SUMMARY
[0003] The present disclosure relates to novel formulations of
obeticholic acid, an FXR agonist, with improved stability,
dissolution, and solubility, methods of preparing the same and
methods of using the novel formulations for treating a disease or
condition. In certain instances, the disease or condition is
primary biliary cirrhosis (PBC), also known as primary biliary
cholangitis. In other instances, the disease or condition is
primary sclerosing cholangitis (PSC), chronic liver disease,
nonalcoholic fatty liver disease (NAFLD), nonalcoholic
steatohepatitis (NASH), hepatitis C infection, alcoholic liver
disease, liver damage due to progressive fibrosis, or liver
fibrosis. In another instance, the disease is NASH. In still other
instances, the disease or condition is solid-tumor cancer such as,
for example, hepatocellular carcinoma (HCC), colorectal cancer,
gastric cancer, liver cancer, breast cancer, kidney cancer, or
pancreatic cancer. Further provided herein are novel dosing
regimens for administration of obeticholic acid for treatment of
the diseases or conditions described herein.
##STR00001##
[0004] A first aspect of the disclosure relates to a composition
comprising obeticholic acid, or a pharmaceutically acceptable salt,
ester, or amino acid conjugate thereof, wherein obeticholic acid or
a pharmaceutically acceptable salt, ester, or amino acid conjugate
thereof is in the form of particles, and wherein at least 50% of
the particles have a diameter of less than 200 .mu.m. Such
compositions include all those described herein.
[0005] Another aspect of the disclosure relates to treating a
disease or condition described herein in a patient in need thereof
by administering a composition that includes obeticholic acid, or a
pharmaceutically acceptable salt, ester, or amino acid conjugate
thereof, where the obeticholic acid or a pharmaceutically
acceptable salt, ester, or amino acid conjugate thereof is in the
form of particles.
[0006] Another aspect of the disclosure relates to treating a
disease or condition described herein in a patient in need thereof
by administering a composition that includes obeticholic acid, or a
pharmaceutically acceptable salt, ester, or amino acid conjugate
thereof, where the obeticholic acid or a pharmaceutically
acceptable salt, ester, or amino acid conjugate thereof is in the
form of particles, and wherein at least 50% of the particles have a
diameter of 200 .mu.m or less.
[0007] Another aspect of the disclosure relates to treating primary
biliary cirrhosis (PBC) in a patient in need thereof by
administering a composition that includes obeticholic acid, or a
pharmaceutically acceptable salt, ester, or amino acid conjugate
thereof, optionally in a titration period, where the obeticholic
acid or a pharmaceutically acceptable salt, ester, or amino acid
conjugate thereof is in the form of particles, and wherein at least
50% of the particles have a diameter of 200 .mu.m or less.
[0008] In still another aspect of the disclosure is a method of
treating primary sclerosing cholangitis (PSC), chronic liver
disease, nonalcoholic fatty liver disease (NAFLD), nonalcoholic
steatohepatitis (NASH), hepatitis C infection, alcoholic liver
disease, liver damage due to progressive fibrosis, or liver
fibrosis in a patient in need thereof by administering a
composition that includes obeticholic acid, or a pharmaceutically
acceptable salt, ester, or amino acid conjugate thereof, optionally
in a titration period, where the obeticholic acid or a
pharmaceutically acceptable salt, ester, or amino acid conjugate
thereof is in the form of particles. In one example, at least 50%
of the particles have a diameter of 200 .mu.m or less.
[0009] In yet another aspect of the disclosure is a method of
treating a solid-tumor cancer in a patient in need thereof by
administering a composition that includes obeticholic acid, or a
pharmaceutically acceptable salt, ester, or amino acid conjugate
thereof, optionally in a titration period, where the obeticholic
acid or a pharmaceutically acceptable salt, ester, or amino acid
conjugate thereof is in the form of particles. In one example, at
least 50% of the particles have a diameter of 200 .mu.m or
less.
[0010] In another aspect of the disclosure is a method of treating
an autoimmune disease in a patient in need thereof by administering
a composition that obeticholic acid, or a pharmaceutically
acceptable salt, ester, or amino acid conjugate thereof, optionally
in a titration period, where the obeticholic acid or a
pharmaceutically acceptable salt, ester, or amino acid conjugate
thereof is in the form of particles. In one example, at least 50%
of the particles have a diameter of 200 .mu.m or less.
[0011] In another aspect of the disclosure are methods of treating
a disease or condition described herein by administering a
obeticholic acid composition described herein where the obeticholic
acid composition is administered as part of a treatment regimen
that includes a titration period and a starting dose of the
obeticholic acid composition at an amount of about 5 mg or 10 mg.
In particular instances, such methods include daily (QD)
administration of an obeticholic acid described herein during the
titration period. In particular instances, such methods also
include administration of an adjusted dose of an obeticholic acid
composition described herein after the titration period.
[0012] Another aspect of the disclosure relates to a composition
comprising obeticholic acid, or a pharmaceutically acceptable salt,
ester, or amino acid conjugate thereof, wherein obeticholic acid or
a pharmaceutically acceptable salt, ester, or amino acid conjugate
thereof is in the form of particles, and wherein at least 50% of
the particles have a diameter of less than 200 am. Another aspect
of the disclosure relates to a composition comprising obeticholic
acid, or a pharmaceutically acceptable salt, ester, or amino acid
conjugate thereof, and a pharmaceutically acceptable excipient
(e.g., sodium starch glycolate) having a low alcohol (e.g., ethanol
or methanol) content (e.g., less than 5% (wt/wt)).
[0013] In another aspect, the disclosure relates to a
pharmaceutical composition, comprising a therapeutically effective
amount of obeticholic acid, or a pharmaceutically acceptable salt,
ester, or amino acid conjugate thereof, in the form of particles,
and a pharmaceutically acceptable excipient (e.g., sodium starch
glycolate) having a low alcohol (e.g., ethanol or methanol) content
(e.g., less than 5% (wt/wt)), wherein at least 50% of the particles
have a diameter of less than 200 .mu.m.
[0014] Another aspect of the disclosure relates to a pharmaceutical
composition, comprising obeticholic acid, or a pharmaceutically
acceptable salt, ester, or amino acid conjugate thereof, in the
form of particles, wherein at least 50% of the particles have a
diameter of less than 200 .mu.m, at about 1% to about 6% by weight,
sodium starch glycolate at about 2% to about 8% by weight having a
low alcohol (e.g., ethanol or methanol) content (e.g., less than 5%
(wt/wt)), a lubricant (e.g., magnesium stearate) at about 0.1% to
about 2.0% by weight, and a diluent (e.g., microcrystalline
cellulose) at about 85% to about 95% by weight.
[0015] In another aspect, the disclosure relates to a method for
preparing a composition comprising obeticholic acid, or a
pharmaceutically acceptable salt, ester, or amino acid conjugate
thereof, in the form of particles, wherein at least 50% of the
particles have a diameter of less than 200 .mu.m, comprising
forming the particles through jet-milling.
[0016] Another aspect of the disclosure relates to a tablet
comprising an intra-granular portion and an extra-granular portion,
the intra-granular portion comprising obeticholic acid, or a
pharmaceutically acceptable salt, ester, or amino acid conjugate
thereof, microcrystalline cellulose, and one or more additional
pharmaceutical excipients, and the extra-granular portion
comprising one or more pharmaceutical excipients.
[0017] Another aspect of the disclosure relates to a tablet
comprising an intra-granular portion and an extra-granular portion,
the intra-granular portion comprising obeticholic acid, or a
pharmaceutically acceptable salt, ester, or amino acid conjugate
thereof, microcrystalline cellulose, and one or more additional
pharmaceutical excipients, and the extra-granular portion
comprising microcrystalline cellulose and one or more additional
pharmaceutical excipients.
[0018] In another aspect, the disclosure relates to methods for
treating or preventing an FXR mediated disease or condition or a
disease or condition in which elevated concentrations of
circulating lipid compounds or glucose in the blood, or decreased
insulin level, or increased insulin resistance is involved, or
inhibiting or reversing fibrosis, comprising administering a
therapeutically effective amount of a composition of the present
disclosure to a subject in need thereof.
[0019] Another aspect of the disclosure relates to use of a
composition of the present disclosure for treating or preventing an
FXR mediated disease or condition or a disease or condition in
which elevated concentrations of circulating lipid compounds or
glucose in the blood, or decreased insulin level, or increased
insulin resistance is involved, or for inhibiting or reversing
fibrosis.
[0020] In another aspect, the disclosure relates to use of a
composition of the present disclosure in the manufacture of a
medicament for treating or preventing an FXR mediated disease or
condition or a disease or condition in which elevated
concentrations of circulating lipid compounds or glucose in the
blood, or decreased insulin level, or increased insulin resistance
is involved, or for inhibiting or reversing fibrosis.
[0021] The compositions and methods of the present disclosure
address unmet needs in the treatment or prevention of an FXR
mediated disease or a disease or disorder in which elevated
concentrations of circulating lipid compounds in the blood such as
cholesterol and triglycerides or glucose are involved.
[0022] The compositions and methods of the present disclosure
address unmet needs in the treatment of diseases and conditions
described herein, including for example, PBC, PSC, NAFLD, NASH,
cancer, and autoimmune diseases described herein.
BRIEF DESCRIPTION OF THE DRAWINGS
[0023] FIG. 1 is a particle size distribution histogram of
obeticholic acid before jet-milling.
[0024] FIG. 2 is a particle size distribution histogram of
obeticholic acid after jet-milling.
[0025] FIG. 3 is a graph showing the dissolution profile of 10 mg
tablets containing unmilled/non-agglomerated,
unmilled/agglomerated, or jet-milled obeticholic acid.
[0026] FIG. 4 is a graph showing the dissolution profile of 5 mg
tablets containing unmilled or jet-milled obeticholic acid.
[0027] FIG. 5 is a graph showing solubility of obeticholic acid in
various buffers at 37.degree. C. over a pH range of about 1.2 to
about 12. The dashed and dotted lines represent the
Biopharmaceutical Classification System (BCS) limit for 5 mg and 10
mg doses, respectively (5 and 10 mg/250 mL)
[0028] FIG. 6 is a graph showing obeticholic acid solubility in
various biologically relevant buffers over a pH range of about 1.2
to about 12. The dashed and dotted lines represent the
Biopharmaceutical Classification System (BCS) high-solubility limit
for 5 mg and 10 mg doses, respectively (5 and 10 mg/250 mL).
[0029] FIG. 7A shows the LC/HRMS spectrum in the positive mode of a
sample of obeticholic acid OCA and the synthesized ethyl ester of
obeticholic acid OCA. FIG. 7B shows the mass spectrum in the
positive mode of a sample of obeticholic acid OCA and the
synthesized ethyl ester of obeticholic acid OCA.
[0030] FIG. 8A shows the total ion count (TIC) chromatogram in the
positive ion mode acquired on Q-TOF LC/MS of a sample of
obeticholic acid OCA containing the PEG impurity.
[0031] FIG. 8B shows the mass spectra in the positive mode acquired
on Q-TOF LC/MS of a sample of obeticholic acid OCA containing the
PEG impurity. FIG. 8C shows the total ion count (TIC) chromatogram
acquired on triple quad (QQQ) mass spectrometer of a sample of
obeticholic acid OCA containing the PEG impurity.
[0032] FIG. 9 shows an enlarged spectrum of the co-eluting peaks
containing obeticholic acid OCA and the PEG impurity displaying
spacing characteristics of PEG.
[0033] FIG. 10 illustrates the percent Change in ALP levels from
Baseline to EOS: mITT Population (N=161).
[0034] FIG. 11 illustrates ALP Concentration (U/L) over duration of
treatment.
[0035] FIG. 12 illustrates TB Concentration (tmol/L) over duration
of treatment.
[0036] FIG. 13 illustrates proposed metabolic pathways of OCA in
human plasma.
[0037] FIGS. 14A-14C illustrate Observed Individual Patient-Level
Change in ALP from Baseline at Month for responders and
non-responders by treatment group (Placebo (FIG. 14A), for OCA
titration (FIG. 14B) and for OCA 10 mg (FIG. 14C)).
[0038] FIG. 15A illustrates mean ALP over time and FIG. 15B
illustrates mean total bilirubin (TB) over time.
[0039] FIG. 16 illustrates the mean plasma concentration-time
profile (Semi-log) of total OCA following a single oral dose of 10
mg OCA (inset shows expanded view of first 24 hours).
[0040] FIG. 17A illustrates ALP levels and FIG. 17B illustrates
change in ALP from baseline with OCA monotherapy and combination
therapy with UDCA, based on pooled data from study 747-201, study
747-202 and Phase 3 study 747-301.
[0041] FIGS. 18A-18F illustrate the Goodness of Fit: Observed
Concentrations vs Predicted Concentrations of OCA. FIG. 18A shows
the individual glyco-OCA group, FIG. 18B shows the individual
unconjugated OCA group, FIG. 18C shows individual tauro-OCA group,
FIG. 18D shows the population glyco-OCA group, FIG. 18E shows the
population unconjugated OCA group, and FIG. 18F shows the
population tauro-OCA group.
[0042] FIGS. 19A-19F illustrate the Goodness of Fit: Residuals.
FIG. 19A shows the glyco-OCA group vs. concentration, FIG. 19B
shows the unconjugated OCA group vs. concentration, FIG. 19C shows
the tauro-OCA group vs. concentration, FIG. 19D shows the glyco-OCA
group vs. time, FIG. 19E shows the unconjugated OCA group vs. time,
and FIG. 19F shows the tauro-OCA group vs. time.
[0043] FIGS. 20A-20F illustrate External Validation of Model in
Subjects with Normal Hepatic Function. FIG. 20A shows the single
dose of 5 mg OCA, FIG. 20B shows the single dose of 10 mg OCA, FIG.
20C shows the single dose of 25 mg OCA, FIG. 20D shows the multiple
dose of 5 mg OCA, FIG. 20E shows the multiple dose of 10 mg OCA,
and FIG. 20F shows the multiple dose of 25 mg OCA.
[0044] FIGS. 21A-21D illustrate External Validation of Model in
Subjects with Normal Hepatic Function. FIG. 21A shows the 6 day
profile in Period 1, FIG. 21B shows the 24 hour profile in Period
1, FIG. 21C shows the 6 day profile in Period 2, and FIG. 21D shows
the 24 hour profile in Period 2.
[0045] FIGS. 22A-22F illustrate External Validation of Model in
Patients with Impaired Hepatic Function. FIG. 22A shows the effect
of 10 mg OCA in mild impairment, FIG. 20B shows the effect of 10 mg
OCA in moderate impairment, FIG. 20C shows the effect of 10 mg OCA
in severe impairment, FIG. 22D shows the effect of 25 mg OCA in
mild impairment, FIG. 20E shows the effect of 25 mg OCA in moderate
impairment, and FIG. 20F shows the effect of 25 mg OCA in severe
impairment.
[0046] FIG. 23A and FIG. 23B illustrate plasma OCA Concentrations
are a Poor Surrogate for Liver OCA Concentrations.
[0047] FIG. 24A, FIG. 24B, and FIG. 24C illustrate changes in
4FIB-4, APRI Score, and NFS during the course of treating NASH
using the obeticholic acid compositions described herein,
respectively. *p<0.05, **p<0.01, ***p<0.0001; P-values
were calculated using ANCOVA models, regressing change from
baseline at each post-baseline visit on treatment group and
baseline value of the outcome.
[0048] FIGS. 25A-25D illustrate a Visual Predictive Check of PK
Model in Subjects with Normal Hepatic Function where FIG. 25A shows
a 6-day profile, FIG. 25B shows a 24-hour profile, FIG. 25C shows a
6-day profile over period 2 and FIG. 25D shows a 24-hour profile
over period 2.
[0049] FIGS. 26A-26D show Visual Predictive Check of PK model in
Patients with Normal and Impaired Hepatic Function where FIG. 26A
shows normal function, FIG. 26B shows mild impairment, FIG. 26C
shows moderate impairment and FIG. 26D shows severe impairment.
[0050] FIGS. 27A-27F show External Validation of Model in Subjects
with Normal Hepatic Function where FIG. 27A shows a single dose of
OCA 5 mg, FIG. 27B shows a single dose of OCA 10 mg, FIG. 27C shows
a single dose of OCA 25 mg, FIG. 27D shows a multiple dose of OCA 5
mg, FIG. 27E shows a multiple dose of OCA 10 mg, and FIG. 27F shows
a multiple dose of OCA 25 mg.
[0051] FIGS. 28A-28F show External Validation of Model in Patients
with Impaired Hepatic Function where FIG. 28A shows mild impairment
of OCA 10 mg, FIG. 28B shows moderate impairment of OCA 10 mg, FIG.
28C shows severe impairment of OCA 10 mg, FIG. 28D shows mild
impairment of OCA 25 mg, FIG. 28E shows moderate impairment of OCA
25 mg, and FIG. 28F shows severe impairment of OCA 25 mg.
DETAILED DESCRIPTION
[0052] Pharmaceutical preparations containing a poorly
water-soluble drug require some tools for improving the dissolution
property of the drug, for example, adding a surfactant or other
additive, or amorphizing the drug. However, the addition of the
surfactant or other additive can chemically destabilize the drug,
and methods of amorphizing the drug may require changing the
crystal form.
[0053] When compositions containing a high concentration of a
poorly water-soluble drug are produced, usually, powders are
tableted by direct compression or granules are produced by dry or
wet granulation methods and tableted. However, tableting by direct
compression and granulation are largely affected by the physical
properties of the drug and often have great weight variations and
poor content uniformity at the time of tableting, resulting in poor
manufacturability in consideration of productivity. Moreover, these
approaches can provide a drug product with poor dissolution.
[0054] The present application is directed to compositions and
formulations of obeticholic acid, a pharmaceutically active
ingredient (also known as INT-747) having the chemical
structure:
##STR00002##
or a pharmaceutically acceptable salt, ester, or amino acid
conjugate (such as, e.g., glycine, taurine or sarcosine conjugate)
thereof having improved dissolution, solubility, and stability for
the treatment of a disease or condition described herein.
[0055] The details of the disclosure are set forth in the
accompanying description below. Although methods and materials
similar or equivalent to those described herein can be used in the
practice or testing of the present disclosure, illustrative methods
and materials are now described. Other features, objects, and
advantages of the disclosure will be apparent from the description
and from the claims. In the specification and the appended claims,
the singular forms also include the plural unless the context
clearly dictates otherwise. Unless defined otherwise, all technical
and scientific terms used herein have the same meaning as commonly
understood by one of ordinary skill in the art to which this
disclosure belongs. In the case of conflict, the present
specification will control. All patents and publications cited in
this specification are incorporated herein by reference in their
entireties.
[0056] All percentages and ratios used herein, unless otherwise
indicated, are by weight.
[0057] The term "viscosity enhancer," as used herein, refers to an
agent or a mixture of agents that increases the thickness of a
liquid thereby keeping the active ingredient suspended to allow
accurate dosing. Viscosity enhancers include, but are not limited
to, xantham gum, guar gum, acacia, alginic acid, sodium alginate,
propylene glycol alginate, povidone, carbomer, salts of
carboxymethylcellulose, methylcellulose, ethylcellulose,
hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl
methylcellulose, bentonite, polydextrose, carrageenan, sucrose,
sorbitol, xylitol, dextrose, fructose, malitol, gelatin,
tragacanth, a polyvinyl alcohol, cetearyl alcohol, colloidal
silicon dioxide and mixtures thereof. In one embodiment, the
viscosity enhancer can be any viscosity enhancer known in the
art.
[0058] The term "flavoring agent," as used herein, refers to an
agent or a mixture of agents that adds flavor to a mixture.
Flavoring agents include, but are not limited to, artificial
strawberry flavor, art banana flavor and artificial cream flavor.
In one embodiment, the flavoring agent can be any flavoring agent
known in the art.
[0059] The term "preservative," as used herein, refers to an agent
or mixture of agents that is used to protect a composition against
antimicrobial (e.g., yeast, mold, bacteria) activity. Preservatives
include, but are not limited to, sodium benzoate, benzoic acid,
ethylenediaminetetraacetic acid, sorbic acid, benzethonium
chloride, benzalkonium chloride, bronopol, butyl paraben, methyl
paraben, ethylparaben, propyl paraben, thiomerosol, sodium
propionate, chlorhexidine, chlorobutanol, chlorocresol, cresol,
imidurea, phenol, phenylmercuric salts, potassium sorbate,
propylene glycol, and mixtures thereof. In one embodiment, the
preservative can be any preservative known in the art.
[0060] The term "organ" refers to a differentiated structure (as in
a heart, lung, kidney, liver, etc.) consisting of cells and tissues
and performing some specific function in an organism. This term
also encompasses bodily parts performing a function or cooperating
in an activity (e.g., an eye and related structures that make up
the visual organs). The term "organ" further encompasses any
partial structure of differentiated cells and tissues that is
potentially capable of developing into a complete structure (e.g.,
a lobe or a section of a liver).
[0061] As used herein the term "6-ethyl chenodeoxycholic acid",
"6-ECDCA", "obeticholic acid" or "OCA" refers to a compound having
the chemical structure:
##STR00003##
[0062] Other chemical names for obeticholic acid include:
3.alpha.,7.alpha.-dihydroxy-6.alpha.-ethyl-5.beta.-cholan-24-oic
acid, 6.alpha.-ethyl-chenodeoxycholic acid, 6-ethyl-CDCA, 6ECDCA,
cholan-24-oic
acid,6-ethyl-3,7-dihydroxy-,(3.alpha.,5.beta.,6.alpha.,7.alpha.)-
and INT-747. The CAS registry number for obeticholic acid is
459789-99-2. This term refers to all forms of obeticholic acid,
e.g., non-crystalline, crystalline and substantially pure.
[0063] An "obeticholic acid composition" described herein refers to
obeticholic acid administered to a patient in any form described
herein including as a component of a pharmaceutical
composition.
[0064] The articles "a" and "an" are used in this disclosure to
refer to one or more than one (i.e., to at least one) of the
grammatical object of the article. By way of example, "an element"
means one element or more than one element.
[0065] The term "and/or" is used in this disclosure to mean either
"and" or "or" unless indicated otherwise.
[0066] As used herein, the term "purity" refers to a chemical
analysis of a compound obtained from, e.g., HPLC. In one
embodiment, the purity of a compound is compared to the purity of
the reference standard, e.g., obeticholic acid, via the area under
their respective peak for comparisons. In one embodiment, purity
accounts for the organic impurities in a sample.
[0067] "Treating", includes any effect, e.g., lessening, reducing,
modulating, or eliminating, that results in the improvement of the
condition, disease, disorder, etc. "Treating" or "treatment" of a
disease state includes: inhibiting the disease state, i.e.,
arresting the development of the disease state or its clinical
symptoms; or relieving the disease state, i.e., causing temporary
or permanent regression of the disease state or its clinical
symptoms.
[0068] The term "regimen" refers to a protocol for dosing and/or
timing the administration of one or more therapies (e.g., an
obeticholic acid composition described herein or another active
agent such as for example UDCA) for treating a disease, disorder,
or condition described herein. A regimen can include periods of
active administration and periods of rest as known in the art.
Active administration periods include administration of the
obeticholic acid compositions described herein in a defined course
of time, including, for example, the number of and timing of
dosages of the compositions. In some regimens, one or more rest
periods can be included where no compound is actively administered,
and in certain instances, includes time periods where the efficacy
of such compounds can be minimal.
[0069] The term "enhance" refers to an increase or improvement in
the function or activity of a protein or cell after administration
or contacting with a combination described herein compared to the
protein or cell prior to such administration or contact.
[0070] "Preventing" the disease state includes causing the clinical
symptoms of the disease state not to develop in a subject that may
be exposed to or predisposed to the disease state, but does not yet
experience or display symptoms of the disease state.
[0071] The term "inhibiting" or "inhibition," as used herein,
refers to any detectable positive effect on the development or
progression of a disease or condition. Such a positive effect may
include the delay or prevention of the onset of at least one
symptom or sign of the disease or condition, alleviation or
reversal of the symptom(s) or sign(s), and slowing or prevention of
the further worsening of the symptom(s) or sign(s).
[0072] "Disease state" means any disease, disorder, condition,
symptom, or indication.
[0073] The term "effective amount" as used herein refers to an
amount of obeticholic acid (e.g., an FXR-activating ligand) that
produces an acute or chronic therapeutic effect upon appropriate
dose administration. The effect includes the prevention,
correction, inhibition, or reversal of the symptoms, signs and
underlying pathology of a disease/condition (e.g., fibrosis of the
liver, kidney, or intestine) and related complications to any
detectable extent.
[0074] "A therapeutically effective amount" means the amount of
obeticholic acid that, when administered to a mammal for treating a
disease, is sufficient to effect such treatment for the disease.
The "therapeutically effective amount" will vary depending on
obeticholic acid, the disease and its severity and the age, weight,
etc., of the mammal to be treated. A therapeutically effective
amount can refer to a starting dose or adjusted dose as set forth
herein.
[0075] A therapeutically effective amount of obeticholic acid can
be formulated with a pharmaceutically acceptable carrier for
administration to a human or an animal. Accordingly, obeticholic
acid or its formulations can be administered, for example, via
oral, parenteral, or topical routes, to provide an effective amount
of the compound. In alternative embodiments, obeticholic acid
prepared in accordance with the present disclosure can be used to
coat or impregnate a medical device, e.g., a stent.
[0076] For any compound, the therapeutically effective amount can
be estimated initially either in cell culture assays or in animal
models, usually rats, mice, rabbits, dogs, or pigs. The animal
model may also be used to determine the appropriate concentration
range and route of administration. Such information can then be
used to determine useful doses and routes for administration in
humans. Therapeutic/prophylactic efficacy and toxicity may be
determined by standard pharmaceutical procedures in cell cultures
or experimental animals, e.g., ED.sub.50 (the dose therapeutically
effective in 50% of the population) and LD.sub.50 (the dose lethal
to 50% of the population). The dose ratio between toxic and
therapeutic effects is the therapeutic index, and it can be
expressed as the ratio, LD.sub.50/ED.sub.50. Pharmaceutical
compositions that exhibit large therapeutic indices are preferred.
The dosage may vary within this range depending upon the dosage
form employed, sensitivity of the patient, and the route of
administration.
[0077] Dosage and administration are adjusted to provide sufficient
levels of the active agent(s) or to maintain the desired effect.
Factors which may be taken into account include the severity of the
disease state, general health of the subject, age, weight, and
gender of the subject, diet, time and frequency of administration,
drug combination(s), reaction sensitivities, and tolerance/response
to therapy.
[0078] A "starting dose" as used herein refers to an initial dose
provided to a patient to provide a clinical effect while minimizing
onset or occurrence of an adverse effect. A starting dose can, in
certain instances, be less than an amount typically administered to
a patient. A starting dose is provided in an amount that is
titrated or gradually increased over the course of a titration
period or during the course of treatment with an obeticholic acid
composition described herein.
[0079] A "titration period" refers to a length of time for which a
starting dose is administered to a patient. A titration period
continues for a specified length of time, where the patient is
often monitored for liver function and/or liver biochemistry as
described herein. In one embodiment a titration period concludes
when a patient tolerates an obeticholic acid composition described
herein but has a decreased or minimal reduction in alkaline
phosphatase.
[0080] An "adjusted dose" as used herein refers to a dose of an
obeticholic acid composition described herein administered after
the termination of a titration period. An adjusted dose is often
increased compared to a starting dose but, as provided herein,
patient tolerance and other factors described herein determine the
dosage amount of an adjusted dose. A "re-adjusted dose" as used
herein refers to any changed dosage amount or dose frequency of an
adjusted dose in a patient.
[0081] "Hepatic impairment" is used in accordance with its standard
meaning(s) in the art and can, in certain embodiments herein refer
to scoring based upon the Child-Pugh Score of A, B, and C.
[0082] The term "administering" refers to the act of delivering an
obeticholic acid composition described herein into a subject by
such routes as oral, mucosal, topical, suppository, intravenous,
parenteral, intraperitoneal, intramuscular, intralesional,
intrathecal, intranasal or subcutaneous administration. Parenteral
administration includes intravenous, intramuscular, intra-arterial,
intradermal, subcutaneous, intraperitoneal, intraventricular, and
intracranial administration. The term can also refer to the
frequency (e.g., daily, weekly, monthly, etc.) of providing an
obeticholic acid composition described herein to a patient.
Administration generally occurs after the onset of the disease,
disorder, or condition, or its symptoms but, in certain instances,
can occur before the onset of the disease, disorder, or condition,
or its symptoms (e.g., administration for patients prone to such a
disease, disorder, or condition). In certain embodiments,
administration as used herein refers to oral administration.
[0083] The term "co-administration" refers to administration of two
or more agents (e.g., an obeticholic acid composition described
herein and another active agent such as UDCA or an anti-cancer
agent described herein). The timing of co-administration depends in
part of the combination and the compositions administered and can
include administration at the same time, prior to, or after the
administration of one or more additional therapies. An obeticholic
acid composition of the instant invention can be administered alone
or can be coadministered to the patient. Co-administration is meant
to include simultaneous or sequential administration of an
obeticholic acid composition individually or in combination (more
than one compound or agent). Thus, the preparations can also be
combined, when desired, with other active substances (e.g., to
reduce metabolic degradation). The obeticholic acid compositions
described herein can be used in combination with each other (i.e.,
two different obeticholic acid compositions), with other active
agents known to be useful in treating a disease, or with adjunctive
agents that are not effective alone, but can contribute to or
enhance the efficacy of the active agent.
[0084] The term "anti-cancer agent" is used in accordance with its
plain ordinary meaning and refers to a composition having
anti-neoplastic properties or the ability to inhibit the growth or
proliferation of cells. In embodiments, an anti-cancer agent is a
chemotherapeutic agent. In embodiments, an anti-cancer agent is an
agent identified herein having utility in methods of treating
cancer. In embodiments, an anti-cancer agent is an agent approved
by the FDA or similar regulatory agency of a country other than the
USA, for treating cancer.
[0085] "Pharmacological effect" as used herein encompasses effects
produced in the subject that achieve the intended purpose of a
therapy. In one embodiment, a pharmacological effect means that
primary indications of the subject being treated are prevented,
alleviated, or reduced. For example, a pharmacological effect would
be one that results in the prevention, alleviation or reduction of
primary indications in a treated subject. In another embodiment, a
pharmacological effect means that disorders or symptoms of the
primary indications of the subject being treated are prevented,
alleviated, or reduced. For example, a pharmacological effect would
be one that results in the prevention or reduction of primary
indications in a treated subject.
[0086] "Geometric Isomers" means the diastereomers that owe their
existence to hindered rotation about double bonds. These
configurations are differentiated in their names by the prefixes
cis and trans, or Z and E, which indicate that the groups are on
the same or opposite side of the double bond in the molecule
according to the Cahn-Ingold-Prelog rules.
[0087] "Solvates" means solvent addition forms that contain either
stoichiometric or non-stoichiometric amounts of solvent.
Obeticholic acid may have a tendency to trap a fixed molar ratio of
solvent molecules in the crystalline solid state, thus forming a
solvate. If the solvent is water the solvate formed is a hydrate,
when the solvent is alcohol, the solvate formed is an alcoholate.
Hydrates are formed by the combination of one or more molecules of
water with one of the substances in which the water retains its
molecular state as H.sub.2O, such combination being able to form
one or more hydrate. Additionally, the compounds of the present
disclosure, for example, the salts of the compounds, can exist in
either hydrated or unhydrated (the anhydrous) form or as solvates
with other solvent molecules. Non-limiting examples of hydrates
include monohydrates, dihydrates, etc. Non-limiting examples of
solvates include ethanol solvates, acetone solvates, etc.
[0088] "Tautomers" refers to compounds whose structures differ
markedly in arrangement of atoms, but which exist in easy and rapid
equilibrium. It is to be understood that obeticholic acid may be
depicted as different tautomers. It should also be understood that
when obeticholic acid and synthetic intermediates of the disclosure
have tautomeric forms, all tautomeric forms are intended to be
within the scope of the disclosure, and the naming of obeticholic
acid does not exclude any tautomer form. obeticholic acid and
synthetic intermediates of the disclosure can exist in several
tautomeric forms, including the keto-enol. For example, in
keto-enol tautomerism a simultaneous shift of electrons and a
hydrogen atom occurs. Tautomers exist as mixtures of a tautomeric
set in solution. In solid form, usually one tautomer predominates.
Even though one tautomer may be described, the present disclosure
includes all tautomers of the present compounds.
[0089] It is to be understood accordingly that the isomers arising
from asymmetric carbon atoms (e.g., all enantiomers and
diastereomers) are included within the scope of the disclosure,
unless indicated otherwise. Such isomers can be obtained in
substantially pure form by classical separation techniques and by
stereochemically controlled synthesis. Furthermore, the structures
and other compounds and moieties discussed in this application also
include all tautomers thereof. Alkenes can include either the E- or
Z-geometry, where appropriate. Obeticholic acid and synthetic
intermediates may exist in stereoisomeric form, and therefore can
be produced as individual stereoisomers or as mixtures.
[0090] A "pharmaceutical composition" is a formulation containing
obeticholic acid in a form suitable for administration to a
subject. In one embodiment, the pharmaceutical composition is in
bulk or in unit dosage form. It is can be advantageous to formulate
compositions in dosage unit form for ease of administration and
uniformity of dosage. Dosage unit form, as used herein, refers to
physically discrete units suited as unitary dosages for the subject
to be treated; each unit containing a predetermined quantity of
active reagent calculated to produce the desired therapeutic effect
in association with the required pharmaceutical carrier. The
specification for the dosage unit forms of the disclosure are
dictated by and directly dependent on the unique characteristics of
the active reagent and the particular therapeutic effect to be
achieved, and the limitations inherent in the art of compounding
such an active agent for the treatment of individuals.
[0091] The term "unit dosage form" refers to physically discrete
units suitable as unitary dosages for human subjects and other
mammals, each unit containing a predetermined quantity of active
material calculated to produce the desired therapeutic effect, in
association with a suitable pharmaceutical excipient as described
above.
[0092] The unit dosage form is any of a variety of forms,
including, for example, a capsule, an IV bag, a tablet, a single
pump on an aerosol inhaler, or a vial. The quantity obeticholic
acid (e.g., a formulation of obeticholic acid, or a
pharmaceutically acceptable salt, solvate, or amino acid conjugate
thereof) in a unit dose of composition is an effective amount and
is varied according to the particular treatment involved. One
skilled in the art will appreciate that it is sometimes necessary
to make routine variations to the dosage, depending on the age and
condition of the patient. The dosage will also depend on the route
of administration. A variety of routes are contemplated, including
oral, pulmonary, rectal, parenteral, transdermal, subcutaneous,
intravenous, intramuscular, intraperitoneal, inhalational, buccal,
sublingual, intrapleural, intrathecal, intranasal, and the like.
Dosage forms for the topical or transdermal administration of a
compound of this disclosure include powders, sprays, ointments,
pastes, creams, lotions, gels, solutions, patches and inhalants. In
one embodiment, obeticholic acid is mixed under sterile conditions
with a pharmaceutically acceptable carrier, and with any
preservatives, buffers, or propellants that are required.
[0093] The term "flash dose" refers to obeticholic acid
formulations that are rapidly dispersing dosage forms.
[0094] The term "immediate release" is defined as a release of
obeticholic acid from a dosage form in a relatively brief period of
time, generally up to about 60 minutes. The term "modified release"
is defined to include delayed release, extended release, and pulsed
release. The term "pulsed release" is defined as a series of
releases of drug from a dosage form. The term "sustained release"
or "extended release" is defined as continuous release of
obeticholic acid from a dosage form over a prolonged period.
[0095] A "subject" or "patient" includes mammals, e.g., humans,
companion animals (e.g., dogs, cats, birds, and the like), farm
animals (e.g., cows, sheep, pigs, horses, fowl, and the like) and
laboratory animals (e.g., rats, mice, guinea pigs, birds, and the
like). In one embodiment, the patient is human. In one embodiment,
the subject is human child (e.g., between about 30 kg to about 70
kg). In one embodiment, the human child has had a Kasai procedure,
where the Kasai procedure effectively gives them a functional bile
duct when they are born either without a bile duct or a bile duct
that is completely blocked at birth.
[0096] As used herein, the phrase "pharmaceutically acceptable"
refers to those compounds, materials, compositions, carriers,
and/or dosage forms which are, within the scope of sound medical
judgment, suitable for use in contact with the tissues of human
beings and animals without excessive toxicity, irritation, allergic
response, or other problem or complication, commensurate with a
reasonable benefit/risk ratio.
[0097] "Pharmaceutically acceptable excipient" means an excipient
that is useful in preparing a pharmaceutical composition that is
generally safe, non-toxic and neither biologically nor otherwise
undesirable, and includes excipient that is acceptable for
veterinary use as well as human pharmaceutical use. A
"pharmaceutically acceptable excipient" as used in the
specification and claims includes both one and more than one such
excipient.
[0098] A pharmaceutical composition of the disclosure is formulated
to be compatible with its intended route of administration.
Examples of routes of administration include parenteral, e.g.,
intravenous, intradermal, subcutaneous, oral (e.g., inhalation),
transdermal (topical), and transmucosal administration. Solutions
or suspensions used for parenteral, intradermal, or subcutaneous
application can include the following components: a sterile diluent
such as water for injection, saline solution, fixed oils,
polyethylene glycols, glycerine, propylene glycol or other
synthetic solvents; antibacterial agents such as benzyl alcohol or
methyl parabens; antioxidants such as ascorbic acid or sodium
bisulfite; chelating agents such as ethylenediaminetetraacetic acid
(EDTA); buffers such as acetates, citrates or phosphates, and
agents for the adjustment of tonicity such as sodium chloride or
dextrose. The pH can be adjusted with acids or bases, such as
hydrochloric acid or sodium hydroxide. The parenteral preparation
can be enclosed in ampoules, disposable syringes or multiple dose
vials made of glass or plastic.
[0099] "Process of the disclosure" refers to a method for preparing
obeticholic acid as described herein, wherein the method comprises
preparing a crystalline form of obeticholic acid.
[0100] A "control" as used herein refers to a baseline level
determined on a patient-by-patient basis, an amount or level
considered by those skilled in the art as a normal value, or any
level or measure of a condition or biomarker described herein taken
from a patient or population of patients at any given time for a
given condition.
[0101] "Fibrosis" refers to a condition involving the development
of excessive fibrous connective tissue, e.g., scar tissue, in a
tissue or organ. Such generation of scar tissue may occur in
response to infection, inflammation, or injury of the organ due to
a disease, trauma, chemical toxicity, and so on. Fibrosis may
develop in a variety of different tissues and organs, including the
liver, kidney, intestine, lung, heart, etc.
[0102] As used herein, a "cholestatic condition" refers to any
disease or condition in which bile excretion from the liver is
impaired or blocked, which can occur either in the liver or in the
bile ducts. Intrahepatic cholestasis and extrahepatic cholestasis
are the two types of cholestatic conditions. Intrahepatic
cholestasis (which occurs inside the liver) is most commonly seen
in primary biliary cirrhosis, primary sclerosing cholangitis,
sepsis (generalized infection), acute alcoholic hepatitis, drug
toxicity, total parenteral nutrition (being fed intravenously),
malignancy, cystic fibrosis, and pregnancy. Extrahepatic
cholestasis (which occurs outside the liver) can be caused by bile
duct tumors, strictures, cysts, diverticula, stone formation in the
common bile duct, pancreatitis, pancreatic tumor or pseudocyst, and
compression due to a mass or tumor in a nearby organ.
[0103] Clinical symptoms and signs of a cholestatic condition
include: itching (pruritus), fatigue, jaundiced skin or eyes,
inability to digest certain foods, nausea, vomiting, pale stools,
dark urine, and right upper quadrant abdominal pain. A patient with
a cholestatic condition can be diagnosed and followed clinically
based on a set of standard clinical laboratory tests, including
measurement of levels of alkaline phosphatase, .gamma.-glutamyl
transpeptidase (GGT), 5' nucleotidase, bilirubin, bile acids, and
cholesterol in a patient's blood serum. Generally, a patient is
diagnosed as having a cholestatic condition if serum levels of all
three of the diagnostic markers alkaline phosphatase, GGT, and 5'
nucleotidase, are considered abnormally elevated. The normal serum
level of these markers may vary to some degree from laboratory to
laboratory and from procedure to procedure, depending on the
testing protocol. Thus, a physician will be able to determine,
based on the specific laboratory and test procedure, what an
abnormally elevated blood level is for each of the markers. For
example, a patient suffering from a cholestatic condition generally
has greater than about 125 IU/L alkaline phosphatase, greater than
about 65 IU/L GGT, and greater than about 17 NIL 5' nucleotidase in
the blood. Because of the variability in the level of serum
markers, a cholestatic condition may be diagnosed on the basis of
abnormal levels of these three markers in addition to at least one
of the symptoms mentioned above, such as itching (pruritus).
[0104] In one aspect, the disclosure provides a composition
comprising obeticholic acid, or a pharmaceutically acceptable salt,
ester, or amino acid conjugate thereof, wherein obeticholic acid or
a pharmaceutically acceptable salt, ester, or amino acid conjugate
thereof is in the form of particles, and wherein at least 50% of
the particles have a diameter of less than 200 .mu.m. The
composition of the disclosure possesses advantageous properties,
including improved dissolution profile and solubility.
[0105] In one embodiment, 90% of the particles have a diameter of
400 .mu.m or less, 300 .mu.m or less, 200 .mu.m or less, 100 .mu.m
or less, 90 .mu.m or less, 80 .mu.m or less, 70 .mu.m or less, 60
.mu.m or less, 50 .mu.m or less, 25 .mu.m or less. In a further
embodiment, 90% of the particles have a diameter of 300 .mu.m or
less, such as 200 .mu.m or less, 100 .mu.m or less, 90 .mu.m or
less, 80 .mu.m or less, 70 .mu.m or less, 60 .mu.m or less, 50
.mu.m or less, 25 .mu.m or less. In a further embodiment, 90% of
the particles have a diameter of 100 .mu.m or less, such as 90
.mu.m or less, 80 .mu.m or less, 70 .mu.m or less, more preferably
60 .mu.m or less, more preferably 50 .mu.m or less, 25 .mu.m or
less. In a further embodiment, 90% of the particles have a diameter
of 90 .mu.m or less, such as 80 .mu.m or less, 70 .mu.m or less, 60
.mu.m or less, 50 .mu.m or less, 25 .mu.m or less. In a further
embodiment, 90% of the particles have a diameter of 50 .mu.m or
less, such as 25 .mu.m or less. In a further embodiment, 90% of the
particles have a diameter of 25 .mu.m or less.
[0106] In one embodiment, 50% of the particles have a diameter of
200 .mu.m or less, such as 150 .mu.m or less, 100 .mu.m or less, 80
.mu.m or less, 60 .mu.m or less, 40 .mu.m or less, 20 .mu.m or
less, 15 .mu.m or less, 10 .mu.m or less, 5 .mu.m or less. In a
further embodiment, 50% of the particles have a diameter of 100
.mu.m or less, such as 80 .mu.m or less, 60 .mu.m or less, 40 .mu.m
or less, 20 .mu.m or less, 15 .mu.m or less, more preferably 10
.mu.m or less, 5 .mu.m or less. In a further embodiment, 50% of the
particles have a diameter of 20 .mu.m or less, such as 15 .mu.m or
less, 10 .mu.m or less, 5 .mu.m or less. In a further embodiment,
50% of the particles have a diameter of 10 .mu.m or less, such as 5
.mu.m or less. In a further embodiment, 50% of the particles have a
diameter of 5 .mu.m or less.
[0107] In one embodiment, 10% of the particles have a diameter of 5
.mu.m or less, such as 4 .mu.m or less, 3 .mu.m or less, 2 .mu.m or
less, 1 .mu.m or less. In a further embodiment, 10% of the
particles have a diameter of 3 .mu.m or less, 2 .mu.m or less, or 1
.mu.m or less. In a further embodiment, 10% of the particles have a
diameter of 2 .mu.m or less, such as, e.g.,1 .mu.m or less. In a
further embodiment, 10% of the particles have a diameter of 1 .mu.m
or less.
[0108] In one embodiment, 90% of the particles have a diameter of
400 .mu.m or less, 50% of the particles have a diameter of 200
.mu.m or less, and 10% of the particles have a diameter of 5 .mu.m
or less. In a further embodiment, 90% of the particles have a
diameter of 300 .mu.m or less, 50% of the particles have a diameter
of 150 .mu.m or less, and 10% of the particles have a diameter of 5
.mu.m or less. In another embodiment, 90% of the particles have a
diameter of 100 .mu.m or less, 50% of the particles have a diameter
of 50 .mu.m or less, and 10% of the particles have a diameter of 5
.mu.m or less. In another embodiment, 90% of the particles have a
diameter of 100 .mu.m or less, 50% of the particles have a diameter
of 20 .mu.m or less, and 10% of the particles have a diameter of 5
.mu.m or less.
[0109] In yet another embodiment, 90% of the particles have a
diameter of 100 .mu.m or less, 50% of the particles have a diameter
of 10 .mu.m or less, and 10% of the particles have a diameter of 5
.mu.m or less. In yet another embodiment, 90% of the particles have
a diameter of 90 .mu.m or less, 50% of the particles have a
diameter of 10 .mu.m or less, and 10% of the particles have a
diameter of 5 .mu.m or less. In another embodiment, 90% of the
particles have a diameter of 50 m or less, 50% of the particles
have a diameter of 10 .mu.m or less, and 10% of the particles have
a diameter of 5 .mu.m or less. In a further embodiment, 90% of the
particles have a diameter of 50 .mu.m or less, 50% of the particles
have a diameter of 5 .mu.m or less, and 10% of the particles have a
diameter of 1 .mu.m or less. In a further embodiment, 90% of the
particles have a diameter of 25 .mu.m or less, 50% of the particles
have a diameter of 5 .mu.m or less, and 10% of the particles have a
diameter of 1 .mu.m or less.
[0110] In one embodiment, 99% of the particles have a diameter of
200 .mu.m or less, such as 1 .mu.m to 100 .mu.m, and 1 .mu.m to 80
.mu.m; 90% of the particles have a diameter of 200 .mu.m or less,
such as 2 .mu.m to 100 .mu.m, and 2 .mu.m to 80 .mu.m; and 50% of
the particles have a diameter of 200 .mu.m or less, such as 7 .mu.m
to 100 .mu.m, 8 .mu.m to 100 .mu.m, and 9 .mu.m to 80 .mu.m.
Furthermore preferably 90% of the particles have a diameter of 100
.mu.m or less, and 50% of the particles have a diameter of 90 .mu.m
or less.
[0111] In one embodiment, 50% of the particles have a diameter of
100 .mu.m or less, such as 5 .mu.m to 100 .mu.m, and 5 .mu.m to 50
.mu.m; 90% of the particles have a diameter of 200 .mu.m or less,
such as 3 .mu.m to 200 .mu.m, and 3 .mu.m to 150 .mu.m; and 99% of
the particles have a diameter of 300 .mu.m or less, such as 1 .mu.m
to 300 .mu.m, and 1 .mu.m to 200 .mu.m. In a further embodiment,
90% of the particles have a diameter of 150 .mu.m or less, such as
3 .mu.m to 150 .mu.m, and 3 .mu.m to 100 .mu.m; and 99% of the
particles have a diameter of 200 .mu.m or less, such as 1 .mu.m to
200 .mu.m, and 1 .mu.m to 150 .mu.m. In a further embodiment, 99%
of the particles have a diameter of 150 .mu.m or less, preferably 2
.mu.m to 150 .mu.m, and more preferably 2 .mu.m to 100 .mu.m.
[0112] In the present disclosure, the "particle size reduction" is
carried out for the purpose of crushing solid particles by the
application of mechanical force such as impact, shearing, or
friction thereto to reduce the particle sizes, thereby facilitating
the formation of a homogeneous mixed state and improving the
dissolution rate and bioavailability of the drug owing to the
increased surface area (which refers to as specific surface area,
or "SSA") of the drug. Known particle size reduction methods
include, but are not limited to: high-speed rotating impact mills
(hammer mills and impact mills), which reduce particle size by
means of the impact force of a high-speed rotating hammer or pin in
a chamber; carrier mills (ball mills or vibration mills) which
reduce particle size powder by means of impact force or friction
force in a rotating cylinder in which the powder and magnetic balls
are placed; and fluid energy mills (jet mills), which reduce
particle size by jetting compressed air and raw material particles
from a nozzle and colliding the particles accelerated by the jet of
air with swirling particles in a chamber. In one embodiment, the
particle size of obeticholic acid is reduced using a jet mill.
"Micronization," as defined herein, is a reduction of particle size
of an active ingredient, i.e., obeticholic acid, to a diameter that
is less than about 200 .mu.m, such as less than about 100 .mu.m,
less than about 50 .mu.m, and less than 25 .mu.m.
[0113] In some examples, obeticholic acid has a particle size
distribution with a D.sub.50 of not more than 100 .mu.m. In
specific embodiments, the D.sub.50 is not more than 50 .mu.m, not
more than 20 .mu.m, or not more than 10 .mu.m. In other examples,
the D.sub.90 is not more than 200 .mu.m, or not more than 100
.mu.m. In still other examples, the D.sub.10 is not more than 20
.mu.m, not more than 10 .mu.m, or not more than 5 .mu.m.
[0114] Particle size analysis can be carried out via different
methods. Non-limiting examples of the methods include, but are not
limited to, sieve technique, wet dispersion method with laser
diffraction analysis, dry dispersion method with laser diffraction
analysis, or a combination thereof. Particle size analysis is not
limited to the methods described herein and can be carried out
using any method known to one skilled in the art. In one
embodiment, particle size analysis can be performed via a sieve
technique. In another embodiment, particle size analysis can be
performed using a wet dispersion method (e.g., water as the
dispersing agent, and analysis by laser diffraction using, e.g.,
Sympatec equipment). In yet another embodiment, particle size
analysis can be performed using a dry dispersion method and
analyzed by laser diffraction using, e.g., Sympatec equipment.
[0115] In one embodiment, particle size distribution (% volume at
each particle size) is measured via a Sympatec laser diffraction
analyzer (e.g., Helos/KF-Magic F71000 with Rodos Dispersing Unit,
Vibri sampling unit with Sniffer rotation, Nilfisk exhaustion, or
equivalent). In another embodiment, particle size distribution (%
volume at each particle size) is measured via a Malvern laser
diffraction analyzer.
[0116] For example, particles can be measured using the
following:
[0117] Particle diameter distribution measurement apparatus: HELOS
(KF-Magic F71000) & RODOS System (manufactured by Sympatec
GmbH);
[0118] Measurement range of laser diffraction apparatus: 0.5/0.9 to
175 .mu.m;
[0119] Calculation mode of laser diffraction apparatus: Fraunhofer
HRLD (v3.2 Rel. 2);
[0120] Disperser: RODOS, dry dispersion system;
[0121] Dispersive pressure: 1.0 bar.
[0122] The composition of the present disclosure comprising
obeticholic acid or a pharmaceutically acceptable salt, ester, or
amino acid conjugate thereof, in the form of particles, offers
improved dissolution and solubility.
[0123] Without any intent to be bound by theory, obeticholic acid
(OCA) (pKa=4.82) exhibits a pH-solubility profile consistent with
that of a weak acid. Solutions of OCA at pH 6.8 to 10 produce clear
solutions. However, recovery of OCA steadily diminishes at pH
higher than 8.0, indicating basic decomposition of OCA. Despite the
solubility observed at pH 6.8 to 10, the particle size distribution
of OCA is believed to impact its dissolution rate.
[0124] In one embodiment, in vitro dissolution rates or profiles of
the entire active ingredient of the pharmaceutical composition are
measured from the entire pharmaceutical composition according to
the steps and conditions in Example 3. The dissolution rate can be
measured in a variety of buffers, which optionally contains one or
more surfactants. Non-limiting examples of buffers include acetate
buffer, phosphate buffers, and alkaline borate buffers, or a
combination thereof. Non-limiting examples of surfactants include,
polysorbate 80 (Tween 80.RTM.), potassium laurate, sodium laurate,
triethanol ammonium laurate, potassium myristate, sodium myristate,
triethanol ammonium myristate, sodium lauryl sulfate,
polyoxyethylene alkyl ether sodium sulfate, sodium alkyl j-alanine,
sodium sulfosuccinate, acylmethyl taurine, sodium alkylethane
sulfonate, polyoxyethylene alkyl ether sodium carboxylate,
trinethyl ammonium chloride, benzalkonium chloride, lauryl amine
oxide, amide propyl betaine coconut fatty acid, amide propyl
betaine laurate, amide propyl betaine myistate, sorbitan
monolaurate, sorbitan monopalmnitate, sorbitan sesquioleate,
polyoxyethylene sorbitan monolaurate, polyethylene glycol
monooleate, polyoxyethylene alkyl ether, polyglycol diester,
lauroyl diethlanol amide, fatty acid isopropanol amide, maltitol
hydroxy fatty acid alkyl ether, alkylated polysaccharide, alkyl
glucoside, and sucrose fatty acid ester or a combination thereof.
In one embodiment, the dissolution rate is measured in Disodium
Hydrogen Phosphate Buffer (Na.sub.2HPO.sub.4). In another
embodiment, the dissolution rate is measured in a buffer containing
a surfactant (e.g., 0.01-0.1% wt/wt). In one embodiment, the
surfactant is polysorbate 80 (Tween 80.RTM.).
[0125] In one embodiment, in vitro dissolution rates or profiles
are measured by using a using USP II paddle apparatus in Disodium
Hydrogen Phosphate Buffer (Na.sub.2HPO.sub.4) at a temperature of
about 37.+-.0.5.degree. C. and paddles rotation between about 50
rpm to about 100 rpm. In another embodiment, in vitro dissolution
rates or profiles are measured by using a using USP II paddle
apparatus in Disodium Hydrogen Phosphate Buffer (Na.sub.2HPO.sub.4)
containing polysorbate 80 (Tween 80.RTM.) (e.g., 0.01-0.1% wt/wt)
at a temperature of about 37.+-.0.5.degree. C. and paddles rotation
between about 50 rpm to about 100 rpm. The entire pharmaceutical
composition includes the entire active ingredient and if the
pharmaceutical composition contains a capsule shell, carrier,
excipient, diluent, disintegrating agent, lubricant, binder or any
additional agent described in the Pharmaceutical Composition
Section below, the measurement is performed with those
components.
[0126] In one embodiment, in vitro dissolution is conducted at
about 75 rpm using Disodium Hydrogen Phosphate Buffer
(Na.sub.2HPO.sub.4). In another embodiment, in vitro dissolution is
conducted at 75 rpm using about 900 mL of a Disodium Hydrogen
Phosphate Buffer (Na.sub.2HPO.sub.4). Solutions are collected at 15
minutes, 30 minutes, 45 minutes, 60 minutes, and 75 minutes after
the start of the dissolution. The dissolution rate of the compound
is measured by high-performance liquid chromatography (HPLC) with
Corona Charged Aerosol Detection (CAD).
[0127] In one embodiment, the concentration for OCA (e.g., in a
Disodium Hydrogen Phosphate Buffer, optionally containing a
surfactant, such as polysorbate 80 (Tween 80.RTM.)), after
dissolution is between about 0.001 mg/mL to about 0.01 mg/mL, or
between about 0.001 mg/mL to about 0.03 mg/mL. Above pH 6.8, the
solubility of OCA is well above 0.01 mg/mL.
[0128] In one embodiment, the concentration for dissolved 5 mg
tablets of OCA is between about 0.001 mg/mL to about 0.02 mg/mL. In
another embodiment, the concentration for dissolved 5 mg tablets of
OCA is between about 0.003 mg/mL to about 0.01 mg/mL. In yet
another embodiment, the concentration for dissolved 5 mg tablets of
OCA is between about 0.004 mg/mL to about 0.009 mg/mL. In another
embodiment, the concentration for dissolved 5 mg tablets of OCA is
between about 0.005 mg/mL to about 0.008 mg/mL. In yet another
embodiment, the concentration for dissolved 5 mg tablets of OCA is
between about 0.006 mg/mL to about 0.007 mg/mL. In another
embodiment, the concentration for dissolved 5 mg tablets of OCA is
about 0.006 mg/mL. In yet another embodiment, the concentration for
dissolved 5 mg tablets of OCA is about 0.0056 mg/mL.
[0129] In one embodiment, the concentration for dissolved 10 mg
tablets of OCA is between about 0.001 mg/mL to about 0.03 mg/mL. In
another embodiment, the concentration for dissolved 10 mg tablets
of OCA is between about 0.005 mg/mL to about 0.025 mg/mL. In yet
another embodiment, the concentration for dissolved 10 mg tablets
of OCA is between about 0.008 mg/mL to about 0.02 mg/mL. In another
embodiment, the concentration for dissolved 10 mg tablets of OCA is
between about 0.009 mg/mL to about 0.015 mg/mL. In yet another
embodiment, the concentration for dissolved 10 mg tablets of OCA is
about 0.011 mg/mL. In another embodiment, the concentration for
dissolved 10 mg tablets of OCA is about 0.010 mg/mL.
[0130] In one embodiment, the concentration for dissolved 25 mg
tablets of OCA is between about 0.001 mg/mL to about 0.05 mg/mL. In
another embodiment, the concentration for dissolved 25 mg tablets
of OCA is between about 0.01 mg/mL to about 0.08 mg/mL. In yet
another embodiment, the concentration for dissolved 25 mg tablets
of OCA is between about 0.02 mg/mL to about 0.06 mg/mL. In another
embodiment, the concentration for dissolved 25 mg tablets of OCA is
between about 0.025 mg/mL to about 0.04 mg/mL. In yet another
embodiment, the concentration for dissolved 25 mg tablets of OCA is
about 0.026 mg/mL to about 0.03 mg/mL. In another embodiment, the
concentration for dissolved 25 mg tablets of OCA is about 0.028
mg/mL.
[0131] In one embodiment, the composition of the present disclosure
comprising obeticholic acid or a pharmaceutically acceptable salt,
ester, or amino acid conjugate thereof, in the form of particles,
provides improved dissolution of obeticholic acid or a
pharmaceutically acceptable salt, ester, or amino acid conjugate
thereof. For example, obeticholic acid or a pharmaceutically
acceptable salt, ester, or amino acid conjugate thereof in the
particle composition of the present disclosure dissolves (e.g., in
a Disodium Hydrogen Phosphate Buffer) at a rate that is at least
2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 30%, 40%, 50%, 80%,
or 100% faster than the dissolution rate when obeticholic acid or a
pharmaceutically acceptable salt, ester, or amino acid conjugate
thereof is not present in the particle composition of the present
disclosure.
[0132] For example, about 55% to about 95% of obeticholic acid or a
pharmaceutically acceptable salt, ester, or amino acid conjugate
thereof in the particle composition of the present disclosure is
dissolved within about 15 minutes, or about 65% to about 95% is
dissolved within about 30 minutes, or about 80% to about 95% is
dissolved within about 45 minutes, or about 87% to about 97% is
dissolved within about 60 minutes, or about 87% to about 99% is
dissolved within about 75 minutes. For example, about 60% to about
84% of obeticholic acid or a pharmaceutically acceptable salt,
ester, or amino acid conjugate thereof in the particle composition
of the present disclosure is dissolved within about 15 minutes, or
about 75% to about 91% is dissolved within about 30 minutes, or
about 85% to about 93% is dissolved within about 45 minutes, or
about 90% to about 96% is dissolved within about 60 minutes, or
about 90% to about 97% is dissolved within about 75 minutes. For
example, about 62% to about 83% of obeticholic acid or a
pharmaceutically acceptable salt, ester, or amino acid conjugate
thereof in the particle composition of the present disclosure is
dissolved within about 15 minutes, or about 80% to about 90% is
dissolved within about 30 minutes, or about 87% to about 94% is
dissolved within about 45 minutes, or about 92% to about 96% is
dissolved within about 60 minutes, or about 91% to about 97% is
dissolved within about 75 minutes. For example, about 60% to about
84% obeticholic acid or a pharmaceutically acceptable salt, ester,
or amino acid conjugate thereof in the particle composition of the
present disclosure is dissolved within about 15 minutes, or about
70% to about 90% is dissolved within about 30 minutes, or about 85%
to about 92% is dissolved within about 45 minutes, or about 89% to
about 96% is dissolved within about 60 minutes, or about 90% to
about 96% is dissolved within about 75 minutes. For example, at
least about 60% obeticholic acid or a pharmaceutically acceptable
salt, ester, or amino acid conjugate thereof in the particle
composition of the present disclosure is dissolved within about 15
minutes, or at least about 90% is dissolved within about 60
minutes. For example, obeticholic acid or a pharmaceutically
acceptable salt, ester, or amino acid conjugate thereof in the
particle composition of the present disclosure has an in vitro
dissolution profile of about 51% dissolved within about 15 minutes,
or about 66% dissolved within about 30 minutes, or about 79%
dissolved within about 45 minutes, or about 85% dissolved within
about 60 minutes.
[0133] In one embodiment, the composition of the present disclosure
comprising obeticholic acid or a pharmaceutically acceptable salt,
ester, or amino acid conjugate thereof, in the form of particles,
provides improved solubility of obeticholic acid or a
pharmaceutically acceptable salt, ester, or amino acid conjugate
thereof. For example, obeticholic acid or a pharmaceutically
acceptable salt, ester, or amino acid conjugate thereof in the
particle composition of the present disclosure has a solubility
(e.g., in a Disodium Hydrogen Phosphate Buffer) that is at least
2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 30%, 40%, 50%, 80%,
or 100% higher than the solubility when obeticholic acid or a
pharmaceutically acceptable salt, ester, or amino acid conjugate
thereof is not present in the particle composition of the present
disclosure. For example, obeticholic acid or a pharmaceutically
acceptable salt, ester, or amino acid conjugate thereof in the
particle composition of the present disclosure has a solubility
(e.g., in a Disodium Hydrogen Phosphate Buffer) that is at least
2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, or 20% higher than the
solubility when obeticholic acid or a pharmaceutically acceptable
salt, ester, or amino acid conjugate thereof is not present in the
particle composition of the present disclosure at a pH (e.g., pH
6.8) at which obeticholic acid has the highest solubility (e.g.,
freely soluble) when not present in the particle composition of the
present disclosure.
[0134] In one embodiment, obeticholic acid, or a pharmaceutically
acceptable salt, ester, or amino acid conjugate thereof, and/or
particles of obeticholic acid, or a pharmaceutically acceptable
salt, ester, or amino acid conjugate thereof, has a solubility of
about 0.001 to about 0.600 mg/mL. In another embodiment,
obeticholic acid, or a pharmaceutically acceptable salt, ester, or
amino acid conjugate thereof, and/or particles of obeticholic acid,
or a pharmaceutically acceptable salt, ester, or amino acid
conjugate thereof, has a solubility of about 0.02 to about 0.500
mg/mL. In yet another embodiment, obeticholic acid, or a
pharmaceutically acceptable salt, ester, or amino acid conjugate
thereof, and/or particles of obeticholic acid, or a
pharmaceutically acceptable salt, ester, or amino acid conjugate
thereof, has a solubility of about 0.03 to about 0.48 mg/mL. In
another embodiment, obeticholic acid, or a pharmaceutically
acceptable salt, ester, or amino acid conjugate thereof, and/or
particles of obeticholic acid, or a pharmaceutically acceptable
salt, ester, or amino acid conjugate thereof, has a solubility of
about 0.05 to about 0.46 mg/mL. In yet another embodiment,
obeticholic acid, or a pharmaceutically acceptable salt, ester, or
amino acid conjugate thereof, and/or particles of obeticholic acid,
or a pharmaceutically acceptable salt, ester, or amino acid
conjugate thereof, has a solubility of about 0.1 to about 0.5
mg/mL. In another embodiment, obeticholic acid, or a
pharmaceutically acceptable salt, ester, or amino acid conjugate
thereof, and/or particles of obeticholic acid, or a
pharmaceutically acceptable salt, ester, or amino acid conjugate
thereof, has a solubility of about 0.2 to about 0.6 mg/mL.
[0135] The disclosure also comprehends isotopically-labeled
obeticholic acid, or pharmaceutically acceptable salts, solvate, or
amino acid conjugates thereof, which are identical to those recited
in formulae of the disclosure and following, but for the fact that
one or more atoms are replaced by an atom having an atomic mass or
mass number different from the atomic mass or mass number most
commonly found in nature. Examples of isotopes that can be
incorporated into obeticholic acid, or pharmaceutically acceptable
salts, solvate, or amino acid conjugates thereof include isotopes
of hydrogen, carbon, nitrogen, fluorine, such as .sup.3H, .sup.11C,
.sup.14C and .sup.18F.
[0136] Obeticholic acid, or pharmaceutically acceptable salts,
solvates, or amino acid conjugates thereof that contain the
aforementioned isotopes and/or other isotopes of other atoms are
within the scope of the present disclosure. Isotopically-labeled
obeticholic acid, or pharmaceutically acceptable salts, solvates,
or amino acid conjugates thereof, for example those into which
radioactive isotopes such as .sup.3H, .sup.14C are incorporated,
are useful in drug and/or substrate tissue distribution assays.
Tritiated, i.e., .sup.3H, and carbon-14, i.e., .sup.14C, isotopes
are particularly preferred for their ease of preparation and
detectability. Further, substitution with heavier isotopes such as
deuterium, i.e., .sup.2H, can afford certain therapeutic advantages
resulting from greater metabolic stability, for example increased
in vivo half-life or reduced dosage requirements and, hence, may be
preferred in some circumstances, isotopically labeled obeticholic
acid, or pharmaceutically acceptable salts, solvates, or amino acid
conjugates thereof can generally be prepared by carrying out the
procedures disclosed in the Schemes and/or in the Examples of the
disclosure, by substituting a readily available isotopically
labeled reagent for a non-isotopically labeled reagent. In one
embodiment, obeticholic acid, or pharmaceutically acceptable salts,
solvates, or amino acid conjugates thereof are not isotopically
labeled. In one embodiment, deuterated obeticholic acid is useful
for bioanalytical assays. In another embodiment, obeticholic acid,
or pharmaceutically acceptable salts, solvates, or amino acid
conjugates thereof are radiolabeled.
[0137] In another aspect, the disclosure provides a composition
comprising obeticholic acid, or a pharmaceutically acceptable salt,
ester, or amino acid conjugate thereof, and a pharmaceutically
acceptable excipient having a low alcohol (e.g., an impurity having
at least one primary OH group, such as ethanol or methanol)
content. In one embodiment, the alcohol is a primary alcohol. As
defined herein "primary alcohol" is an alcohol which has a hydroxy
group connected to a primary carbon atom. The composition of the
disclosure possesses advantageous properties, including improved
stability of obeticholic acid in the composition.
[0138] The excipient can be any excipient present in the
composition comprising obeticholic acid, or a pharmaceutically
acceptable salt, ester, or amino acid conjugate thereof. Examples
of excipients include, but are not limited to, calcium phosphate,
microcrystalline cellulose, sodium starch glycolate and magnesium
stearate, or a combination thereof. In one embodiment, the
excipient can be any excipient known in the art. In another
embodiment, the excipient is selected from calcium phosphate,
microcrystalline cellulose, sodium starch glycolate and magnesium
stearate. In yet another embodiment, the excipient is selected from
microcrystalline cellulose, sodium starch glycolate and magnesium
stearate. In another embodiment, the excipient is the excipient is
magnesium stearate. In yet another embodiment, the excipient is
microcrystalline cellulose. In a further embodiment, the excipient
is sodium starch glycolate.
[0139] In one embodiment, the excipient has an impurity having a
primary alcohol group. In another embodiment, the impurity in the
excipient is ethanol, methanol, polyvinyl alcohol, polyethylene
glycol, or a substance having at least one primary OH moiety.
[0140] In one embodiment, the total alcohol (e.g., the impurity
having at least one primary OH group) content in the excipient is
less than 6%, 5%, 4.5%, 4%, 3.5%, 3%, 2.5%, 2%, 1.5%, 1%, or 0.5%
(wt/wt). In one embodiment, the alcohol is a substance having at
least one primary OH moiety. In one embodiment, the alcohol is
ethanol, methanol, polyvinyl alcohol, polyethylene glycol, or a
combination thereof. In one embodiment, the total content of
ethanol, methanol, polyvinyl alcohol, polyethylene glycol, or a
combination thereof in the excipient is less than 6%, 5%, 4.5%, 4%,
3.5%, 3%, 2.5%, 2%, 1.5%, 1%, or 0.5% (wt/wt).
[0141] In one embodiment, the alcohol is ethanol. In one
embodiment, the total ethanol content in the excipient is less than
6%, 5%, 4.5%, 4%, 3.5%, 3%, 2.5%, 2%, 1.5%, 1%, or 0.5% (wt/wt). In
another embodiment, the excipient is sodium starch glycolate. In
one embodiment, the sodium starch glycolate comprises less than 6%,
5%, 4.5%, 4%, 3.5%, 3%, 2.5%, 2%, 1.5%, 1%, or 0.5% (wt/wt)
ethanol.
[0142] In one embodiment, the alcohol is methanol. In one
embodiment, the total methanol content in the excipient is less
than 6%, 5%, 4.5%, 4%, 3.5%, 3%, 2.5%, 2%, 1.5%, 1%, or 0.5%
(wt/wt).
[0143] In another embodiment, the alcohol is a substance having at
least one primary OH moiety. In one embodiment, the total content
of the substance having at least one primary OH moiety in the
excipient is less than 6%, 5%, 4.5%, 4%, 3.5%, 3%, 2.5%, 2%, 1.5%,
1%, or 0.5% (wt/wt).
[0144] In one embodiment, the alcohol is polyvinyl alcohol. In one
embodiment, the total polyvinyl alcohol content in the excipient is
less than 6%, 5%, 4.5%, 4%, 3.5%, 3%, 2.5%, 2%, 1.5%, 1%, or 0.5%
(wt/wt). In one embodiment, the excipient is sodium starch
glycolate. In one embodiment, the sodium starch glycolate comprises
less than 6%, 5%, 4.5%, 4%, 3.5%, 3%, 2.5%, 2%, 1.5%, 1%, or 0.5%
(wt/wt) polyvinyl alcohol.
[0145] In one embodiment, the alcohol is polyethylene glycol. In
one embodiment, the total polyethylene glycol content in the
excipient is less than 6%, 5%, 4.5%, 4%, 3.5%, 3%, 2.5%, 2%, 1.5%,
1%, or 0.5% (wt/wt). In one embodiment, the excipient is sodium
starch glycolate. In one embodiment, the sodium starch glycolate
comprises less than 6%, 5%, 4.5%, 4%, 3.5%, 3%, 2.5%, 2%, 1.5%, 1%,
or 0.5% (wt/wt) polyethylene glycol.
[0146] The composition comprising obeticholic acid, or a
pharmaceutically acceptable salt, ester, or amino acid conjugate
thereof, and a pharmaceutically acceptable excipient having low
alcohol content offers advantageous stability of obeticholic acid
upon storage under various conditions.
[0147] In one embodiment, the composition comprising obeticholic
acid, or a pharmaceutically acceptable salt, ester, or amino acid
conjugate thereof, and a pharmaceutically acceptable excipient
having a low primary alcohol content comprises a decreased amount
of impurities, as compared to an obeticholic acid composition
comprising an excipient having a high alcohol (e.g., greater than
or equal to 6% (wt/wt) content).
[0148] In one embodiment, the impurity is an ester of obeticholic
acid. In one embodiment, the amount of the ester of obeticholic
acid is decreased by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%,
80%, 90%, 95%, or 99%. In one embodiment, the amount of the ester
of obeticholic acid is decreased by at least 50%, 60%, 70%, 80%,
90%, 95%, or 99%.
[0149] In one embodiment, the impurity is an ethyl ester of
obeticholic acid. In one embodiment, the amount of the ethyl ester
of obeticholic acid is decreased by at least 10%, 20%, 30%, 40%,
50%, 60%, 70%, 80%, 90%, 95%, or 99%. In one embodiment, the amount
of the ethyl ester of obeticholic acid is decreased by at least
50%, 60%, 70%, 80%, 90%, 95%, or 99%. In another embodiment, the
amount of the ethyl ester of obeticholic acid is less than 0.5%,
0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%,
0.03%, 0.02%, or 0.01% (wt/wt). In a further embodiment, the amount
of the ethyl ester of obeticholic acid is less than 0.5%, 0.4%,
0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%,
0.02%, or 0.01% (wt/wt) at the storage condition of 40.degree. C.,
75% RH for 4 weeks. In a further embodiment, the amount of the
ethyl ester of obeticholic acid is less than 0.2%, 0.1%, 0.09%,
0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, or 0.01% (wt/wt)
at the storage condition of 40.degree. C., 75% RH for 4 weeks.
[0150] In one embodiment, the impurity is a methyl ester of
obeticholic acid. In one embodiment, the amount of the methyl ester
of obeticholic acid is decreased by at least 10%, 20%, 30%, 40%,
50%, 60%, 70%, 80%, 90%, 95%, or 99%. In one embodiment, the amount
of the methyl ester of obeticholic acid is decreased by at least
50%, 60%, 70%, 80%, 90%, 95%, or 99%. In another embodiment, the
amount of the methyl ester of obeticholic acid is less than 0.5%,
0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%,
0.03%, 0.02%, or 0.01% (wt/wt).
[0151] An analysis of the impurities in an obeticholic acid
composition (e.g., the obeticholic acid composition of the present
disclosure) can be conducted with methods known to one skilled in
the art, for example, with LC/HRMS using LTQ-Orbitrap. The
identities of various impurities can be confirmed through various
techniques available in the art. For example, to determine whether
an ethyl ester of obeticholic acid is an impurity, obeticholic acid
can be dissolved in ethanol, and treated with concentrated acid and
heated to synthesize the ethyl ester. The retention time and mass
spectrometry of the impurity can be compared with those of the
synthesized ethyl ester of obeticholic acid. The excipients were
analyzed for ethanol content and excipients containing higher
ethanol content were substituted with a low ethanol content
excipient.
[0152] The composition comprising obeticholic acid, or a
pharmaceutically acceptable salt, ester, or amino acid conjugate
thereof, in the form of particles, or the composition comprising
obeticholic acid, or a pharmaceutically acceptable salt, ester, or
amino acid conjugate thereof, and a pharmaceutically acceptable
excipient having a low alcohol content, as disclosed herein, can be
incorporated into a pharmaceutical composition suitable for
administration (e.g., oral administration).
[0153] Thus, in another aspect, the present disclosure provides a
pharmaceutical composition, comprising a therapeutically effective
amount of obeticholic acid, or a pharmaceutically acceptable salt,
ester, or amino acid conjugate thereof, and a pharmaceutically
acceptable excipient having a low alcohol content. In one
embodiment, the pharmaceutical composition has a low alcohol
content as described herein. In another embodiment, the
pharmaceutical composition comprises sodium starch glycolate
comprising less than 5% alcohol (e.g., ethanol).
[0154] In another embodiment, the pharmaceutical composition
comprises a therapeutically effective amount of obeticholic acid,
or a pharmaceutically acceptable salt, ester, or amino acid
conjugate thereof, and a pharmaceutically acceptable excipient
having a low alcohol content, wherein obeticholic acid is in the
form of particles. In one embodiment, the particles have a size
distribution as described herein.
[0155] In one embodiment, the pharmaceutical composition further
comprises one or more pharmaceutical excipients. The excipient can
be one or more selected from the group consisting of diluents,
sweeteners, viscosity enhancing agents, dispersing agents,
preservatives, flavoring agents and the like. One excipient can
perform more than one function. In one embodiment, the one or more
pharmaceutical excipients include a lubricant and/or a diluent.
[0156] Non-limiting examples of sweeteners include natural
sweeteners such as sugars, e.g., fructose, glucose, sucrose, sugar
alcohols such as mannitol, sorbitol or mixtures thereof and
artificial sweeteners such as sodium saccharine, sodium cyclamate
and aspartame. In one embodiment, the sweetener can be any
sweetener known in the art. In another embodiment, the sweetener is
selected from fructose, glucose, sucrose, mannitol, and sorbitol,
or a combination thereof.
[0157] Dispersing agents include, but are not limited to, colloidal
silicon dioxide and surfactants, wherein the surfactant is used
alone or as an admixture with one or more surfactant. In one
embodiment, the dispersing agent can be any dispersing agent known
in the art. Combinations of colloidal silicon dioxide with one or
more surfactants can also be used.
[0158] In one embodiment, the lubricant can be any lubricant known
in the art. Non-limiting examples of lubricants include magnesium
stearate, calcium stearate, stearic acid, glyceryl behenate,
hydrogenated vegetable oil, and glycerine fumarate, and/or a
combination thereof. In another embodiment, the lubricant is
selected from magnesium stearate, calcium stearate, stearic acid,
glyceryl behenate, hydrogenated vegetable oil, and glycerine
fumarate. In another embodiment, the lubricant is calcium stearate.
In yet another embodiment, the lubricant is stearic acid. In
further embodiment, the lubricant is magnesium stearate.
[0159] In one embodiment, the diluent can be any diluent known in
the art. Non-limiting examples of diluents include starch,
pregelatinized starch, microcrystalline cellulose, calcium
carbonate, dibasic calcium phosphate, tribasic calcium phosphate,
calcium phosphate, lactose, dextrose, fructose, lactitol, lactose,
magnesium carbonate, magnesium oxide, maltitol, maltodextrin,
maltose, simethicone, sodium chloride, talc, xylitol, sorbitol,
mannitol, and sucrose, and/or a combination thereof. In another
embodiment, the diluent is selected from starch, pregelatinized
starch, microcrystalline cellulose, calcium phosphate, lactose,
sorbitol, mannitol, and sucrose. In another embodiment, the diluent
is calcium phosphate. In yet another embodiment, the diluent is
mannitol. In further embodiment, the diluent is microcrystalline
cellulose.
[0160] In one embodiment, the pharmaceutical composition may
further comprise a coating agent such as sugar-based coating
agents, water-soluble film coating agents, enteric coating agents
and delayed release coating agents or a coating composition
comprising any combination thereof. In another embodiment, the
coating agent can be any coating agent known in the art. Examples
of coating agents include, but are not limited to, saccharose used
alone or together with any of the agents such as talc, calcium
carbonate, calcium phosphate, calcium sulphate, gelatine, gum
arabic, polyvinylpyrrolidone and pullulan or any combination
thereof; cellulose derivatives such as hydroxypropyl cellulose,
hydroxypropyl methyl cellulose, hydroxyethyl cellulose, methyl
hydroxyethyl cellulose and sodium carboxymethyl cellulose;
synthetic polymers such as polyvinyl acetal diethyl amino acetate,
aminoalkyl methacrylate copolymers and polyvinylpyrrolidone;
polysaccharides such as pullulan; hydroxypropyl methyl cellulose
phthalate; hydroxypropyl methyl cellulose acetate succinate;
carboxymethyl ethyl cellulose; cellulose acetate phthalate; acrylic
acid derivatives such as methacrylic acid copolymer L, methacrylic
acid copolymer LD and methacrylic acid copolymer S; natural
substances such as shellac; titanium dioxide; polyvinyl alcohol
(e.g., Opadry.RTM.); polyethylene glycol; talc; lecithin; and/or
combinations thereof. In one embodiment, the coating agent is
selected from hydroxypropyl cellulose, hydroxypropyl methyl
cellulose, hydroxyethyl cellulose, methyl hydroxyethyl cellulose,
sodium carboxymethyl cellulose, polyvinyl acetal diethyl amino
acetate, polyvinyl alcohol, polyethylene glycol, and lecithin, or a
combination thereof. In another embodiment, the coating agent is
Opadry.RTM. II (e.g., Opadry.RTM. II green, white, yellow,
etc.).
[0161] In one embodiment, the pharmaceutical composition comprising
obeticholic acid, or a pharmaceutically acceptable salt, ester, or
amino acid conjugate thereof, in the form of particles, at about 1%
to about 6% by weight, sodium starch glycolate at about 2% to about
8% by weight having a low alcohol content, a lubricant (e.g.,
magnesium stearate) at about 0.1% to about 2.0% by weight, and a
diluent (e.g., microcrystalline cellulose) at about 85% to about
95% by weight. In one embodiment, the sodium starch glycolate
comprises less than 6% (wt/wt) ethanol.
[0162] In one embodiment, the pharmaceutically composition is in
solid particle form. Any inert excipient that is commonly used as a
carrier or diluent may be used in the pharmaceutical composition of
the present disclosure, such as for example, a gum, a starch, a
sugar, a cellulosic material, a glycolate, an acrylate, or mixtures
thereof. In one embodiment, the filler/diluent is microcrystalline
cellulose. The pharmaceutical composition may further comprise a
disintegrating agent (e.g., sodium starch glycolate) and/or a
lubricant (e.g., magnesium stearate). Also, the pharmaceutical
composition may comprise one or more additives selected from a
buffer, a surfactant, a solubilizing agent, a plasticizer, an
emulsifier, a stabilizing agent, a viscosity increasing agent, a
sweetener, a film forming agent, or any combination thereof.
Furthermore, the pharmaceutical composition of the present
disclosure may be in the form of controlled release of immediate
release formulations.
[0163] The percentage of the active ingredient (i.e., obeticholic
acid, or a pharmaceutically acceptable salt, ester, or amino acid
conjugate thereof) and various excipients in the pharmaceutical
composition of the present disclosure may vary. For example, the
composition may comprise between about 0.1 and about 99%, between
about 1-50%, between about 1-25%, or about 1-6% by weight of active
ingredient. Furthermore, the composition may comprise between about
20-99%, between about 45-97%, between about 65-96%, or between
about 85-95% by weight microcrystalline cellulose as a filler or
diluent. Furthermore, the composition may comprise between about
1-30%, between about 1-20%, or between about 2-8% by weight sodium
starch glycolate as a disintegrant. Furthermore, the composition
may comprise between about 0.1-5% or about 0.5-2.0% by weight
magnesium stearate as a lubricant.
[0164] In one embodiment, the pharmaceutical composition of the
present disclosure is about 0.1% to about 10% by weight of active
ingredient (i.e., obeticholic acid, or a pharmaceutically
acceptable salt, ester, or amino acid conjugate thereof), about
0.1% to about 20% by weight of sodium starch glycolate, about 0.01%
to about 8.0% by weight of magnesium stearate, and about 65% to
about 99% by weight of microcrystalline cellulose. In another
embodiment, the pharmaceutical composition of the present
disclosure is about 0.5% to about 8% by weight of active
ingredient, about 1% to about 10% by weight of sodium starch
glycolate, about 0.05% to about 4.0% by weight of magnesium
stearate, and about 75% to about 97% by weight of microcrystalline
cellulose. In yet another embodiment, the pharmaceutical
composition of the present disclosure is about 1% to about 6% by
weight of active ingredient, about 2% to about 8% by weight of
sodium starch glycolate, about 0.1% to about 2.0% by weight of
magnesium stearate, and about 85% to about 95% by weight of
microcrystalline cellulose. In one embodiment, obeticholic acid, or
a pharmaceutically acceptable salt, ester, or amino acid conjugate
thereof, in the pharmaceutical composition is in the form of
particles, as described herein.
[0165] In another aspect, the present disclosure provides a
pharmaceutical composition, comprising a therapeutically effective
amount of obeticholic acid, or a pharmaceutically acceptable salt,
ester, or amino acid conjugate thereof, in the form of particles,
and a pharmaceutically acceptable excipient having a low alcohol
content. In one embodiment, the obeticholic acid particle
composition is an obeticholic acid particle composition described
herein. In one embodiment, the pharmaceutical composition has a low
alcohol content as described herein. In one embodiment, the
pharmaceutical composition comprises sodium starch glycolate
comprising less than 6% alcohol (e.g., ethanol).
[0166] In another aspect, the present disclosure provides a method
for preparing a pharmaceutical composition containing a
therapeutically effective amount of obeticholic acid, or a
pharmaceutically acceptable salt, ester, or amino acid conjugate
thereof, in the form of particles, comprising i) micronizing
obeticholic acid acceptable salt, ester, or amino acid conjugate
thereof until at least 90% of the particles have a diameter of less
than 100 .mu.m, such as less than 90 .mu.m, less than 50 .mu.m,
less than 25 .mu.m, less than 20 .mu.m, less than 15 .mu.m, less
than 10 .mu.m, less than 5 .mu.m, or less than 1 .mu.m, and ii)
combining the micronized obeticholic acid particles with at least
one pharmaceutically acceptable excipient. In one embodiment, the
micronizing is carried out using a jet-mill.
[0167] In another aspect, the present disclosure provides a method
for preparing a pharmaceutical composition containing a
therapeutically effective amount of obeticholic acid, or a
pharmaceutically acceptable salt, ester, or amino acid conjugate
thereof, in the form of particles, comprising i) micronizing
obeticholic acid acceptable salt, ester, or amino acid conjugate
thereof until at least 50% of the particles have a diameter of less
than 10 .mu.m, i.e., less than 5 .mu.m, and ii) combining the
micronized obeticholic acid particles with at least one
pharmaceutically acceptable excipient. In one embodiment, the
micronizing is carried out using a jet-mill.
[0168] In another aspect, the present disclosure provides a method
for preparing a pharmaceutical composition containing a
therapeutically effective amount of obeticholic acid, or a
pharmaceutically acceptable salt, ester, or amino acid conjugate
thereof, in the form of particles, comprising i) micronizing
obeticholic acid acceptable salt, ester, or amino acid conjugate
thereof until at least 10% of the particles have a diameter of less
than 5 .mu.m, i.e., less than 1 .mu.m, and ii) combining the
micronized obeticholic acid particles with at least one
pharmaceutically acceptable excipient. In one embodiment, the
micronizing is carried out using a jet-mill.
[0169] In another aspect, the present disclosure provides a method
for preparing a pharmaceutical composition containing a
therapeutically effective amount of obeticholic acid, or a
pharmaceutically acceptable salt, ester, or amino acid conjugate
thereof, in the form of particles, comprising i) micronizing
obeticholic acid acceptable salt, ester, or amino acid conjugate
thereof until at least 90% of the particles have a diameter of less
than 100 .mu.m, preferably less than 90 .mu.m, less than 50 .mu.m,
less than 25 .mu.m, less than 20 .mu.m, less than 15.mu., less than
10 .mu.m, less than 5 .mu.m, less than 1 .mu.m; at least 50% of the
particles have a diameter of less than 10 .mu.m, less than 5 .mu.m,
less than 1 .mu.m; and at least 10% of the particles have a
diameter of less than 5 .mu.m, or less than 1 .mu.m, and ii)
combining the micronized obeticholic acid particles with at least
one pharmaceutically acceptable excipient. In one embodiment, the
micronizing is carried out using a jet-mill.
[0170] In another aspect, the present disclosure provides a method
for preparing a pharmaceutical composition containing a
therapeutically effective amount of obeticholic acid, or a
pharmaceutically acceptable salt, ester, or amino acid conjugate
thereof, in the form of particles, comprising i) micronizing
obeticholic acid acceptable salt, ester, or amino acid conjugate
thereof until at least 90% of the particles have a diameter of less
than 100 .mu.m, at least 50% of the particles have a diameter of
less than 10 .mu.m, and at least 10% of the particles have a
diameter of less than 5 .mu.m, and ii) combining the micronized
obeticholic acid particles with at least one pharmaceutically
acceptable excipient. In one embodiment, the micronizing is carried
out using a jet-mill.
[0171] In another aspect, the present disclosure provides a method
for preparing a pharmaceutical composition containing a
therapeutically effective amount of obeticholic acid, or a
pharmaceutically acceptable salt, ester, or amino acid conjugate
thereof, in the form of particles, comprising i) micronizing
obeticholic acid acceptable salt, ester, or amino acid conjugate
thereof until at least 90% of the particles have a diameter of less
than 25 .mu.m, at least 50% of the particles have a diameter of
less than 5 .mu.m, and at least 10% of the particles have a
diameter of less than 1 .mu.m, and ii) combining the micronized
obeticholic acid particles with at least one pharmaceutically
acceptable excipient. In one embodiment, the micronizing is carried
out using a jet-mill.
[0172] In another aspect the present disclosure provides a method
for treating or preventing a disease or condition, comprising
administering an effective amount of an obeticholic acid
composition of the present disclosure to a patient in need
thereof.
[0173] In one aspect, the present disclosure provides a method for
treating a disease or condition by administering an effective
amount of an obeticholic acid composition described herein to a
patient in need thereof. In certain embodiments herein the
effective amount refers to a titrated dosage administered during a
titration period as set forth herein. In other embodiments, the
effective amount refers to an adjusted or re-adjusted dosage
administered after a titration period as set forth herein.
[0174] It is to be understood that the methods described herein
refer generally to the obeticholic acid compositions set forth
herein. The methods described herein can include any specific
formulation provided herein, for example, that provided in Example
11. In one embodiment, the obeticholic acid composition useful in
the methods of treating described herein is a composition provided
in Example 11. In another embodiment, the obeticholic acid
composition useful in the methods of treating described herein is a
composition that includes microcrystalline cellulose, sodium starch
glycolate, and magnesium stearate as excipients. Such a composition
can be provided in a dosage form set forth herein, e.g., an oral
dosage form such as a tablet or coated tablet. Thus, in certain
instances, the obeticholic acid composition useful in the methods
is a tablet or coated tablet for oral administration. In one
embodiment, the oral dosage form of the obeticholic acid
composition includes a film coating that includes one or more
excipients selected from polyvinyl alcohol (part hydrolyzed),
titanium dioxide, macrogol (polyethylene glycol 3350), talc, and
iron oxide.
[0175] In one embodiment, the disease or condition is an FXR
mediated disease or condition. Examples of the FXR mediated
diseases or conditions include, but not limited to, liver diseases
such as a cholestatic liver disease such as primary biliary
cirrhosis (PBC) also known as primary biliary cholangitis (PBC),
primary sclerosing cholangitis (PSC), chronic liver disease,
nonalcoholic fatty liver disease (NAFLD), nonalcoholic
steatohepatitis (NASH), hepatitis C infection, alcoholic liver
disease, liver damage due to progressive fibrosis, and liver
fibrosis. Examples of FXR mediated diseases also include portal
hypertension, bile acid diarrhea, hyperlipidemia, high
LDL-cholesterol, high HDL-cholesterol, high triglycerides, and
cardiovascular disease.
[0176] In another aspect, the present disclosure provides methods
of treating or preventing a disease or condition described herein
by administering an obeticholic acid composition described herein
(e.g., obeticholic acid or a pharmaceutically acceptable salt,
ester, or amino acid conjugate thereof, where the obeticholic acid
or a pharmaceutically acceptable salt, ester, or amino acid
conjugate thereof is in the form of particles, and wherein at least
50% of the particles have a diameter of 200 .mu.m or less).
[0177] In still another aspect the present disclosure provides a
method of treating primary biliary cirrhosis (PBC) by administering
an obeticholic acid composition described herein (e.g., obeticholic
acid or a pharmaceutically acceptable salt, ester, or amino acid
conjugate thereof, where the obeticholic acid or a pharmaceutically
acceptable salt, ester, or amino acid conjugate thereof is in the
form of particles, and wherein at least 50% of the particles have a
diameter of 200 .mu.m or less), optionally in a titration period.
In some examples, the method comprise administering a starting dose
in a titration period. The starting dose, adjusted dose, and
titration period are as described below.
[0178] The PBC can be advanced stage PBC. "Advanced stage PBC"
refers to PBC characterized by one or more of the following:
Baseline total bilirubin >upper liming of normal (ULN); Baseline
total ALP>5.times.ULN; Baseline transient elastography
(TE)>10.7 kPa; Cirrhosis based on an initial or baseline biopsy
result or patient having an Ishak score 6 (cirrhosis) or
Ludwig/Scheuer PBC Stage 4; or Medical history of ascites, hepatic
cirrhosis, jaundice, portal hypertension, portal hypertensive
gastropathy or varices esophageal.
[0179] Further provided herein are methods of treating primary
sclerosing cholangitis (PSC), chronic liver disease, nonalcoholic
fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH),
hepatitis C infection, alcoholic liver disease, liver damage due to
progressive fibrosis, or liver fibrosis in a patient in need
thereof by administering an effective amount of an obeticholic acid
composition described above. In another embodiment, the method is a
method of treating NAFLD by administering an effective amount of an
obeticholic acid composition described above. In still another
embodiment, the method is a method of treating PSC by administering
an effective amount of an obeticholic acid composition described
above. In yet another embodiment, the method is a method of
treating fibrosis (e.g., progressive or liver fibrosis) by
administering an effective amount of an obeticholic acid
composition described above. In yet another embodiment, the method
is a method of treating cirrhosis by administering an effective
amount of an obeticholic acid composition described above.
[0180] NAFLD is a medical condition that is characterized by the
buildup of fat (called fatty infiltration) in the liver. NAFLD is
one of the most common causes of chronic liver disease, and
encompasses a spectrum of conditions associated with lipid
deposition in hepatocytes. It ranges from steatosis (simple fatty
liver), to nonalcoholic steatohepatitis (NASH), to advanced
fibrosis and cirrhosis. The disease is mostly silent and is often
discovered through incidentally elevated liver enzyme levels. NAFLD
is strongly associated with obesity and insulin resistance and is
currently considered by many as the hepatic component of the
metabolic syndrome.
[0181] Nonalcoholic steatohepatitis (NASH) is a condition that
causes inflammation and accumulation of fat and fibrous (scar)
tissue in the liver. Liver enzyme levels in the blood may be more
elevated than the mild elevations seen with nonalcoholic fatty
liver (NAFL). Although similar conditions can occur in people who
abuse alcohol, NASH occurs in those who drink little to no alcohol.
NASH affects 2 to 5 percent of Americans, and is most frequently
seen in people with one of more of the following conditions:
obesity, diabetes, hyperlipidemia, insulin resistance, uses of
certain medications, and exposure to toxins. NASH is an
increasingly common cause of chronic liver disease worldwide and is
associated with increased liver-related mortality and
hepatocellular carcinoma, even in the absence of cirrhosis. NASH
progresses to cirrhosis in 15-20% of affected individuals and is
now one of the leading indications for liver transplantation in the
United States. At present there are no approved therapies for
NASH.
[0182] In one embodiment, the method is a method of treating NASH
by administering an obeticholic acid composition described herein,
optionally in a titration period as described herein. The NASH
patient can be a high risk NASH patient. A "high risk NASH patient"
refers to characterization by one or more of: NAS.gtoreq.4;
baseline fibrosis stage 2 or 3; or baseline fibrosis stage 1 with a
comorbidity (type 2 diabetes, BMI.gtoreq.30 kg/m2 or ALT.gtoreq.60
U/L).
[0183] In one embodiment, the disease or condition is
hyperlipidemia. In one embodiment, the disease or condition is a
cholestatic liver disease. In one embodiment, the disease or
condition is PBC. In another embodiment, the disease or condition
is a cardiovascular disease. In another embodiment, the
cardiovascular disease is atherosclerosis, hypercholesteremia, or
hypertriglyceridemia.
[0184] The present disclosure also provides a method for treating
or preventing NAFLD or NASH. In one embodiment, the present
disclosure provides a method for treating or preventing NAFLD or
NASH that is associated with hyperlipidemia. In one embodiment, the
present disclosure provides a method for treating or preventing
NASH. In one embodiment, the present disclosure provides a method
for treating or preventing NASH that is associated with
hyperlipidemia.
[0185] In another aspect, the present disclosure also provides a
method for decreasing liver enzymes, comprising administering a
therapeutically effective amount of the composition of the present
disclosure to a subject in need thereof. In one embodiment, the
subject is not suffering from a cholestatic condition. In another
embodiment, the subject is suffering from a cholestatic condition.
In one embodiment, the liver enzyme is alkaline phosphatase,
7-glutamyl transpeptidase (GGT), and/or 5' nucleotidase.
[0186] In certain instances, the methods described herein also
include assessing, monitoring, measuring, or otherwise detecting
liver function. Assessing, monitoring, measuring, or otherwise
detecting liver function can be performed before, during, or after
a titration period described herein, or in other instances,
performed during the course of any treatment described herein.
Liver function can be determined by, for example, assessing,
monitoring, measuring, or otherwise detecting a level of one or
more liver biomarkers compared to a control. In certain instances
the control is a baseline taken from the patient before beginning
treatment. In other instances the control is preestablished
baseline considered as a normal value.
[0187] Values for measure or detection of liver function biomarkers
and controls can be expressed as a comparison to Upper Limit of
Normal (ULN).
[0188] Liver biomarkers can be used to ascertain, quantify the
efficacy of the course of treatment with an obeticholic acid
composition described herein. In other instances, liver biomarkers
described herein can be used to ascertain, quantify liver function
during the course of treatment with an obeticholic acid composition
described herein. Liver biomarkers can also be used to predict
whether a patient or patient population will be susceptible to
treatment with an obeticholic acid composition described herein. In
one embodiment, the liver biomarkers include assessing, monitoring,
measuring or otherwise detecting an amount or level of aspartate
transaminase (AST), alanine transaminase (ALT), alkaline
phosphatase (ALP), bilirubin, glycine conjugated obeticholic acid,
taurine conjugated obeticholic acid, a bile acid, a bile acid
glycine conjugate, or a bile acid taurine conjugate. For example,
the liver biomarker assessed, monitored, measured, or detected can
be ALP.
[0189] The ALP level can be a measure of ULN. In one embodiment, a
patient before treatment can have an ALP level of at least
1.1.times.ULN to at least 20.times.ULN; at least 1.1.times.ULN to
at least 15.times.ULN; at least 1.1.times.ULN to at least
12.times.ULN; at least 1.1.times.ULN to at least 10.times.ULN; at
least 1.1.times.ULN to at least 8.times.ULN; at least 1.1.times.ULN
to at least 6.times.ULN; at least 1.1.times.ULN to at least
5.times.ULN; at least 1.1.times.ULN to at least 4.times.ULN; at
least 1.1.times.ULN to at least 3.times.ULN; or at least
1.1.times.ULN to at least 2.times.ULN.
[0190] A patient before a treatment described herein can have an
ALP level of about 1.5.times.ULN to about 20.times.ULN; about
1.5.times.ULN to about 15.times.ULN; about 1.5.times.ULN to about
10 ULN; about 1.5.times.ULN to about 5.times.ULN; or about
1.5.times.ULN to about 3.times.ULN. A patient before treatment can
have an ALP level before a treatment described herein of about
1.5.times., 2.times., 3.times., 4.times., 5.times., 8.times.,
10.times., 15.times., or 20.times.ULN.
[0191] A patient before treatment can have an ALP level before a
treatment described herein of greater than about 1.5.times.,
2.times., 3.times., 4.times., 5.times., 8.times., 10.times.,
15.times., or 20.times.ULN. In one embodiment, a patient has an ALP
level of about 1.5.times.ULN. In one embodiment, a patient has an
ALP level of about 2.times.ULN. In one embodiment, a patient has a
ALP level of about 5.times.ULN. In one embodiment, a patient has an
ALP level of about 10.times.ULN. In one embodiment, a patient has a
bilirubin level of about 15.times.ULN. In one embodiment, a patient
has an ALP level greater than about 1.5.times.ULN. In one
embodiment, a patient has an ALP level greater than about
2.times.ULN. In one embodiment, a patient has a ALP level greater
than about 5.times.ULN. In one embodiment, a patient has an ALP
level greater than about 10.times.ULN. In one embodiment, a patient
has a bilirubin level greater than about 15.times.ULN.
[0192] In another example, the liver biomarker assessed, monitored,
measured, or detected can be bilirubin. The bilirubin level can be
a measure of ULN. In one embodiment, a patient before treatment can
have a bilirubin level of at least 1.1.times.ULN to at least
20.times.ULN; at least 1.1.times.ULN to at least 15.times.ULN; at
least 1.1.times.ULN to at least 12.times.ULN; at least
1.1.times.ULN to at least 10.times.ULN; at least 1.1.times.ULN to
at least 8.times.ULN; at least 1.1.times.ULN to at least
6.times.ULN; at least 1.1.times.ULN to at least 5.times.ULN; at
least 1.1.times.ULN to at least 4.times.ULN; at least 1.1.times.ULN
to at least 3.times.ULN; or at least 1.1.times.ULN to at least
2.times.ULN.
[0193] A patient before a treatment described herein can have a
bilirubin level of about 1.5.times.ULN to about 20.times.ULN; about
1.5.times.ULN to about 15.times.ULN; about 1.5.times.ULN to about
10 ULN; about 1.5.times.ULN to about 5.times.ULN; or about
1.5.times.ULN to about 3.times.ULN. In another example a patient
before a treatment described herein can have a bilirubin level of
about 2.times.ULN to about 20.times.ULN; about 2.times.ULN to about
15.times.ULN; about 2.times.ULN to about 10 ULN; about 2.times.ULN
to about 5.times.ULN; or about 2.times.ULN to about 3.times.ULN. In
another example a patient before a treatment described herein can
have a bilirubin level of greater than about 2.times.ULN to greater
than about 20.times.ULN; greater than about 2.times.ULN to greater
than about 15.times.ULN; greater than about 2.times.ULN to greater
than about 10 ULN; greater than about 2.times.ULN to greater than
about 5.times.ULN; or greater than about 2.times.ULN to greater
than about 3.times.ULN.
[0194] A patient before treatment can have a bilirubin level before
a treatment described herein of about 1.5.times., 2.times.,
3.times., 4.times., 5.times., 8.times., 10.times., 15.times., or
20.times.ULN. A patient before treatment can have a bilirubin level
before a treatment described herein of greater than about
1.5.times., 2.times., 3.times., 4.times., 5.times., 8.times.,
10.times., 15.times., or 20.times.ULN. In one embodiment, a patient
has a bilirubin level greater than about 2.times.ULN. In one
embodiment, a patient has a bilirubin level greater than about
5.times.ULN. In one embodiment, a patient has a bilirubin level
greater than about 10.times.ULN. In one embodiment, a patient has a
bilirubin level greater than about 15.times.ULN. In one embodiment,
a patient has a bilirubin level less than about 2.times.ULN. In one
embodiment, a patient has a bilirubin level less than about
5.times.ULN. In one embodiment, a patient has a bilirubin level
less than about 10.times.ULN. In one embodiment, a patient has a
bilirubin level less than about 15.times.ULN.
[0195] In some instances it can be useful to assess, monitor,
measure, or detect ALP and bilirubin to assess, monitor, measure,
or otherwise detect liver function or changes in liver function
during treatment with an obeticholic acid composition described
herein. In certain instances, a patient has an ALP level as
provided above (e.g., about 1.5.times.ULN to about 10.times.ULN)
and a bilirubin level as provided above (e.g., less than about
5.times.ULN). In one embodiment, the patient has an ALP level
between about 1.5.times.ULN to about 10.times.ULN and a bilirubin
level less than about 2.times.ULN.
[0196] Treatment with a obeticholic acid composition described
herein can reduce the levels of ALP and/or bilirubin in a patient
described herein. For example, treatment of a disease or condition
described herein (e.g., PBC) with an obeticholic acid composition
described herein can reduce the level of ALP by 2, 4, 5, 6, 8, 9,
10, 12, 15, 18, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 35, 40,
45, 50, 55, 60, 65, 70, 75, 80, 85, 88, 90, 92, 94, 96, 97, 98, 99,
99.2, 99.4, 99.6, 99.7, 99.8, 99.9, or 100%. In another example,
the level of ALP can be reduced by at least 100%, at least 125%, at
least 150%, at least 175%, at least 200%, at least 225%, at least
250% or at least 300%.
[0197] In another example, the level of ALP can be reduced by about
5% to about 50%; about 10% to about 55%; about 10% to about 45%;
about 10% to about 40%; about 10% to about 33%, about 10% to about
30%; about 15% to about 30%; about 15% to about 25%; about 20% to
about 50%, about 20% to about 40%; about 20% to about 35%; about
20% to about 30%; 20% to about 27%; or about 20% to about 27%. In
another example, the level of ALP can be reduced by at least 50%.
The level of ALP can be reduced by at least 40%. The level of ALP
can be reduced by at least 35%. The level of ALP can be reduced by
at least 30%. The level of ALP can be reduced by at least 27%. The
level of ALP can be reduced by at least 25%. The level of ALP can
be reduced by at least 20%.
[0198] The reduction of ALP levels can be represented by the fold
change over ULN. For example, treatment with an obeticholic acid
described herein can reduce the ALP level of a patient described
herein to less than about 5.times.ULN; less than about 4.times.ULN,
less than about 3.times.ULN, less than about 2.times.ULN, less than
about 1.7.times.ULN, less than about 1.5.times.ULN, less than about
1.25.times.ULN, or less than about ULN.
[0199] In another example, the ALP level is reduced by at least 1,
2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 40, or 50 fold compared
to a baseline value. For example, the ALP level after treatment
with an obeticholic acid composition described herein can be
reduced by 1, 1,2, 1,4, 1.6, 1.8, or 2 fold, including intervening
values therein, compared to a baseline value. In another example,
the ALP level can be reduced by 2, 2.2, 2.4, 2.6, 2.8, or 3 fold,
including intervening values therein, compared to a baseline value.
In another example, the ALP level can be reduced 3, 4, or 5 fold,
including intervening values therein, compared to a baseline value.
In another example, the ALP level can be reduced 5, 7, 9, or 10
fold, including intervening values therein, compared to a baseline
value. In another example, the ALP level can be reduced 10, 12, 15,
or 20 fold, including intervening values therein, compared to a
baseline value.
[0200] Treatment of a disease or condition described herein (e.g.,
PBC) with an obeticholic acid composition described herein can
reduce the level of bilirubin by 2, 4, 5, 6, 8, 9, 10, 12, 15, 18,
20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 35, 4-, 45, 50, 55, 60,
65, 70, 75, 80, 85, 88, 90, 92, 94, 96, 97, 98, 99, 99.2, 99.4,
99.6, 99.7, 99.8, 99.9, or 100%. In another example, the level of
bilirubin can be reduced by at least 100%, at least 125%, at least
150%, at least 175%, at least 200%, at least 225%, at least 250% or
at least 300%.
[0201] In another example, the level of bilirubin can be reduced by
about 5% to about 50%; about 10% to about 55%; about 10% to about
45%; about 10% to about 40%; about 10% to about 33%, about 10% to
about 30%; about 15% to about 30%; about 15% to about 25%; about
20% to about 50%, about 20% to about 40%; about 20% to about 35%;
about 20% to about 30%; 20% to about 27%; or about 20% to about
27%. In another example, the level of bilirubin can be reduced by
at least 50%. The level of bilirubin can be reduced by at least
40%. The level of bilirubin can be reduced by at least 35%. The
level of bilirubin can be reduced by at least 30%. The level of
bilirubin can be reduced by at least 27%. The level of bilirubin
can be reduced by at least 25%. The level of bilirubin can be
reduced by at least 20%.
[0202] The reduction of bilirubin levels can be represented by the
fold change over ULN. For example, treatment with an obeticholic
acid described herein can reduce the bilirubin level of a patient
described herein to less than about 5.times.ULN; less than about
4.times.ULN, less than about 3.times.ULN, less than about
2.times.ULN, less than about 1.7.times.ULN, less than about
1.5.times.ULN, less than about 1.25.times.ULN, or less than about
ULN.
[0203] In another example, the bilirubin level is reduced by at
least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 40, or 50 fold
compared to a baseline value. For example, the bilirubin level
after treatment with an obeticholic acid composition described
herein can be reduced by 1, 1,2, 1,4, 1.6, 1.8, or 2 fold,
including intervening values therein, compared to a baseline value.
In another example, the bilirubin level can be reduced by 2, 2.2,
2.4, 2.6, 2.8, or 3 fold, including intervening values therein,
compared to a baseline value. In another example, the bilirubin
level can be reduced 3, 4, or 5 fold, including intervening values
therein, compared to a baseline value. In another example, the
bilirubin level can be reduced 5, 7, 9, or 10 fold, including
intervening values therein, compared to a baseline value. In
another example, the bilirubin level can be reduced 10, 12, 15, or
20 fold, including intervening values therein, compared to a
baseline value.
[0204] In another embodiment, one or more biomarkers can stratify a
patient population undergoing or who will undergo treatment with an
obeticholic acid composition described herein. For example, a PBC
patient can be stratified for the risk of hepatocellular carcinoma
(HCC).
[0205] In yet another embodiment, liver biomarkers useful for
detection can include metabolites and bile acids. For example,
assessing, monitoring, measuring, or otherwise detecting levels of
glycine and taurine conjugates of obeticholic acid can be useful
for measuring efficacy of a treatment regimen described herein. For
example, assessing, monitoring, measuring, or otherwise detecting
levels or detecting plasma levels of bile acids including cholic
acid, chenodeoxycholic acid, deoxycholic acid, lithocholic acid,
and urosodeoxycholic acid, including glycine and taurine conjugates
thereof, and optionally comparing the levels to a control, can be
useful for measuring efficacy of a treatment regimen described
herein.
[0206] In still other embodiments, calculating an AST to platelet
index (APRI) can be useful for assessing, monitoring, measuring, or
otherwise detecting liver function (including changes thereof). The
obeticholic acid compositions described herein can reduce the APRI
of a patient described herein. In certain instances, monitoring or
measuring the APRI can be used to determine efficacy of treatment
with an obeticholic acid composition described herein. In some
embodiments, a reduction in APRI is observed in a patient (e.g., a
PBC or NASH patient) after administration of an obeticholic acid
composition described herein. For example, the APRI may be reduced
by about 5% to about 50% in patients treated with obeticholic acid
relative to baseline levels measured before dose administration.
The reduction may be up to about 5%, 10%, 15%, 20%, 25%, 30%, 35%,
40%, 45% or 50%.
[0207] Further provided herein is a method for treating PBC in a
patient in need thereof by administering a starting dose of an
obeticholic acid composition described herein in a titration
period. The method includes assessing liver function of the patient
before, during, and after said titration period by either
calculating an APRI score for said patient; or by measuring the
level of one or more liver biomarker selected from ALP, bilirubin,
AST, ALT, glycine conjugated obeticholic acid, taurine conjugated
obeticholic acid, a bile acid, a bile acid glycine conjugate, or a
bile acid taurine conjugate, where a reduced APRI score compared to
a control or a reduced level of the one or more liver biomarkers
compared to a control indicates non-impaired liver function. The
method further includes assessing tolerance of the patient to the
starting dose by grading the severity of one or more adverse
effects, if present, and administering an adjusted dose of the
obeticholic acid composition, where the adjusted dose includes an
amount equal to or greater than an amount of the starting dose. The
starting dose, adjusted dose, and titration period are as described
below. For example, the starting dose can be about 5 to about 50 mg
(e.g., 5 mg) and the adjusted dose can be about 5 to about 50 mg
(e.g., 5 mg, 10 mg, or 25 mg) and the titration period can be a
time of about 1 to about 6 months, e.g., 1 month, 2 months, 3
months, 4 months, 5 months, or 6 months.
[0208] Also provided herein are methods to reduce or eliminate
rejection failure of a liver transplant by administering an
effective amount of an obeticholic acid composition described
above. In certain instances administration of an obeticholic acid
composition described herein reduces expression or levels of ALP
and/or bilirubin. In one embodiment, administration of an
obeticholic acid composition described herein reduces ALP and
bilirubin levels, thereby reducing transplant complications or
rejection. In another embodiment, administration of an effective
amount of an obeticholic acid composition described herein
increases post-transplantation survival rate of a liver
transplantee.
[0209] In one aspect, obeticholic acid may mediate its action
primarily via FXR agonism, wherein FGF-19 released from gut
enterocytes (in response to FXR agonist) into portal circulation
down regulates endogenous bile acid synthesis in the liver. The
present disclosure comprehends a method of measuring FXR agonist
activity by, for example, measuring release of FGF-19 into the
bloodstream or circulation of a patient administered with OCA.
Levels of FGF-19 may be measured by methods known in the art, such
as those described herein.
[0210] Obeticholic acid administration may lead to a significant
and a dose-dependent increase in the levels of FGF-19 and in some
embodiments, a decrease in the levels of endogenous bile acids and
C4 (a bile acid precursor). In some embodiments, a significant
increase in FGF-19 levels may be observed from baseline to month 3,
month 6 and month 12 after dose administration. In some examples,
the FGF-19 levels may increase from about 5% to about 200%. In
specific embodiments, the levels may increase by about 5%, 10%,
15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%,
80%, 85%, 90%, 95% or 100%.
[0211] In some embodiments, the plasma levels of FGF-19, a marker
of FXR activation, are determined using a qualified method and a
validated method using an enzyme-linked immunosorbent assay (ELISA)
method. The plasma concentrations of FGF-19 may be quantitated at
predose and after administration of dose.
[0212] In some examples, a monoclonal antibody specific for FGF-19
is pre-coated onto a microplate. Standards, quality controls and
samples are pipetted into the wells and any FGF-19 present is bound
by the immobilized antibody. After washing away any unbound
substances, an enzyme-linked polyclonal antibody specific for
FGF-19 is added to the wells. Following a wash to remove any
unbound antibody-enzyme reagent, a substrate solution is added to
the wells and color develops in the proportion to the amount of
FGF-19 bound in the initial step. The color development is stopped
and the intensity of the color is measured. The calibration range
of the method is 15.625 pg/ml to 1000 pg/ml for FGF-19 using a 100
.mu.l aliquot of standard curve, quality control and sample. In
some embodiments, no minimum required dilution is used. In other
embodiments, samples may be subjected to a 3.times. minimum
required dilution.
[0213] Also provided herein are methods to reduce or eliminate
rejection failure of a liver transplant by administering an
effective amount of an obeticholic acid composition described
above. In certain instances, administration of an obeticholic acid
composition described herein reduces expression or levels of ALP
and/or bilirubin. In one embodiment, administration of an
obeticholic acid composition described herein reduces ALP and
bilirubin levels, thereby reducing transplant complications or
rejection. In another embodiment, administration of an effective
amount of an obeticholic acid composition described herein
increases post-transplantation survival rate of a liver
transplantee.
[0214] In another aspect of the disclosure is a method of treating
a solid-tumor cancer by administering an effective amount of an
obeticholic acid composition as described herein. In another
aspect, such methods include treating hepatocellular carcinoma
(HCC), colorectal cancer, gastric cancer, liver cancer, breast
cancer, renal cancer, or pancreatic cancer by administering an
obeticholic acid composition as described herein. In one embodiment
is a method of treating HCC by administering an effective amount of
an obeticholic acid composition as described herein. In one
embodiment is a method of treating colorectal cancer by
administering an effective amount of an obeticholic acid
composition as described herein. In another embodiment is a method
of treating gastric cancer by administering an effective amount of
an obeticholic acid composition as described herein. In another
embodiment is a method of treating liver cancer by administering an
effective amount of an obeticholic acid composition as described
herein. In still another embodiment is a method of treating renal
cancer by administering an effective amount of an obeticholic acid
composition as described herein. In still another embodiment is a
method of treating pancreatic cancer by administering an effective
amount of an obeticholic acid composition as described herein. It
is understood that the treatment of a cancer described herein can
be performed by administering an effective amount of an obeticholic
acid composition described herein in combination with one or more
anticancer agents, such as those described herein. In some
embodiments, the effective amount administered is a starting dose
as described herein.
[0215] Still further provided herein are methods of treating an
autoimmune disease in a patient in need thereof by administering an
effective amount of an obeticholic acid composition as described
herein. In one instance, the autoimmune disease is selected from
multiple sclerosis, rheumatoid arthritis, and type I diabetes. In
one embodiment is a method of treating multiple sclerosis by
administering an effective amount of an obeticholic acid
composition as described herein. In another embodiment is a method
of treating rheumatoid arthritis by administering an effective
amount of an obeticholic acid composition as described herein. In
still another embodiment is a method of treating type I diabetes by
administering an effective amount of an obeticholic acid
composition as described herein. In certain instances, the
treatment of the autoimmune disease includes further administering
another active agent useful for the treatment, such as without
limitation, non-steroidal anti-inflammatory agents (NSAIDs) such as
ibuprofen, naproxen, corticosteroids, disease-modifying
anti-rheumatic drugs such as methotrexate (Trexall, Otrexup,
Rasuvo), leflunomide (Arava), hydroxychloroquine (Plaquenil) and
sulfasalazine (Azulfidine), biologic agents such as abatacept
(Orencia), adalimumab (Humira), anakinra (Kineret), certolizumab
(Cimzia), etanercept (Enbrel), golimumab (Simponi), infliximab
(Remicade), rituximab (Rituxan), tocilizumab (Actemra) and
tofacitinib (Xeljanz), interferons, such as interferon alpha,
interferon beta, interferon gamma, and PEGylated versions thereof,
glatiramer acetate (also known in the art as Copaxone), dimethyl
fumarate (also known in the art as Tecfidera), fingolimod (also
known in the art as Gilenya), teriflunomide (also known in the art
as Aubagio), natalizumab (also known in the art as Tysabri),
alemtuzumab (also known in the art as Lemtrada), and mitoxantrone.
For example, an obeticholic acid composition described herein can
be administered in combination with metformin, insulin, insulin
mimetic, or any other known anti-diabetic or anti-glycemic agent
for treatment of diabetes. In some embodiments, the effective
amount administered is a starting dose as described herein.
[0216] In another aspect, the present disclosure also provides a
method for inhibiting or reversing fibrosis, comprising
administering a therapeutically effective amount of the composition
of the present disclosure to a subject in need thereof. In one
embodiment, the subject is not suffering from a cholestatic
condition. In another embodiment, the subject is suffering from a
cholestatic condition.
[0217] In one embodiment, the subject is not suffering from a
cholestatic condition associated with a disease or condition
selected from the group consisting of cancers, such as, e.g.,
cancers as described herein, including primary liver and biliary
cancer, metastatic cancer, sepsis, chronic total parenteral
nutrition, cystic fibrosis, and granulomatous liver disease. In
embodiments, the fibrosis to be inhibited occurs in an organ where
FXR is expressed.
[0218] In one embodiment, a cholestatic condition is defined as
having an abnormally elevated serum level of alkaline phosphatase,
7-glutamyl transpeptidase (GGT), and/or 5' nucleotidase. In another
embodiment, a cholestatic condition is further defined as
presenting with at least one clinical symptom. In one embodiment,
the symptom is itching (pruritus). In another embodiment, a
cholestatic condition is selected from the group consisting of
primary biliary cirrhosis (PBC), primary sclerosing cholangitis
(PBS), biliary atresia, drug-induced cholestasis, hereditary
cholestasis, and intrahepatic cholestasis of pregnancy.
[0219] In one embodiment, the fibrosis is selected from the group
consisting of liver fibrosis, kidney fibrosis, and intestinal
fibrosis.
[0220] In one embodiment, the subject has liver fibrosis associated
with a disease selected from the group consisting of hepatitis B;
hepatitis C; parasitic liver diseases; post-transplant bacterial,
viral and fungal infections; alcoholic liver disease (ALD);
non-alcoholic fatty liver disease (NAFLD); non-alcoholic
steatohepatitis (NASH); liver diseases induced by methotrexate,
isoniazid, oxyphenistatin, methyldopa, chlorpromazine, tolbutamide,
or amiodarone; autoimmune hepatitis; sarcoidosis; Wilson's disease;
hemochromatosis; Gaucher's disease; types III, IV, VI, IX and X
glycogen storage diseases; cl-antitrypsin deficiency; Zellweger
syndrome; tyrosinemia; fructosemia; galactosemia; vascular
derangement associated with Budd-Chiari syndrome, veno-occlusive
disease, or portal vein thrombosis; and congenital hepatic
fibrosis.
[0221] In another embodiment, the subject has intestinal fibrosis
associated with a disease selected from the group consisting of
Crohn's disease, ulcerative colitis, post-radiation colitis, and
microscopic colitis.
[0222] In another embodiment, the subject has renal fibrosis
associated with a disease selected from the group consisting of
diabetic nephropathy, hypertensive nephrosclerosis, chronic
glomerulonephritis, chronic transplant glomerulopathy, chronic
interstitial nephritis, and polycystic kidney disease.
[0223] In another aspect, the present disclosure also provides a
method for treating or preventing all forms of conditions related
to elevated lipid levels. In one embodiment, the condition is
hyperlipidemia where it is associated with a condition selected
from resistant primary biliary cirrhosis; primary biliary cirrhosis
where there is associated liver function test elevation and
hyperlipidemia, primary sclerosing cholangitis, non-alcohol-induced
steatohepatitis; and chronic liver disease associated with
hepatitis B, C or alcohol. In another embodiment, the present
disclosure provides a method for treating or preventing
hyperlipidemia, where the hyperlipidemia is primary hyperlipidemia
with or without a genetic component, or hyperlipidemia associated
with coronary artery disease, cerebrovascular arterial disease,
peripheral vascular disease, aortic aneurisms, or carotid
atherosclerosis.
[0224] In one aspect, the present disclosure provides a method for
treating or preventing primary sclerosing cholangitis for similar
biochemical abnormalities, as well as chronic hepatitis caused by
hepatitis B, C or by alcohol. In one aspect, the present disclosure
provides a method for treating or preventing other arterial
disorders associated with hyperlipidemia. In one aspect, the
present disclosure provides a method for treating or preventing
hypertriglyceridemia.
[0225] Therapies with FXR agonists may produce various side
effects, one of which is pruritus. Pruritus or itch is defined as
an unpleasant sensation of the skin that provokes the urge to
scratch. It is a characteristic feature of many skin diseases and
an unusual sign of some systemic diseases. Pruritus may be
localized or generalized and can occur as an acute or chronic
condition. Itching lasting more than 6 weeks is termed chronic
pruritus. Itching can be intractable and incapacitating, as well as
a diagnostic and therapeutic challenge.
[0226] One of the advantages of the compositions of the present
disclosure includes a decrease in the incidence and/or severity of
pruritus in subjects treated with the compositions and according to
the methods of the present disclosure.
[0227] In one embodiment, the incidence of pruritus decreases by at
least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% in
subjects treated with the compositions of the present disclosure.
In a further embodiment, the incidence of pruritus decreases by at
least 20%, 25%, 30%, 35%, 40%, 45%, or 50% in subjects treated with
the compositions of the present disclosure. In a further
embodiment, the incidence of pruritus decreases by at least 5%,
10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% in subjects treated
with the compositions of the present disclosure during the first
one month, two months, three months, four months, five months, or
six months after the beginning of the treatment. In a further
embodiment, the incidence of pruritus decreases by at least 20%,
25%, 30%, 35%, 40%, 45%, or 50% in subjects treated with the
compositions of the present disclosure during the first one month,
two months, three months, four months, five months, or six months
after the beginning of the treatment.
[0228] In one embodiment, the severity of the pruritus decreases by
at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% in
subjects treated with the compositions of the present disclosure.
In a further embodiment, the severity of pruritus decreases by at
least 20%, 25%, 30%, 35%, 40%, 45%, or 50% in subjects treated with
the compositions of the present disclosure. In a further
embodiment, the severity of pruritus decreases by at least 5%, 10%,
15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% in subjects treated with
the compositions of the present disclosure during the first one
month, two months, three months, four months, five months, or six
months after the beginning of the treatment. In a further
embodiment, the severity of pruritus decreases by at least 20%,
25%, 30%, 35%, 40%, 45%, or 50% in subjects treated with the
compositions of the present disclosure during the first one month,
two months, three months, four months, five months, or six months
after the beginning of the treatment.
[0229] Obeticholic acid compositions described herein can be
administered to a patient in an amount of between about: 1 mg to
about 50 mg; 1 to about 40 mg; 1 to about 30 mg; 1 to about 25 mg;
1 to about 20 mg; 1 mg to about 10 mg; or 1 mg to about 5 mg. In
one embodiment, the obeticholic acid composition can be
administered to a patient in an amount of about: 5 to about 50 mg;
5 to about 40 mg; 5 to about 30 mg; 5 to about 25 mg; 5 to about 20
mg; or 5 to about 10 mg. In other instances, the obeticholic acid
composition can be administered in an amount of about 1, 2, 3, 4,
5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22,
23, 24, 25, 30, 35, 40, 45, or 50 mg. In still other instances, the
obeticholic acid composition described herein can be administered
at an amount of about 5 mg, 10 mg, 15 mg, 25 mg, or 50 mg. For
example, an effective amount of a obeticholic acid composition
described herein can be about 5 mg, 10 mg, 25 mg, or 50 mg. In
another example, the amount of a starting dose of an obeticholic
acid composition described herein can be about 5 mg, 10 mg, 25 mg,
or 50 mg. In another example, the amount of an adjusted dose or
re-adjusted dose of an obeticholic acid composition described
herein can be about 5 mg, 10 mg, 25 mg, or 50 mg. It is to be
understood the amount of an obeticholic acid composition described
herein as administered to a patient described herein refers to the
amount of obeticholic acid in the composition.
[0230] The amount of an obeticholic acid composition as provided
above can refer to an effective amount as described herein. In
certain embodiments, an effective amount of the obeticholic acid
composition administered to a patient described herein can be 5 mg.
In another embodiment, an effective amount of the obeticholic acid
composition administered to a patient described herein can be 10
mg. In still another embodiment, an effective amount of the
obeticholic acid composition administered to a patient described
herein can be 25 mg. In yet another embodiment, an effective amount
of the obeticholic acid composition administered to a patient
described herein can be 50 mg.
[0231] The amount of an obeticholic acid composition as provided
above can optionally refer to a starting dose administered during a
titration period as described herein. In certain embodiments, a
starting dose of the obeticholic acid composition administered to a
patient described herein can be 5 mg. In another embodiment, a
starting dose of the obeticholic acid composition administered to a
patient described herein can be 10 mg. In still another embodiment,
a starting dose of the obeticholic acid composition administered to
a patient described herein can be 25 mg. In yet another embodiment,
a starting dose of the obeticholic acid composition administered to
a patient described herein can be 50 mg.
[0232] The amount of an obeticholic acid composition as provided
above can refer to an adjusted dose administered after a titration
period as described herein. In certain embodiments, an adjusted
dose of the obeticholic acid composition administered to a patient
described herein can be 5 mg. In another embodiment, an adjusted
dose of the obeticholic acid composition administered to a patient
described herein can be 10 mg. In still another embodiment, an
adjusted dose of the obeticholic acid composition administered to a
patient described herein can be 25 mg. In yet another embodiment,
an adjusted dose of the obeticholic acid composition administered
to a patient described herein can be 50 mg.
[0233] The amount of an obeticholic acid composition as provided
above can refer to a re-adjusted dose administered after a
titration period as described herein. In certain embodiments, a
re-adjusted dose of the obeticholic acid composition administered
to a patient described herein can be 5 mg. In another embodiment, a
re-adjusted dose of the obeticholic acid composition administered
to a patient described herein can be 10 mg. In still another
embodiment, a re-adjusted dose of the obeticholic acid composition
administered to a patient described herein can be 25 mg. In yet
another embodiment, a re-adjusted dose of the obeticholic acid
composition administered to a patient described herein can be 50
mg.
[0234] While it is possible to administer obeticholic acid directly
without any formulation, obeticholic acid is usually administered
in the form of pharmaceutical formulations comprising a
pharmaceutically acceptable excipient and obeticholic acid. These
formulations can be administered by a variety of routes including
oral, buccal, rectal, intranasal, transdermal, subcutaneous,
intravenous, intramuscular, and intranasal. Oral formulation of
obeticholic acid are described further herein under the section
entitled "Oral Formulation and Administration".
[0235] In one embodiment, obeticholic acid can be administered
transdermally. In order to administer transdermally, a transdermal
delivery device ("patch") is needed. Such transdermal patches may
be used to provide continuous or discontinuous infusion of a
compound of the present disclosure in controlled amounts. The
construction and use of transdermal patches for the delivery of
pharmaceutical agents is well known in the art. See, e.g., U.S.
Pat. No. 5,023,252. Such patches may be constructed for continuous,
pulsatile, or on demand delivery of pharmaceutical agents.
[0236] Pharmaceutical compositions suitable for injectable use
include sterile aqueous solutions (where water soluble) or
dispersions and sterile powders for the extemporaneous preparation
of sterile injectable solutions or dispersion. For intravenous
administration, suitable carriers include physiological saline,
bacteriostatic water, Cremophor EL.TM. (BASF, Parsippany, N.J.) or
phosphate buffered saline (PBS). In all cases, the composition must
be sterile and should be fluid to the extent that easy
syringeability exists. It must be stable under the conditions of
manufacture and storage and must be preserved against the
contaminating action of microorganisms such as bacteria and fungi.
The carrier can be a solvent or dispersion medium containing, for
example, water, ethanol, polyol (for example, glycerol, propylene
glycol, and liquid polyethylene glycol, and the like), and suitable
mixtures thereof. The proper fluidity can be maintained, for
example, by the use of a coating such as lecithin, by the
maintenance of the required particle size in the case of dispersion
and by the use of surfactants. Prevention of the action of
microorganisms can be achieved by various antibacterial and
antifungal agents, for example, parabens, chlorobutanol, phenol,
ascorbic acid, thimerosal, and the like. In many cases, it will be
preferable to include isotonic agents, for example, sugars,
polyalcohols such as mannitol, sorbitol, sodium chloride in the
composition. Prolonged absorption of the injectable compositions
can be brought about by including in the composition an agent which
delays absorption, for example, aluminum monostearate and
gelatin.
[0237] Sterile injectable solutions can be prepared by
incorporating the active compound, obeticholic acid or obeticholic
acid particles, in the required amount in an appropriate solvent
with one or a combination of ingredients enumerated herein, as
required, followed by filtered sterilization. Generally,
dispersions are prepared by incorporating the obeticholic acid into
a sterile vehicle that contains a basic dispersion medium and the
required other ingredients from those enumerated above. In the case
of sterile powders for the preparation of sterile injectable
solutions, methods of preparation are vacuum drying and
freeze-drying that yields a powder of the obeticholic acid or
obeticholic acid particles, plus any additional desired ingredient
from a previously sterile-filtered solution thereof.
[0238] It can be useful to orally administer an obeticholic acid
composition described herein. Oral compositions generally include
an inert diluent or an edible pharmaceutically acceptable carrier.
They can be enclosed in gelatin capsules or compressed into
tablets. For the purpose of oral therapeutic administration, the
active compound, obeticholic acid or obeticholic acid particles,
can be incorporated with excipients and used in the form of
tablets, troches, or capsules. Oral compositions can also be
prepared using a fluid carrier for use as a mouthwash, wherein the
obeticholic acid or obeticholic acid particles in the fluid carrier
is applied orally and swished and expectorated or swallowed.
Pharmaceutically compatible binding agents, and/or adjuvant
materials can be included as part of the composition. The tablets,
pills, capsules, troches and the like can contain any of the
following ingredients, or compounds of a similar nature: a binder
such as microcrystalline cellulose, gum tragacanth or gelatin; an
excipient such as sodium starch glycolate, starch or lactose, a
diluent such as microcrystalline cellulose, a disintegrating agent
such as alginic acid, Primogel, or corn starch; a lubricant such as
magnesium stearate or Sterotes; a glidant such as colloidal silicon
dioxide; a sweetening agent such as sucrose or saccharin; or a
flavoring agent such as peppermint, methyl salicylate, or orange
flavoring.
[0239] For administration by inhalation, the obeticholic acid or
obeticholic acid particles is delivered in the form of an aerosol
spray from pressured container or dispenser, which contains a
suitable propellant, e.g., a gas such as carbon dioxide, or a
nebulizer.
[0240] Systemic administration can also be by transmucosal or
transdermal means. For transmucosal or transdermal administration,
penetrants appropriate to the barrier to be permeated are used in
the formulation. Such penetrants are generally known in the art,
and include, for example, for transmucosal administration,
detergents, bile salts, and fusidic acid derivatives. Transmucosal
administration can be accomplished through the use of nasal sprays
or suppositories. For transdermal administration, the obeticholic
acid or obeticholic acid particles is formulated into ointments,
salves, gels, or creams as generally known in the art.
[0241] The obeticholic acid or obeticholic acid particles can be
prepared with pharmaceutically acceptable carriers that will
protect the compound against rapid elimination from the body, such
as a controlled release formulation, including implants and
microencapsulated delivery systems. Biodegradable, biocompatible
polymers can be used, such as ethylene vinyl acetate,
polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and
polylactic acid. Methods for preparation of such formulations will
be apparent to those skilled in the art. The materials can also be
obtained commercially from Alza Corporation and Nova
Pharmaceuticals, Inc. Liposomal suspensions (including liposomes
targeted to infected cells with monoclonal antibodies to viral
antigens) can also be used as pharmaceutically acceptable carriers.
These can be prepared according to methods known to those skilled
in the art, for example, as described in U.S. Pat. No.
4,522,811.
[0242] It is especially advantageous to formulate oral or
parenteral compositions in dosage unit form for ease of
administration and uniformity of dosage. Dosage unit form as used
herein refers to physically discrete units suited as unitary
dosages for the subject to be treated; each unit containing a
predetermined quantity of obeticholic acid or obeticholic acid
particles calculated to produce the desired therapeutic effect in
association with the required pharmaceutical carrier. The
specification for the dosage unit forms of the disclosure are
dictated by and directly dependent on the unique characteristics of
the obeticholic acid or obeticholic acid particles and the
particular therapeutic effect to be achieved.
[0243] In one embodiment of the present disclosure, there is
provided a pharmaceutical formulation comprising at least
obeticholic acid as described above in a formulation adapted for
buccal and/or sublingual, or nasal administration. This embodiment
provides administration of obeticholic acid in a manner that avoids
gastric complications, such as first pass metabolism by the gastric
system and/or through the liver. This administration route may also
reduce adsorption times, providing more rapid onset of therapeutic
benefit. The compounds of the present disclosure may provide
particularly favorable solubility profiles to facilitate
sublingual/buccal formulations. Such formulations typically require
relatively high concentrations of active ingredients to deliver
sufficient amounts of active ingredients to the limited surface
area of the sublingual/buccal mucosa for the relatively short
durations the formulation is in contact with the surface area, to
allow the absorption of the active ingredient. Thus, the very high
activity of obeticholic acid, combined with its high solubility,
facilitates its suitability for sublingual/buccal formulation.
[0244] Obeticholic acid is preferably formulated in a unit dosage
form, each dosage containing from about 0.05 mg to about 1500 mg.
In another embodiment, the formulation comprises about 0.05 mg to
about 100 mg. In yet another embodiment, the formulation comprises
about 1 mg to about 100 mg. In another embodiment, the formulation
comprises about 0.05 mg to about 50 mg. In yet another embodiment,
the formulation comprises about 0.05 mg to about 30 mg. In another
embodiment, the formulation comprises about 0.05 mg to about 20 mg.
In yet another embodiment, the formulation comprises about 0.5 mg
to about 30 mg. In another embodiment, the formulation comprises
about 0.5 mg to about 25 mg. In yet another embodiment, the
formulation comprises about 1 mg to about 25 mg. In another
embodiment, the formulation comprises about 4 mg to about 26 mg. In
another embodiment, the formulation comprises about 5 mg to about
25 mg. In yet another embodiment, the formulation comprises about
0.05 mg to about 2 mg. In another embodiment, the formulation
comprises about 1 mg to about 2 mg. In one embodiment, the
formulation comprises about 1.2 mg to about 1.8 mg. In one
embodiment, the formulation comprises about 1.3 mg to about 1.7 mg.
In one embodiment, the formulation comprises about 1.5 mg. In one
embodiment, the formulation comprises about 0.05 mg to about 0.5
mg. In another embodiment, the formulation comprises about 0.08 mg
to about 0.8 mg. In yet another embodiment, the formulation
comprises about 0.1 mg to about 0.5 mg. In another embodiment, the
formulation comprises about 0.25 mg.
[0245] Obeticholic acid is generally effective over a wide dosage
range. For examples, dosages per day normally fall within the range
of about 0.0001 to about 30 mg/kg of body weight. In the treatment
of adult humans, the range of about 0.1 to about 15 mg/kg/day, in
single or divided dose, is especially preferred. In one embodiment,
the formulation comprises about 0.05 mg to about 1500 mg. In
another embodiment, the formulation comprises about 0.05 mg to
about 100 mg. In yet another embodiment, the formulation comprises
about 1 mg to about 100 mg. In another embodiment, the formulation
comprises about 0.05 mg to about 50 mg. In another embodiment, the
formulation comprises about 0.05 mg to about 30 mg. In yet another
embodiment, the formulation comprises about 0.05 mg to about 20 mg.
In yet another embodiment, the formulation comprises about 0.05 mg
to about 10 mg.
[0246] In one embodiment, the formulation comprises about 3 mg to
about 30 mg. In another embodiment, the formulation comprises about
0.05 mg to about 25 mg. In another embodiment, the formulation
comprises about 4 mg to about 25 mg. In another embodiment, the
formulation comprises about 5 mg to about 25 mg. In another
embodiment, the formulation comprises about 5 mg to about 10 mg. In
one embodiment, the formulation comprises about 1 mg to about 2 mg.
In one embodiment, the formulation comprises about 1.2 mg to about
1.8 mg. In one embodiment, the formulation comprises about 1.3 mg
to about 1.7 mg. In one embodiment, the formulation comprises about
0.05 mg to about 0.5 mg. In another embodiment, the formulation
comprises about 0.08 mg to about 0.8 mg. In yet another embodiment,
the formulation comprises about 0.1 mg to about 0.5 mg. In another
embodiment, the formulation comprises about 25 mg. In another
embodiment, the formulation comprises about 10 mg. In one
embodiment, the formulation comprises about 5 mg. In another
embodiment, the formulation comprises about 0.25 mg. However, it
will be understood that the amount of obeticholic acid actually
administered will be determined by a physician, in the light of the
relevant circumstances, including the condition to be treated, the
chosen route of administration, the form of obeticholic acid
administered, the age, weight, and response of the individual
patient, and the severity of the patient's symptoms, and therefore
the above dosage ranges are not intended to limit the scope of the
disclosure in any way. In some instances dosage levels below the
lower limit of the aforesaid range may be more than adequate, while
in other cases still larger doses may be employed without causing
any harmful side effect, provided that such larger doses are first
divided into several smaller doses for administration throughout
the day.
[0247] The tablet of the present disclosure can comprise an
intra-granular portion and an extra-granular portion. The
intra-granular portion can contain obeticholic acid, or a
pharmaceutically acceptable salt, ester, or amino acid conjugate
thereof, and one or more pharmaceutical excipients. The
extra-granular portion can contain obeticholic acid, or a
pharmaceutically acceptable salt, ester, or amino acid conjugate
thereof, and one or more pharmaceutical excipients. In one
embodiment, the intra-granular portion and the extra-granular
portion of the tablet contain obeticholic acid, or a
pharmaceutically acceptable salt, ester, or amino acid conjugate
thereof, and one or more pharmaceutical excipients. In another
embodiment, the intra-granular portion contains obeticholic acid,
or a pharmaceutically acceptable salt, ester, or amino acid
conjugate thereof and/or the extra-granular portion does not
contain obeticholic acid, or a pharmaceutically acceptable salt,
ester, or amino acid conjugate thereof.
[0248] The presence of microcrystalline cellulose in the
intra-granular portion and/or the extra-granular portion of a
tablet comprising obeticholic acid or a pharmaceutically acceptable
salt, ester, or amino acid conjugate thereof, can affect the
properties of the tablet. In one embodiment, when microcrystalline
cellulose is added to only the intra-granular portion of the
tablet, tablets of moderate hardness can be produced. In another
embodiment, when microcrystalline cellulose is added to only the
intra-granular portion of the tablet, tablets of tolerable hardness
may be produced. In another embodiment, addition of
microcrystalline cellulose to both the intra-granular and
extra-granular portions can provide tablets having superior tablet
hardness and an improved dissolution profile. In one embodiment,
microcrystalline cellulose is added to the intra-granular portion
of the tablet. In another embodiment, microcrystalline cellulose is
added to both the intra-granular portion and extra-granular portion
of the tablet.
[0249] When the microcrystalline cellulose is present in the
intra-granular portion it can be present in a ratio of
microcrystalline cellulose to obeticholic acid, or a
pharmaceutically acceptable salt, ester, or amino acid conjugate
thereof, between about 20:1 to about 1:5. In one embodiment, the
ratio of microcrystalline cellulose to obeticholic acid, or a
pharmaceutically acceptable salt, ester, or amino acid conjugate
thereof, may be, e.g., between about 19:1 to about 1:5, between
about 19:1 to about 1:4, between about 19:1 to about 1:3, between
about 19:1 to about 1:2, between about 18:1 to about 1:5, between
about 18:1 to about 1:4, between about 18:1 to about 1:3, between
about 18:1 to about 1:2, between about 17:1 to about 1:5, between
about 17:1 to about 1:4, between about 17:1 to about 1:3, between
about 17:1 to about 1:2, between about 16:1 to about 1:5, between
about 16:1 to about 1:4, between about 16:1 to about 1:3, between
about 16:1 to about 1:2, between about 15:1 to about 1:5, between
about 15:1 to about 1:4, between about 15:1 to about 1:3, between
about 15:1 to about 1:2, between about 14:1 to about 1:5, between
about 14:1 to about 1:4, between about 14:1 to about 1:3, between
about 14:1 to about 1:2, between about 13:1 to about 1:5, between
about 13:1 to about 1:4, between about 13:1 to about 1:3, between
about 13:1 to about 1:2, between about 12:1 to about 1:5, between
about 12:1 to about 1:4, between about 12:1 to about 1:3, between
about 12:1 to about 1:2, between about 11:1 to about 1:5, between
about 11:1 to about 1:4, between about 11:1 to about 1:3, or
between about 11:1 to about 1:2. In another embodiment, the ratio
of microcrystalline cellulose to obeticholic acid, or a
pharmaceutically acceptable salt, ester, or amino acid conjugate
thereof, is between about 10:1 to about 1:5, between about 10:1 to
about 1:4, between about 10:1 to about 1:3, or between about 10:1
to about 1:2. In another embodiment, the ratio of microcrystalline
cellulose to obeticholic acid, or a pharmaceutically acceptable
salt, ester, or amino acid conjugate thereof, is between about 9:1
to about 1:4, between about 9:1 to about 1:3, between about 9:1 to
about 1:2, or between about 9:1 to about 1:1. In yet another
embodiment, the ratio of microcrystalline cellulose to obeticholic
acid, or a pharmaceutically acceptable salt, ester, or amino acid
conjugate thereof, is between about 8:1 to about 1:3, between about
8:1 to about 1:2, or between about 8:1 to about 1:1. In another
embodiment, the ratio of microcrystalline cellulose to obeticholic
acid, or a pharmaceutically acceptable salt, ester, or amino acid
conjugate thereof, is between about 7:1 to about 1:2 or between
about 7:1 to about 1:1. In yet another embodiment, the ratio of
microcrystalline cellulose to obeticholic acid, or a
pharmaceutically acceptable salt, ester, or amino acid conjugate
thereof, is between about 6:1 to about 1:1. In other embodiments,
the ratio of microcrystalline cellulose to obeticholic acid, or a
pharmaceutically acceptable salt, ester, or amino acid conjugate
thereof, is between about 20:1 to about 1:1, between about 19:1 to
about 1:1, between about 18:1 to about 1:1, between about 17:1 to
about 1:1, between about 16:1 to about 1:1, between about 15:1 to
about 1:1, between about 14:1 to about 1:1, between about 13:1 to
about 1:1, between about 12:1 to about 1:1, or between about 11:1
to about 1:1. In another embodiments, the ratio of microcrystalline
cellulose to obeticholic acid, or a pharmaceutically acceptable
salt, ester, or amino acid conjugate thereof, is between about 20:1
to about 2:1, between about 20:1 to about 3:1, between about 20:1
to about 4:1, between about 20:1 to about 5:1, between about 20:1
to about 6:1, between about 20:1 to about 7:1, between about 20:1
to about 8:1, between about 20:1 to about 9:1, between about 20:1
to about 10:1, between about 20:1 to about 11:1, between about 19:1
to about 2:1, between about 19:1 to about 3:1, between about 19:1
to about 4:1, between about 19:1 to about 5:1, between about 19:1
to about 6:1, between about 19:1 to about 7:1, between about 19:1
to about 8:1, between about 19:1 to about 9:1, between about 19:1
to about 10:1, between about 19:1 to about 11:1, between about 18:1
to about 2:1, between about 18:1 to about 3:1, between about 18:1
to about 4:1, between about 18:1 to about 5:1, between about 18:1
to about 6:1, between about 18:1 to about 7:1, between about 18:1
to about 8:1, between about 18:1 to about 9:1, between about 18:1
to about 10:1, between about 18:1 to about 11:1, between about 17:1
to about 2:1, between about 17:1 to about 3:1, between about 17:1
to about 4:1, between about 17:1 to about 5:1, between about 17:1
to about 6:1, between about 17:1 to about 7:1, between about 17:1
to about 8:1, between about 17:1 to about 9:1, between about 17:1
to about 10:1, between about 17:1 to about 11:1, between about 16:1
to about 2:1, between about 16:1 to about 3:1, between about 16:1
to about 4:1, between about 16:1 to about 5:1, between about 16:1
to about 6:1, between about 16:1 to about 7:1, between about 16:1
to about 8:1, between about 16:1 to about 9:1, between about 16:1
to about 10:1, between about 16:1 to about 11:1, between about 15:1
to about 2:1, between about 15:1 to about 3:1, between about 15:1
to about 4:1, between about 15:1 to about 5:1, between about 15:1
to about 6:1, between about 15:1 to about 7:1, between about 15:1
to about 8:1, between about 15:1 to about 9:1, between about 15:1
to about 10:1, between about 15:1 to about 11:1, between about 14:1
to about 2:1, between about 14:1 to about 3:1, between about 14:1
to about 4:1, between about 14:1 to about 5:1, between about 14:1
to about 6:1, between about 14:1 to about 7:1, between about 14:1
to about 8:1, between about 14:1 to about 9:1, between about 14:1
to about 10:1, between about 14:1 to about 11:1, between about 13:1
to about 2:1, between about 13:1 to about 3:1, between about 13:1
to about 4:1, between about 13:1 to about 5:1, between about 13:1
to about 6:1, between about 13:1 to about 7:1, between about 13:1
to about 8:1, between about 13:1 to about 9:1, between about 13:1
to about 10:1, between about 13:1 to about 11:1, between about 12:1
to about 2:1, between about 12:1 to about 3:1, between about 12:1
to about 4:1, between about 12:1 to about 5:1, between about 12:1
to about 6:1, between about 12:1 to about 7:1, between about 12:1
to about 8:1, between about 12:1 to about 9:1, between about 12:1
to about 10:1, between about 12:1 to about 11:1, between about 11:1
to about 2:1, between about 11:1 to about 3:1, between about 11:1
to about 4:1, between about 11:1 to about 5:1, between about 11:1
to about 6:1, between about 11:1 to about 7:1, between about 11:1
to about 8:1, or between about 11:1 to about 9:1, or between about
11:1 to about 10:1. Preferably, the ratio of microcrystalline
cellulose to obeticholic acid, or a pharmaceutically acceptable
salt, ester, or amino acid conjugate thereof, may be between about
20:1 to about 5:1, between about 16:1 to about 6:1, or between
about 16:1 to about 11:1, or any of the above-mentioned ratio
ranges between about 20:1 to about 5:1. In another embodiment, the
ratio of microcrystalline cellulose to obeticholic acid, or a
pharmaceutically acceptable salt, ester, or amino acid conjugate
thereof, is about 16:1. In yet another embodiment, the ratio of
microcrystalline cellulose to obeticholic acid, or a
pharmaceutically acceptable salt, ester, or amino acid conjugate
thereof, is about 11:1. In another embodiment, the ratio of
microcrystalline cellulose to obeticholic acid, or a
pharmaceutically acceptable salt, ester, or amino acid conjugate
thereof, is about 6:1. In yet another embodiment, the ratio of
microcrystalline cellulose to obeticholic acid, or a
pharmaceutically acceptable salt, ester, or amino acid conjugate
thereof, is between about 10:1 to about 1:1. In another embodiment,
the ratio of microcrystalline cellulose to obeticholic acid, or a
pharmaceutically acceptable salt, ester, or amino acid conjugate
thereof, is between about 5:1 to about 1:1. In yet another
embodiment, the ratio of microcrystalline cellulose to obeticholic
acid, or a pharmaceutically acceptable salt, ester, or amino acid
conjugate thereof, is between about 3:1 to about 1:1. In another
embodiment, the ratio of microcrystalline cellulose to obeticholic
acid, or a pharmaceutically acceptable salt, ester, or amino acid
conjugate thereof, is between about 2:1 to about 1:1. In another
embodiment, the ratio of microcrystalline cellulose to obeticholic
acid, or a pharmaceutically acceptable salt, ester, or amino acid
conjugate thereof, is between about 4:1 to about 2:1. In yet
another embodiment, the ratio of microcrystalline cellulose to
obeticholic acid, or a pharmaceutically acceptable salt, ester, or
amino acid conjugate thereof, is between about 3:1 to about 2:1. In
another embodiment, the ratio of microcrystalline cellulose to
obeticholic acid, or a pharmaceutically acceptable salt, ester, or
amino acid conjugate thereof, is about 4:1. In another embodiment,
the ratio of microcrystalline cellulose to obeticholic acid, or a
pharmaceutically acceptable salt, ester, or amino acid conjugate
thereof, is about 3:1. In yet another embodiment, the ratio of
microcrystalline cellulose to obeticholic acid, or a
pharmaceutically acceptable salt, ester, or amino acid conjugate
thereof, is about 2:1. In another embodiment, the ratio of
microcrystalline cellulose to obeticholic acid, or a
pharmaceutically acceptable salt, ester, or amino acid conjugate
thereof, is about 1:1.
[0250] The tablet hardness of an obeticholic acid containing tablet
can be between about 6 kilopascals (kP) to about 14 kP. In one
embodiment, the tablet hardness is between about 7 kP to about 12
kP. In another embodiment, the tablet hardness is between about 8
kP to about 12 kP. In yet another, the tablet hardness is between
about 8 kP to about 11 kP. In another embodiment, the tablet
hardness is between about 9 kP to about 11 kP. In yet another
embodiment, the tablet hardness is between about 10 kP to about 11
kP.
[0251] In one embodiment, the tablets of the present disclosure
comprising obeticholic acid or a pharmaceutically acceptable salt,
ester, or amino acid conjugate thereof, microcrystalline cellulose
and optionally one or more additional pharmaceutical excipients in
the intra-granular portion, and one or more pharmaceutical
excipients in the extra-granular portion possess increased
hardness. In one embodiment, the tablets of the present disclosure
comprising obeticholic acid or a pharmaceutically acceptable salt,
ester, or amino acid conjugate thereof, microcrystalline cellulose
and optionally one or more additional pharmaceutical excipients in
the intra-granular portion, and microcrystalline cellulose and
optionally one or more additional pharmaceutical excipients in the
extra-granular portion possess increased hardness. In particular,
the tablets of the present disclosure comprising microcrystalline
cellulose in both the intra-granular portion and extra-granular
portion possess increased hardness, for example, as compared with
tablets comprising microcrystalline cellulose in only the
intra-granular portion. In one embodiment, the hardness is
increased at least about 5%, at least about 10%, at least about
20%, at least about 30%, at least about 40%, at least about 50%, at
least about 60%, or at least about 70%, for example, as compared
with tablets comprising microcrystalline cellulose in only the
intra-granular portion. In one embodiment, the hardness is
increased at least about 20%, at least about 30%, at least about
40%, or at least about 50%, for example, as compared with tablets
comprising microcrystalline cellulose in only the intra-granular
portion. In another embodiment, the hardness is increased between
about 5% and about 45%, between about 10% and about 40%, between
about 15% and about 35%, between about 20% and about 30%, between
about 25% and about 35%, between about 25% and about 40%, between
about 25% and about 50%, or between about 30% and about 50%, for
example, as compared with tablets comprising microcrystalline
cellulose in only the intra-granular portion.
[0252] In one embodiment, the tablets of the present disclosure
comprising obeticholic acid or a pharmaceutically acceptable salt,
ester, or amino acid conjugate thereof, microcrystalline cellulose
and optionally one or more additional pharmaceutical excipients in
the intra-granular portion, and one or more pharmaceutical
excipients in the extra-granular portion possess increased
hardness. In another embodiment, the tablets of the present
disclosure comprising obeticholic acid or a pharmaceutically
acceptable salt, ester, or amino acid conjugate thereof,
microcrystalline cellulose, and optionally one or more additional
pharmaceutical excipients in the intra-granular portion, and
microcrystalline cellulose and optionally one or more additional
pharmaceutical excipients in the extra-granular portion possess
improved dissolution of obeticholic acid or a pharmaceutically
acceptable salt, ester, or amino acid conjugate thereof. In
particular, the tablets of the present disclosure comprising
microcrystalline cellulose in both the intra-granular portion and
extra-granular portion possess improved dissolution of obeticholic
acid or a pharmaceutically acceptable salt, ester, or amino acid
conjugate thereof, for example, as compared with tablets comprising
microcrystalline cellulose in only the intra-granular portion. For
example, obeticholic acid or a pharmaceutically acceptable salt,
ester, or amino acid conjugate thereof in the tablets of the
present disclosure dissolves (e.g., in a Disodium Hydrogen
Phosphate Buffer) at a rate that is at least 2%, 3%, 4%, 5%, 6%,
7%, 8%, 9%, 10%, 15%, 20%, 30%, 40%, 50%, 80%, or 100% faster than,
for example, as compared with the dissolution rate tablets
comprising microcrystalline cellulose in only the intra-granular
portion.
[0253] For example, about 55% to about 95% of obeticholic acid or a
pharmaceutically acceptable salt, ester, or amino acid conjugate
thereof in the tablet of the present disclosure is dissolved within
about 15 minutes, or about 65% to about 95% is dissolved within
about 30 minutes, or about 80% to about 95% is dissolved within
about 45 minutes, or about 87% to about 97% is dissolved within
about 60 minutes, or about 87% to about 99% is dissolved within
about 75 minutes. For example, about 60% to about 84% of
obeticholic acid or a pharmaceutically acceptable salt, ester, or
amino acid conjugate thereof in the tablet of the present
disclosure is dissolved within about 15 minutes, or about 75% to
about 91% is dissolved within about 30 minutes, or about 85% to
about 93% is dissolved within about 45 minutes, or about 90% to
about 96% is dissolved within about 60 minutes, or about 90% to
about 97% is dissolved within about 75 minutes. For example, about
62% to about 83% of obeticholic acid or a pharmaceutically
acceptable salt, ester, or amino acid conjugate thereof in the
tablet of the present disclosure is dissolved within about 15
minutes, or about 80% to about 90% is dissolved within about 30
minutes, or about 87% to about 94% is dissolved within about 45
minutes, or about 92% to about 96% is dissolved within about 60
minutes, or about 91% to about 97% is dissolved within about 75
minutes. For example, about 60% to about 84% obeticholic acid or a
pharmaceutically acceptable salt, ester, or amino acid conjugate
thereof in the tablet of the present disclosure is dissolved within
about 15 minutes, or about 70% to about 90% is dissolved within
about 30 minutes, or about 85% to about 92% is dissolved within
about 45 minutes, or about 89% to about 96% is dissolved within
about 60 minutes, or about 90% to about 96% is dissolved within
about 75 minutes. For example, at least about 60% obeticholic acid
or a pharmaceutically acceptable salt, ester, or amino acid
conjugate thereof in the tablet of the present disclosure is
dissolved within about 15 minutes, or at least about 90% is
dissolved within about 60 minutes. For example, obeticholic acid or
a pharmaceutically acceptable salt, ester, or amino acid conjugate
thereof in the tablet of the present disclosure has an in vitro
dissolution profile of about 51% dissolved within about 15 minutes,
or about 66% dissolved within about 30 minutes, or about 79%
dissolved within about 45 minutes, or about 85% dissolved within
about 60 minutes.
[0254] Obeticholic acid tablets can be manufactured via a
manufacturing process comprising dry granulation by roller
compaction followed by tablet compression and coating. The process
steps used to manufacture OCA tablets include: pre-blending, dry
granulation, final blending, compression, coating, and
packaging.
[0255] Obeticholic acid drug substance and one or more
pharmaceutical excipients (i.e., microcrystalline cellulose, sodium
starch glycolate, and/or magnesium stearate) are added and further
optionally blended to produce a premix. In one embodiment, OCA and
microcrystalline cellulose is blended to produce a premix. In one
embodiment, the premix is blended, passed through a screen and then
again blended. In another embodiment, the one or more
pharmaceutical excipients are added in small portions and blended
between each addition. In one embodiment, the one or more
pharmaceutical excipients are added sequentially. In another
embodiment, the one or more pharmaceutical excipients are added
together.
[0256] The premix is then granulated and optionally milled to
reduce particle size. In one embodiment, the premix is roller
compacted. In another embodiment, the premix is further milled. The
premix can be milled using various methods. In one embodiment, the
premix is milled using a comil. In another embodiment, the premix
is milled using a comil followed by an oscillating bar screen
mill.
[0257] Once the premix is granulated, a final blending of the
obeticholic acid tablet formulation is performed. In the final
blending, one or more pharmaceutical excipients (i.e.,
microcrystalline cellulose, sodium starch glycolate, and/or
magnesium stearate) are added to provide a final blend which is
further optionally blended. In one embodiment, microcrystalline
cellulose is added during the final blending. In one embodiment,
the one or more pharmaceutical excipients are added sequentially.
In another embodiment, the one or more pharmaceutical excipients
are added together.
[0258] The final blend is then compressed to form the tablet. The
compression parameters can be adjusted to produce tablets of the
desired weight, hardness, thickness, and friability. The tablet
press speed and feeder speed can also be adjusted to help reduce
tablet weight variation. The obeticholic acid tablets are then
coated with a coating material (i.e., Opadry.RTM. II white,
Opadry.RTM. II green, or Opadry.RTM. II yellow) using a coating
solution.
[0259] Obeticholic acid compositions described herein can be
administered in accordance with a dosing regimen. A dosing regimen
refers to continual and intermittent administration of a
obeticholic acid composition described herein at one or more of the
amounts described herein. Thus, in certain instances, a dosing
regimen can include administration of a obeticholic acid
composition described herein continually for any number of days,
weeks, months, or years as set forth herein. In other instances, a
dosing regimen can include administration of a obeticholic acid
composition described herein intermittently, where, for example,
the composition is administered for one period of time followed by
a rest period or off period where the obeticholic acid composition
is not administered.
[0260] Obeticholic acid compositions useful in the methods of
treating described herein include administration of such
compositions daily (QD), every other day (Q2D), once a week (QW),
twice a week (BID), three times a week (TIW), once a month (QM), or
twice a month (Q2M). In one embodiment, a obeticholic acid
composition described herein is administered QD. Thus, an effective
amount of an obeticholic acid composition described herein can be
administered QD to treat a disease or condition described herein. A
starting dose described herein can be administered QD during the
course of a titration period described herein to treat a disease or
condition described herein. An adjusted dose described herein can
be administered QD to treat a disease or condition described
herein.
[0261] In another embodiment, an obeticholic acid composition
described herein is administered Q2D. An effective amount of an
obeticholic acid composition described herein can be administered
Q2D to treat a disease or condition described herein. A starting
dose described herein can be administered Q2D during the course of
a titration period described herein to treat a disease or condition
described herein. An adjusted dose described herein can be
administered Q2D to treat a disease or condition described
herein.
[0262] In another embodiment, an obeticholic acid composition is
described herein administered QW. An effective amount of an
obeticholic acid composition described herein can be administered
QW to treat a disease or condition described herein. A starting
dose described herein can be administered QW during the course of a
titration period described herein to treat a disease or condition
described herein. An adjusted dose described herein can be
administered QW to treat a disease or condition described
herein.
[0263] In another embodiment, an obeticholic acid composition is
described herein administered BID. An effective amount of an
obeticholic acid composition described herein can be administered
BID to treat a disease or condition described herein. A starting
dose described herein can be administered BID during the course of
a titration period described herein to treat a disease or condition
described herein. An adjusted dose described herein can be
administered BID to treat a disease or condition described
herein.
[0264] In another embodiment, an obeticholic acid composition is
described herein administered TIW. An effective amount of an
obeticholic acid composition described herein can be administered
TIW to treat a disease or condition described herein. A starting
dose described herein can be administered TIW during the course of
a titration period described herein to treat a disease or condition
described herein. An adjusted dose described herein can be
administered TIW to treat a disease or condition described
herein.
[0265] In another embodiment, an obeticholic acid composition is
described herein administered QM. An effective amount of an
obeticholic acid composition described herein can be administered
QM to treat a disease or condition described herein. A starting
dose described herein can be administered QM during the course of a
titration period described herein to treat a disease or condition
described herein. An adjusted dose described herein can be
administered QM to treat a disease or condition described
herein.
[0266] In another embodiment, an obeticholic acid composition is
described herein administered Q2M. An effective amount of an
obeticholic acid composition described herein can be administered
Q2M to treat a disease or condition described herein. A starting
dose described herein can be administered Q2M during the course of
a titration period described herein to treat a disease or condition
described herein. An adjusted dose described herein can be
administered Q2M to treat a disease or condition described
herein.
[0267] The embodiments described above include administration at an
amount described above. For example, an obeticholic acid
composition described herein can be administered in a frequency
provided above in an amount of 5 mg, 10 mg, 25 mg, or 50 mg.
[0268] Dosing regimens of the obeticholic acid compositions
described herein useful for treating diseases and conditions
described herein can include a titration period. A titration period
typically includes a lower dosage of an obeticholic acid
composition described herein for a period of time. In certain
instances, and without being bound by any particular theory,
administration using a titration period described herein can
decrease or eliminate the onset of adverse effects. In other
instances, and without being bound by any particular theory,
administration using a titration period described herein can permit
increased dosages of obeticholic acid compositions described herein
to an individual over the course of a treatment.
[0269] A titration period can be a period of time of about: 1 month
to about 24 months; 1 month to about 21 months; 1 month to about 18
months; 1 month to about 15 months; 1 month to about 12 months; 1
month to about 9 months; 1 month to about 6 months; or 1 month to
about 3 months. In another embodiment, a titration period includes
a time of about: 3 months to about 24 months; 3 months to about 21
months; 3 months to about 18 months; 3 months to about 15 months; 3
months to about 12 months; 3 or months to about 6 months. In still
another embodiment, a titration period includes a time of about: 6
months to about 24 months; 6 months to about 21 months; 6 months to
about 18 months; 6 months to about 15 months; or 6 months to about
12 months. In yet another embodiment, a titration period includes a
time of about: 2 months to about 4 months; 2 months to about 7
months; 2 months to about 8 months; 4 months to about 8 months; 5
months to about 7 months; or 5 months to about 8 months. For
example, a titration period can be about 1 to about 6 months. In
another example, a titration period can be about 3 to about 6
months.
[0270] A titration period can include a time of about 1, 2, 3, 4,
5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22,
23, or 24 months. In certain embodiments, a titration period
includes a time of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12
months. In another embodiment, the titration period includes a time
of about 1, 2, 3, 4, 5, 6, 7, 8, or 9 months. In another
embodiment, the titration period includes a time of about 1, 2, 3,
4, 5, or 6 months. In another embodiment, the titration period
includes a time of about 1, 2, or 3 months. For example, a
titration period can be about 1 month. In another example a
titration period can be about 2 months. In another example a
titration period can be about 3 months. In still another example a
titration period can be about 4 months. In yet another example a
titration period can be about 5 months. In another example a
titration period can be about 6 months. In one example a titration
period is 3 months or 6 months. In another example a titration
period can be about 7 months. In another example a titration period
can be about 8 months. In another example a titration period can be
about 9 months.
[0271] As provided above, the amounts of a obeticholic acid
composition described herein, optionally administered in a
titration period can be reduced compared to an adjusted amount as
described herein. Accordingly, provided herein are treatment
regimens that include administering obeticholic acid compositions
described herein for the treatment of a disease or condition
described herein (e.g., PBC) wherein the starting dose administered
during a titration period described above is lower than the amount
of an adjusted dose administered after a titration period. Still
further provided herein are treatment regimens that include
administering obeticholic acid compositions described herein for
the treatment of a disease or condition described herein (e.g.,
PBC) where the starting dose administered during a titration period
described above is lower than the amount of an adjusted dose
administered after a titration period and where the frequency of
administration (e.g., QD, Q2D, or QW) for the adjusted dose is
greater than the frequency of administration of the starting dose.
Still further provided herein are treatment regimens that include
administering obeticholic acid compositions described herein for
the treatment of a disease or condition described herein (e.g.,
PBC) where the starting dose administered during a titration period
described above is lower than the amount of an adjusted dose
administered after a titration period and where the frequency of
administration (e.g., QD, Q2D, or QW) for the adjusted dose is less
than the frequency of administration of the starting dose.
Increases in the adjusted dose (or any re-adjusted dose) can be
performed after the patient's liver function is assessed,
monitored, or measured as described herein, where the liver
function is considered not-impaired.
[0272] In embodiments, the adjusted dose can be increased compared
to the starting dose when the level of ALP is about equal to or is
not reduced compared to a control as described herein. In
embodiments, the adjusted can be increased compared to the starting
dose when the level of bilirubin is about equal to or is not
reduced compared to a control as described herein. In embodiments,
the adjusted dose can be increased compared to the starting dose
when the level of ALP and bilirubin are about equal to or are not
reduced compared to a control as described herein. In certain
instances, the adjusted dose can be increased compared to the
starting dose where a patient described herein tolerates the
starting dose amount. In certain embodiments, the starting dose can
be 5 mg. In certain embodiments, the starting dose is 10 mg. In
certain embodiments, the starting dose is 5 mg and the adjusted
dose is greater than 5 mg (e.g., about 6 mg to about 50 mg). In one
embodiment, the starting dose is 5 mg and the adjusted dose is 10
mg.
[0273] Also provided herein are treatment regimens that include
administering obeticholic acid compositions described herein for
the treatment of a disease or condition described herein (e.g.,
PBC) where the starting dose administered during a titration period
described above is equal to the amount of an adjusted dose
administered after a titration period. Further provided herein are
treatment regimens that include administering obeticholic acid
compositions described herein for the treatment of a disease or
condition described herein (e.g., PBC) where the starting dose
administered during a titration period described above is equal to
the amount of an adjusted dose administered after a titration
period and where the frequency of administration (e.g., QD, Q2D, or
QW) for the starting dose is the same as the adjusted dose. Still
further provided herein are treatment regimens that include
administering obeticholic acid compositions described herein for
the treatment of a disease or condition described herein (e.g. PBC)
where the starting dose administered during a titration period
described above is equal to the amount of an adjusted dose
administered after a titration period and where the frequency of
administration (e.g., QD, Q2D, or QW) for the adjusted dose is
greater than the frequency of administration of the starting dose.
Still further provided herein are treatment regimens that include
administering obeticholic acid compositions described herein for
the treatment of a disease or condition described herein (e.g.,
PBC) where the starting dose administered during a titration period
described above is equal to the amount of an adjusted dose
administered after a titration period and where the frequency of
administration (e.g., QD, Q2D, or QW) for the adjusted dose is less
than the frequency of administration of the starting dose. The
adjusted dose (or any re-adjusted dose) can be equal to the
starting dose where the patient's liver function is assessed,
monitored, or measured as described herein, where the liver
function is considered not-impaired.
[0274] In embodiments, the adjusted dose can be equal to the
starting dose when the level of ALP is reduced compared to a
control as described herein. In embodiments, the adjusted dose can
be equal to the starting dose when the level of bilirubin is
reduced compared to a control as described herein. In embodiments,
the adjusted dose can be equal to the starting dose when the level
of ALP and bilirubin are reduced compared to a control as described
herein. In certain instances, the adjusted dose can be equal to the
starting dose where a patient described herein tolerates or poorly
tolerates (e.g., has onset of adverse effects described herein) the
starting dose amount. In certain embodiments, the starting dose can
be 5 mg. In certain embodiments, the starting dose is 10 mg. In
certain embodiments, the starting dose is 5 mg and the adjusted
dose is 5 mg. In one embodiment, the starting dose is 10 mg and the
adjusted dose is 10 mg.
[0275] Further provided herein are treatment regimens that
optionally include a starting dose and an adjusted dose as provided
in the regimens above, where the adjusted dose is further reduced
during the course of treatment. In certain instances, the adjusted
dose is reduced to a new re-adjusted dose having a decreased amount
of an obeticholic acid composition described herein. In other
instances the adjusted dose is reduced to a new re-adjusted dose
having the same amount of an obeticholic acid composition described
herein but a decreased frequency of administration (e.g., from QD
to Q2D or QW). In still other instances, the adjusted dose is
modified such that the re-adjusted dose includes a decreased amount
of an obeticholic acid composition described herein and is
administered at a decreased frequency compared to the adjusted
dose.
[0276] The obeticholic acid composition described herein can be
administered for any number of days, weeks, months, or years,
including indefinitely, provided that the dosage remains
efficacious for the patient and the patient tolerates the dosage
(e.g., an adjusted or re-adjusted dose as described herein). In
certain instances, an obeticholic acid composition described herein
is administered to a patient described herein until loss of
efficacy, or until development of unacceptable toxicity or
undesired adverse effects, such as, for example, those described
herein. Daily dosing of an obeticholic acid composition described
herein can be dependent upon patient tolerance to the dosage,
composition, or frequency of administration. For example, daily
dosing can be administered to a patient described herein where the
patient tolerates a daily dosage amount (e.g., 5 mg, 10 mg, 25 mg,
or 50 mg). Alternatively or additionally, the daily dosing can be
modified to increase or reduce the amount of an obeticholic acid
composition described herein as provided above where the patient is
tolerant or is intolerant to the dose, respectively. In certain
embodiments, modification of the adjusted dose (or any re-adjusted
dose) can be performed after the patient's liver function is
assessed, monitored, or measured as described herein. In certain
instances, the adjusted dose (or re-adjusted dose) is increased or
maintained (e.g., equivalent to a starting dose) where the liver
function is not-impaired. In other instances, the adjusted dose (or
re-adjusted dose) is decreased or maintained (e.g., equivalent to a
starting dose) where the patient's liver function is impaired.
[0277] The amount of an obeticholic acid described herein
administered to a patient described herein can be modified as a
result of intolerability or development of one or more adverse
effects such as those described herein. For example, in one
instance the amount of an obeticholic acid composition described
herein administered to a patient can be changed from a QD dosage to
a Q2D dosage. In certain embodiments, the dosage of an obeticholic
acid described herein is modified from a QD to Q2D dosage upon
development of an adverse effect described herein (e.g., severe
pruritus). In one example, administration of an obeticholic acid
composition described herein at 5 mg QD can be modified to a 5 mg
Q2D dosage. Such a modification can reduce or eliminate undesired
adverse effects while maintaining the desired efficacy. In another
example, administration of an obeticholic acid composition
described herein at 10 mg QD can be reduced to 5 mg QD. It should
be understood that exemplary dosing regimens described herein can
be combined. For example, a reduced dosage of an obeticholic acid
composition described herein from 10 mg to 5 mg QD could be further
reduced to a 5 mg Q2D dosage where undesired adverse effects
remain. In still another example, dosing of the obeticholic acid
composition can be temporarily suspended (e.g., an off period) for
about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days, or 1,
2, 3, or 4 weeks.
[0278] In one exemplary dosing regimen, a PBC patient is
administered an obeticholic acid composition described herein
where: the starting dose of the obeticholic acid composition
described herein is administered QD to a patient described herein
at an amount of 5 mg and the obeticholic acid composition is
administered QD to the patient in an adjusted dose of 5 mg. The
exemplary dosing regimen can include a titration period of about 1
to about 6 months.
[0279] In another exemplary dosing regimen, a PBC patient is
administered an obeticholic acid composition described herein
where: the starting dose of the obeticholic acid composition
described herein is administered QD to a patient described herein
at an amount of 5 mg in a titration period of about 3 months or
about 6 months and the obeticholic acid composition is administered
QD to the patient in an adjusted dose of 5 mg.
[0280] In still another exemplary dosing regimen, a PBC patient is
administered an obeticholic acid composition described herein
where: the starting dose of the obeticholic acid composition
described herein is administered QD to a patient in a titration
period of about 3 months or about 6 months and the obeticholic acid
composition is administered QD to the patient in an adjusted dose
of 10 mg.
[0281] In another exemplary dosing regimen, a PBC patient is
administered an obeticholic acid composition described herein
where: the starting dose of the obeticholic acid composition
described herein is administered QD to a patient in a titration
period of about 3 months or about 6 months and the obeticholic acid
composition is administered QD to the patient in an adjusted dose
of 5 mg, where the adjusted dose is modified to a 5 mg Q2D
re-adjusted dose upon development of an adverse effect (e.g.,
pruritus or severe pruritus).
[0282] In still another exemplary dosing regimen, a PBC patient is
administered a obeticholic acid composition described herein, where
the starting dose of the obeticholic acid composition described
herein is administered QD to a patient in a titration period of
about 3 months or about 6 months and the obeticholic acid
composition is administered QD to the patient in an adjusted dose
of 10 mg, where the adjusted dose is subsequently modified to a 5
mg QD re-adjusted dose upon development of an adverse effect (e.g.,
pruritus or severe pruritus).
[0283] The amount of an obeticholic acid composition described
herein administered to a patient can be determined by the existence
of any preexisting conditions in the patient. For example, where a
patient described herein has or has had hepatic impairment, the
dosage of the obeticholic acid composition described herein can be
modified. In certain instances, the hepatic impairment is a
Child-Pugh Class B or Class C hepatic impairment. In one
embodiment, the hepatic impairment is Child-Pugh Class C. In such
instances, the amount of an obeticholic acid composition described
herein can be administered in a decreased amount during and after a
titration period when compared to administration of the same
obeticholic acid composition to a patient who does not have hepatic
impairment.
[0284] In one example dosing regimen, a patient having hepatic
impairment is administered an obeticholic acid composition
described herein at an amount of about 1 mg to about 5 mg, where
the composition is administered at least once weekly (QW). In one
instance, the obeticholic acid composition described herein is
administered at an amount of about 5 mg once weekly to a patient
diagnosed with hepatic impairment (e.g., Child-Pugh Class B or
C).
[0285] For example, the dosing regimen can include administering an
obeticholic acid composition described herein to a patient having
hepatic impairment, where the obeticholic acid composition is
administered at a starting dose of 5 mg QW for a titration period
of 3 or 6 months and administered at an adjusted dose of 5 mg QW.
The patient's liver function can be assessed, monitored, or
measured as described herein. Where the patient's liver function is
not impaired, the adjusted dose can be increased to a re-adjusted
dose of 5 mg administered BIW or 5 mg QD.
[0286] In certain instances a patient can develop liver impairment
during the course of administration. It is understood, using the
disclosure provided herein, that the adjusted dose can be decreased
in amount or frequency to avoid progression of liver
impairment.
[0287] Further provided herein is a method of treating PBC in a
patient in need thereof by administering an effective amount of a
obeticholic acid composition described herein QD, where the
effective amount is either a 5 mg or 10 mg dose. In another aspect
is a method of treating PBC in a patient in need thereof by
administering a starting dose of 5 mg QD of an obeticholic acid
composition described herein for at least 3 months; evaluating the
tolerance of the patient, the patient's liver function as described
herein, and/or the efficacy of treatment, where patient tolerance,
liver function, and/or lowered efficacy indicate end of a titration
period and administration of an adjusted dose of 10 mg QD. In one
embodiment, the patient tolerance, liver function, and/or lowered
efficacy indicate end of a titration period and administration of
an adjusted dose of 5 mg QD.
[0288] In embodiments described herein, an obeticholic acid
composition described herein can be metabolized to a obeticholic
acid conjugate, such as for example, a glycine, taurine, or
sarcosine conjugate of obeticholic acid. Such metabolites can be
useful in treating a disease or condition provided herein. In
certain instances, production of conjugates can be assessed,
monitored, measured, or detected, as described herein during the
course of a treatment. In some embodiments, increased levels of
obeticholic acid conjugates can result in adjusted dosages of an
obeticholic acid composition described herein.
[0289] Also provided herein are methods of treating a disease or
condition described herein where the treatment further includes
administration of one or more active agents and combinations
thereof. For example, ursodeoxycholic acid (UDCA) is commonly
administered for treatment of PBC, yet a majority of patients
administered UDCA alone have either an inadequate response or no
response to the treatment. In such instances, there is a need for
new medicaments or additional medicaments for the treatment of PBC.
The obeticholic acid compositions described herein can be
administered as described herein (e.g., according to one or more
dosing regimens provided above) in combination with UDCA. In some
instances, the UDCA is administered at an amount of about 10 to 15
mg/kg/day. In another instance, the UDCA is administered at an
amount of about 300, 600, 900, or 1200 mg/day. Administration of
UDCA can include a rest or off period of 1, 2, 3, or 4 weeks. In
one example, an obeticholic acid composition described herein is
administered as described herein in combination with UDCA, where
the UDCA is administered at an amount provided above or in
accordance with a package insert. The term package insert refers to
instructions customarily included in commercial packages of
medicaments approved by the FDA or a similar regulatory agency of a
country other than the USA, which contains information about, for
example, the usage, dosage, administration, contraindications,
and/or warnings concerning the use of such medicaments.
[0290] In another example, the active agent is a peroxisome
proliferator-activated receptor alpha (PPAR.alpha.) agonist, a
peroxisome proliferator-activated receptor delta (PPAR.delta.)
agonist, a dual PPAR.alpha./.delta. agonist, a dual
PPAR.alpha./.gamma. agonist, or pan-PPAR agonist, an HMG CoA
reductase inhibitor, a GLP1 agonist, insulin, insulin mimetic,
metformin, a GTP4 agonist, an HST2 inhibitor, a DPP-IV inhibitor,
an SGLT2 inhibitor or a hydroxysteroid dehydrogenase (HSD)
inhibitor, such as an 11.beta.-HSD1 inhibitor, an ASK1 inhibitor,
an ACC1 inhibitor, a NOX1 and/or NOX4 inhibitor, an inhibitor or
antagonist of one or more chemokine receptors, such as, for
example, CCR2 and CCR5.
[0291] In instances where an obeticholic acid composition described
herein is useful for the treatment of a cancer described herein,
such compositions can be co-administered with one or more cancer
agents.
[0292] The anti-cancer agent useful in methods of treating
solid-tumor cancers provided herein can include any known class of
anti-cancer agents such as, for example, radiation therapy,
operations, alkylating agents, antimetabolites, anthracyclines,
campothecins, vinca alkaloids, taxanes or platinums, as well as
other antineoplastic agents known in the art. Such anti-cancer
agent and antineoplastic agent classifications are known in the art
and used in accordance with their plain and ordinary meaning.
[0293] Exemplary anti-cancer agents include but are not limited to:
ABRAXANE; abiraterone; ace-11; aclarubicin; acivicin; acodazole
hydrochloride; acronine; actinomycin; acylfulvene; adecypenol;
adozelesin; adriamycin; aldesleukin; all trans-retinoic acid
(ATRA); altretamine; ambamustine; ambomycin; ametantrone acetate;
amidox; amifostine; aminoglutethimide; aminolevulinic acid;
amrubicin; amsacrine; anagrelide; anastrozole; andrographolide;
antarelix; anthramycin; aphidicolin glycinate; apurinic acid;
ara-CDP-DL-PTBA; arginine deaminase; ARRY-162; ARRY-300;
ARRY-142266; AS703026; asparaginase; asperlin; asulacrine;
atamestane; atrimustine; AVASTIN; axinastatin 1; axinastatin 2;
axinastatin 3; azasetron; azatoxin; azatyrosine; azacitidine;
AZD8330; azetepa; azotomycin; balanol; batimastat; BAY 11-7082; BAY
43-9006; BAY 869766; bendamustine; benzochlorins; benzodepa;
benzoylstaurosporine; beta-alethine; betaclamycin B; betulinic
acid; b-FGF inhibitor; bicalutamide; bisantrene;
bisaziridinylspermine; bisnafide; bisnafide dimesylate; bistratene
A; bisantrene hydrochloride; bleomycin; bleomycin sulfate;
busulfan; bizelesin; breflate; bortezomib; brequinar sodium;
bropirimine; budotitane; buthionine sulfoximine; bryostatin;
cactinomycin; calusterone; calcipotriol; calphostin C; camptothecin
derivatives; capecitabine; carboxamide-amino-triazole;
carboxyamidotriazole; CaRest M3; CARN 700; caracemide; carbetimer;
carboplatin; carmustine; carubicin hydrochloride; carzelesin;
castanospermine; cecropin B; cedefingol; celecoxib; cetrorelix;
chlorins; chloroquinoxaline sulfonamide; cicaprost; chlorambucil;
Chlorofusin; cirolemycin; cisplatin; CI-1040; cis-porphyrin;
cladribine; clomifene analogues; clotrimazole; collismycin A;
collismycin B; combretastatin A4; combretastatin analogue;
conagenin; crambescidin 816; crisnatol; crisnatol mesylate;
cryptophycin 8; cryptophycin A derivatives; curacin A;
cyclopentanthraquinones; cycloplatam; cypemycin; cyclophosphamide;
cytarabine; cytarabine ocfosfate; cytolytic factor; cytostatin;
dacarbazine; dactinomycin; daunorubicin; daunorubicin
hydrochloride; decarbazine; dacliximab; dasatinib; decitabine;
dehydrodidemnin B; deslorelin; dexamethasone; dexifosfamide;
dexrazoxane; dexverapamil; dexormaplatin; dezaguanine; dezaguanine
mesylate; diaziquone; didemnin B; didox; diethylnorspermine;
dihydro 5 azacytidine; dihydrotaxol; 9-dioxamycin; diphenyl
spiromustine; docosanol; dolasetron; docetaxel; doxorubicin;
doxorubicin hydrochloride; doxifluridine; droloxifene; droloxifene
citrate; dromostanolone propionate; dronabinol; duazomycin;
duocarmycin SA; ebselen; ecomustine; edelfosine; edrecolomab;
edatrexate; eflornithine hydrochloride; eflornithine; elemene;
emitefur; elsamitrucin; enloplatin; enpromate; epipropidine;
epirubicin; epirubicin hydrochloride; epristeride; erbulozole;
eribulin; esorubicin hydrochloride; estramustine; estramustine
phosphate sodium; etanidazole; etoposide; etoposide phosphate;
etoprine; exemestane; fadrozole; fadrozole hydrochloride;
fazarabine; fenretinide; filgrastim; finasteride; flavopiridol;
flezelastine; fluasterone; floxuridine; fludarabine phosphate;
fludarabine; fluorodaunorubicin hydrochloride; forfenimex;
formestane; fluorouracil; floxouridine; flurocitabine; fosquidone;
fostriecin sodium; fostriecin; fotemustine; gadolinium texaphyrin;
gallium nitrate; galocitabine; ganirelix; gelatinase inhibitors;
gemcitabine; geldanamycin; gossyphol; GDC-0973; GSK
1120212/trametinib; herceptin; hydroxyurea; hepsulfam; heregulin;
hexamethylene bisacetamide; hypericin; ibandronic acid; ibrutinib;
idarubicin; idarubicin hydrochloride; ifosfamide; canfosfamide;
ilmofosine; iproplatin; idoxifene; idramantone; ilmofosine;
ilomastat; imidazoacridones; imatinib (e.g., GLEEVEC); imiquimod;
iniparib (BSI 201); iobenguane; iododoxorubicin; ipomeanol;
irinotecan; irinotecan hydrochloride; irsogladine; isobengazole;
isohomohalicondrin B; itasetron; iimofosine; interleukin IL-2
(including recombinant interleukin II; or rlL.sub.2); interferon
alfa-2a; interferon alfa-2b; interferon alfa-nl; interferon
alfa-n3; interferon beta-1a; interferon gamma-1b; jasplakinolide;
kahalalide F; lamellarin N triacetate; lanreotide; leinamycin;
lenograstim; lentinan sulfate; leptolstatin; letrozole;
leuprorelin; levamisole; lenalidomide; lenvatinib; liarozole;
lissoclinamide 7; lobaplatin; lombricine; lometrexol; lonidamine;
losoxantrone; lovastatin; loxoribine; lurtotecan; lutetium
texaphyrin; lysofylline; lanreotide acetate; lapatinib; letrozole;
leucovorin; leuprolide acetate; liarozole hydrochloride; lometrexol
sodium; lomustine; losoxantrone hydrochloride; pomalidomide;
LY294002; maitansine; mannostatin A; marimastat; masoprocol;
maspin; matrilysin inhibitors; menogaril; merbarone; meterelin;
methioninase; metoclopramide; MIF inhibitor; mifepristone;
miltefosine; mirimostim; mitoguazone; mitolactol; mitonafide;
mitoxantrone; mofarotene; molgramostim; mopidamol; mycaperoxide B;
myriaporone; maytansine; mechlorethamine hydrochloride; megestrol
acetate; melengestrol acetate; melphalan; mercaptopurine;
methotrexate; methotrexate sodium; metoprine; meturedepa;
mitindomide; mitocarcin; mitocromin; mitogillin; mitomalcin;
mitomycin; mitosper; mitotane; mitoxantrone hydrochloride;
mycophenolic acid; nafarelin; nagrestip; napavin; naphterpin;
nartograstim; nedaplatin; nemorubicin; neridronic acid; nilutamide;
nisamycin; nitric oxide modulators; nitroxide antioxidant;
nitrullyn; nocodazole; nogalamycin; oblimersen (GENASENSE);
octreotide; okicenone; olaparib (LYNPARZA); oligonucleotides;
onapristone; ondansetron; oracin; oral cytokine inducer;
ormaplatin; oxisuran; oxaloplatin; osaterone; oxaliplatin;
oxaunomycin; palauamine; palmitoylrhizoxin; pamidronic acid;
panaxytriol; panomifene; parabactin; PARP (polyADP ribose
polymerase) inhibitors; pazelliptine; pegaspargase; peldesine;
pentosan polysulfate sodium; pentostatin; pentrozole; perflubron;
perfosfamide; perillyl alcohol; phenazinomycin; phenylacetate;
phosphatase inhibitors; picibanil; pilocarpine hydrochloride;
pirarubicin; piritrexim; placetin A; placetin B; porfiromycin;
prednisone; prostaglandin J2; pyrazoloacridine; paclitaxel;
PD035901; PD184352; PD318026; PD98059; peliomycin; pentamustine;
peplomycin sulfate; PKC412; pipobroman; piposulfan; piroxantrone
hydrochloride; plicamycin; plomestane; podophyllotoxin; polyphenol
E; porfimer sodium; porfiromycin; prednimustine; procarbazine;
procarbazine hydrochloride; puromycin; puromycin hydrochloride;
pyrazofurin; raltitrexed; ramosetron; retelliptine demethylated;
rhizoxin; rituximab; RII retinamide; rogletimide; rohitukine;
romurtide; roquinimex; rubiginone B 1; ruboxyl; riboprine;
romidepsin; rucaparib; safingol; safingol hydrochloride; saintopin;
sarcophytol A; sargramostim; semustine; sizofiran; sobuzoxane;
sodium borocaptate; sodium phenylacetate; solverol; sonermin;
sorafenib; sunitinib; sparfosic acid; spicamycin D; spiromustine;
splenopentin; spongistatin 1; Spongistatin 2; Spongistatin 3;
Spongistatin 4; Spongistatin 5; Spongistatin 6; Spongistatin 7;
Spongistatin 8; and Spongistatin 9; squalamine; stipiamide;
stromelysin inhibitors; sulfinosine; suradista; suramin;
swainsonine; SB239063; selumetinib/AZD6244; simtrazene; SP600125;
sparfosate sodium; sparsomycin; spirogermanium hydrochloride;
spiroplatin; streptonigrin; streptozocin; sulofenur; tallimustine;
tamoxifen methiodide; talazoparib (BMN 673); tauromustine;
tazarotene; tecogalan sodium; tegafur; tellurapyrylium; temoporfin;
temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine;
thaliblastine; thiocoraline; thrombopoietin; thymalfasin;
thymopoietin receptor agonist; thymotrinan; tirapazamine;
titanocene bichloride; topsentin; toremifene; tretinoin;
triacetyluridine; triciribine; trimetrexate; triptorelin;
tropisetron; turosteride; tyrphostins; talisomycin; TAK-733;
taxotere; tegafur; teloxantrone hydrochloride; teroxirone;
testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin;
tirapazamine; toremifene citrate; trastuzumab; trestolone acetate;
triciribine phosphate; trimetrexate; trimetrexate glucuronate;
triptorelin; tubulozole hydrochloride; tumor necrosis
factor-related apoptosis-inducing ligand (TRAIL); UBC inhibitors;
ubenimex; U0126; uracil mustard; uredepa; vapreotide; variolin B;
velaresol; veliparib (ABT-888); veramine; verteporfin; vinorelbine;
vinxaltine; vitaxin; vinblastine; vinblastine sulfate; vincristine
sulfate; vindesine; vindesine sulfate; vinepidine sulfate;
vinglycinate sulfate; vinleurosine sulfate; vinorelbine tartrate;
vinrosidine sulfate; vinzolidine sulfate; vorozole; wortmannin;
XL518; zanoterone; zeniplatin; zilascorb; zinostatin stimalamer;
zinostatin; and zorubicin hydrochloride.
[0294] Other exemplary anti-cancer agents include Erbulozole (e.g.,
R-55104); Dolastatin 10 (e.g., DLS-10 and NSC-376128); Mivobulin
isethionate (e.g., CI-980); NSC-639829; Discodermolide (e.g.,
NVP-XX-A-296); ABT-751 (Abbott; e.g., E-7010); Altorhyrtin A;
Altorhyrtin C; Cemadotin hydrochloride (e.g., LU-103793 and
NSC-D-669356); CEP 9722; Epothilone A; Epothilone B; Epothilone C;
Epothilone D; Epothilone E; Epothilone F; Epothilone B N-oxide;
Epothilone A N-oxide; 16-aza-epothilone B; 21-aminoepothilone B;
21-hydroxyepothilone D; 26-fluoroepothilone; Auristatin PE (e.g.,
NSC-654663); Soblidotin (e.g., TZT-1027); LS-4559-P (Pharmacia;
e.g., LS-4577); LS-4578 (Pharmacia; e.g., LS-477-P); LS-4477
(Pharmacia); LS-4559 (Pharmacia); RPR-112378 (Aventis); DZ-3358
(Daiichi); FR-182877 (Fujisawa; e.g., WS-9265B); GS-164 (Takeda);
GS-198 (Takeda); KAR-2 (Hungarian Academy of Sciences); BSF-223651
(BASF; e.g., ILX-651 and LU-223651); SAH-49960 (Lilly/Novartis);
SDZ-268970 (Lilly/Novartis); AM-97 (Armad/Kyowa Hakko); AM-132
(Armad); AM-138 (Armad/Kyowa Hakko); IDN-5005 (Indena);
Cryptophycin 52 (e.g., LY-355703); AC-7739 (Ajinomoto; e.g.,
AVE-8063A and CS-39.HCl); AC-7700 (Ajinomoto; e.g., AVE-8062;
AVE-8062A; CS-39-L-Ser.HCl; and RPR-258062A); Vitilevuamide;
Tubulysin A; Canadensol; CA-170 (Curis, Inc.); Centaureidin (e.g.,
NSC-106969); T-138067 (Tularik; e.g., T-67; TL-138067 and
TI-138067); COBRA-1 (Parker Hughes Institute; e.g., DDE-261 and
WHI-261); H10 (Kansas State University); H16 (Kansas State
University); Oncocidin A1 (e.g., BTO-956 and DIME); DDE-313 (Parker
Hughes Institute); Fijianolide B; Laulimalide; SPA-2 (Parker Hughes
Institute); SPA-1 (Parker Hughes Institute; e.g., SPIKET-P);
3-IAABU (Cytoskeleton/Mt. Sinai School of Medicine; e.g., MF-569);
Narcosine (e.g., NSC-5366); Nascapine; D-24851 (Asta Medica);
A-105972 (Abbott); Hemiasterlin; 3-BAABU (Cytoskeleton/Mt. Sinai
School of Medicine; e.g., MF-191); TMPN (Arizona State University);
Vanadocene acetylacetonate; T-138026 (Tularik); Monsatrol;
Inanocine (e.g., NSC-698666); 3-IAABE (Cytoskeleton/Mt. Sinai
School of Medicine); A-204197 (Abbott); T-607 (Tularik; e.g.,
T-900607); RPR-115781 (Aventis); Eleutherobins (e.g.,
Desmethyleleutherobin; Desaetyleleutherobin; lsoeleutherobin A; and
Z-Eleutherobin); Caribaeoside; Caribaeolin; Halichondrin B; D-64131
(Asta Medica); D-68144 (Asta Medica); Diazonamide A; A-293620
(Abbott); NPI-2350 (Nereus); Taccalonolide A; TUB-245 (Aventis);
A-259754 (Abbott); Diozostatin; (-)-Phenylahistin (e.g.,
NSCL-96F037); D-62638 (Asta Medica); D-62636 (Asta Medica);
Myoseverin B; D-43411 (Zentaris; e.g., D-81862); A-289099 (Abbott);
A-318315 (Abbott); HTI-286 (e.g., SPA-110; trifluoroacetate salt)
(Wyeth); D-82317 (Zentaris); D-82318 (Zentaris); SC-12983 (NCI);
Resverastatin phosphate sodium; BPR-OY-007 (National Health
Research Institutes); and SSR-250411 (Sanofi)); goserelin;
leuprolide; triptolide; homoharringtonine; topotecan; itraconazole;
deoxyadenosine; sertraline; pitavastatin; clofazimine;
5-nonyloxytryptamine; vemurafenib; dabrafenib; gefitinib (IRESSA);
erlotinib (TARCEVA); cetuximab (ERBITUX); lapatinib (TYKERB);
panitumumab (VECTIBIX); vandetanib (CAPRELSA); afatinib/BIBW2992;
CI-1033/canertinib; neratinib/HKI-272; CP-724714; TAK-285;
AST-1306; ARRY334543; ARRY-380; AG-1478; dacomitinib/PF299804;
OSI-420/desmethyl erlotinib; AZD8931; AEE726; pelitinib/EKB-569;
CUDC-101; WZ8040; WZ4002; WZ3146; AG-490; XL647; PD153035;
5-azathioprine; 5-aza-2'-deoxycytidine;
17-N-Allylamino-17-Demethoxygeldanamycin (17-AAG); 20-epi-1,25
dihydroxyvitamin D3; 5 ethynyluracil; and BMS-599626.
[0295] In one aspect is a method for treating patients with
colorectal cancer (optionally refractory) by administering an
obeticholic acid composition described herein in combination with
capecitabine and/or PLX4032 (Plexxikon).
[0296] In another aspect is a method for treating colorectal cancer
(optionally refractory) by administering an obeticholic acid
composition described herein in combination with capecitabine,
xeloda, and/or CPT-11.
[0297] In another aspect is a method for treating colorectal cancer
(optionally refractory) by administering an obeticholic acid
composition described herein in combination with capecitabine,
xeloda, and/or CPT-11.
[0298] In another aspect is a method for treating patients with
colorectal cancer (optionally refractory) or patients with
unresectable or metastatic colorectal carcinoma by administering an
obeticholic acid composition described herein in combination with
capecitabine and irinotecan.
[0299] In another aspect is a method for treating patients with
unresectable or metastatic hepatocellular carcinoma by
administering an obeticholic acid composition described herein in
combination with interferon alpha or capecitabin.
[0300] In another aspect is a method for treating patients with
pancreatic cancer by administering an obeticholic acid composition
described herein in combination with gemcitabine.
[0301] Patients described herein include a patients having a
disease or condition described herein. A patient can be described
or referred to by the condition treated. For example, a patient
having PBC can be referred to herein as a PBC patient. A patient
described herein can have a preexisting condition (e.g., a
condition other than the disease or condition treated by the
obeticholic acid composition described herein that existed at the
time of first administration). In one instance a patient described
herein has hepatic impairment. In another instance a patient
described herein has renal impairment. In yet another instance the
patient is an elderly/geriatric patient or a pregnant patient. In
another instance the patient is an pediatric patient.
[0302] In some embodiments, administration of an obeticholic acid
composition described herein together with certain contra-active
agents can result in (1) decreased efficacy of the obeticholic acid
composition and/or (2) development of toxicity or adverse effects
described herein. For example, administration of an obeticholic
acid composition described herein with blood clotting and
anti-coagulation agents can result in decreased International
Normalized Ratio (INR). In certain instances, coagulation and
anti-coagulation agents can be administered in combination with an
obeticholic acid composition described herein by monitoring
fluctuations of the INR of the patient and adjusting dosages as
understood in the art to maintain proper INR.
[0303] In another example, administration of an obeticholic acid
composition described herein in combination with a bile acid
binding resin (e.g., cholestyramine, colestipol, or colesevelam)
can result in decreased efficacy of the obeticholic acid
composition at a lower dosage of the composition (e.g., 1 to 5 mg).
In certain embodiments, a bile acid binding resin is administered
in combination with an obeticholic acid composition described
herein at least about 4 to 6 hours before or after the dosage of
the obeticholic acid composition.
[0304] In one embodiment, the compositions described herein reduce
adverse effects associated with other formulations (e.g., larger
particle sized obeticholic acid). For example, an obeticholic acid
composition described herein when administered to a patient
described herein for a condition or disease described herein can
reduce one or more adverse effects selected from Hepatic
encephalopathy, ascites, variceal bleeding, skin eruptions,
prurigo, pruritus (including generalized, eye, anal, vulvovaginal
and rash), fatigue, asthenia, abdominal pain (including upper and
lower pain and tenderness), abdominal discomfort, gastrointestinal
pain, dizziness, urticaria (including cholinergic), rashes
(including macular, popular, maculo-papular, and heat rashes),
arthralgia, oropharyngeal pain, cough, constipation, edemal
peripheral, palpitations, pyrexia, eczema, and procedural pain. In
certain instances, the one or more adverse effects that are reduced
include pruritus. It was discovered, inter alia, that titration of
an obeticholic acid composition described herein can reduce the
incidence of or mean time until onset of severe pruritus.
[0305] In another embodiment, the obeticholic acid compositions
described herein include reduced levels of impurities commonly
found in the synthesis of obeticholic acid.
6.alpha.-ethylursodeoxycholic acid (6-EUDCA),
3.alpha.-hydroxy-6.alpha.-ethyl-7-keto-5.beta.-cholan-24-oic acid,
6.beta.-ethylchenodeoxycholic acid;
3.alpha.,7.alpha.-dihydroxy-6.beta.-ethyl-5.beta.-cholan-24-oic
acid, 3.alpha.,7.alpha.-dihydroxy-6-ethyliden-5.beta.-cholan-24-oic
acid, Chenodeoxycholic acid (CDCA);
3.alpha.,7.alpha.-dihydroxy-5.beta.-cholan-24-oic acid, Dimer of
OCA,
3.alpha.-(3.alpha.,7.alpha.-dihydroxy-6.alpha.-ethyl-5.beta.-cholan-24-oy-
loxy)-7.alpha.-hydroxy-6.alpha.-ethyl-5.beta.-cholan-24-oic acid,
or 3.alpha.-O-Acetyl-6.alpha.-ethylchenodeoxycholic acid;
3.alpha.-O-acetyl-7.alpha.-hydroxy-6.alpha.-ethyl-5.beta.-cholan-24-oic
acid.
[0306] All publications and patent documents cited herein are
incorporated herein by reference as if each such publication or
document was specifically and individually indicated to be
incorporated herein by reference. Citation of publications and
patent documents is not intended as an admission that any is
pertinent prior art, nor does it constitute any admission as to the
contents or date of the same. The disclosure having now been
described by way of written description, those of skill in the art
will recognize that the disclosure can be practiced in a variety of
embodiments and that the foregoing description and examples below
are for purposes of illustration and not limitation of the claims
that follow.
SELECTED EMBODIMENTS
Embodiment 1
[0307] A method of treating primary biliary cirrhosis (PBC) in a
patient in need thereof, the method comprising administering a
composition comprising obeticholic acid, or a pharmaceutically
acceptable salt, ester, or amino acid conjugate thereof, wherein
obeticholic acid or a pharmaceutically acceptable salt, ester, or
amino acid conjugate thereof is in the form of particles, and
wherein at least 50% of the particles have a diameter of 200 .mu.m
or less.
Embodiment 2
[0308] A method of treating primary sclerosing cholangitis (PSC),
chronic liver disease, nonalcoholic fatty liver disease (NAFLD),
nonalcoholic steatohepatitis (NASH), hepatitis C infection,
alcoholic liver disease, liver damage due to progressive fibrosis,
or liver fibrosis in a patient in need thereof, the method
comprising administering a composition comprising obeticholic acid,
or a pharmaceutically acceptable salt, ester, or amino acid
conjugate thereof, wherein obeticholic acid or a pharmaceutically
acceptable salt, ester, or amino acid conjugate thereof is in the
form of particles, and wherein at least 50% of the particles have a
diameter of 200 .mu.m or less.
Embodiment 3
[0309] The method of embodiment 2, wherein the method comprises
treating NASH.
Embodiment 4
[0310] A method of treating a solid-tumor cancer in a patient in
need thereof, the method comprising administering an effective
amount of a composition comprising obeticholic acid, or a
pharmaceutically acceptable salt, ester, or amino acid conjugate
thereof, wherein obeticholic acid or a pharmaceutically acceptable
salt, ester, or amino acid conjugate thereof is in the form of
particles, and wherein at least 50% of the particles have a
diameter of 200 .mu.m or less.
Embodiment 5
[0311] The method of embodiment 1, 2 or 4, wherein the effective
amount comprises a starting dose.
Embodiment 6
[0312] The method of embodiment 5, wherein the starting dose is
administered in a titration period.
Embodiment 7
[0313] The method of any one of embodiments 4 to 6, wherein the
cancer comprises hepatocellular carcinoma (HCC), colorectal cancer,
gastric cancer, liver cancer, kidney cancer, or pancreatic
cancer.
Embodiment 8
[0314] A method of treating an autoimmune disease in a patient in
need thereof, the method comprising administering an effective
amount of a composition comprising obeticholic acid, or a
pharmaceutically acceptable salt, ester, or amino acid conjugate
thereof, wherein obeticholic acid or a pharmaceutically acceptable
salt, ester, or amino acid conjugate thereof is in the form of
particles, and wherein at least 50% of the particles have a
diameter of 200 .mu.m or less.
Embodiment 9
[0315] The method of embodiment 7, wherein the effective amount
comprises a starting dose.
Embodiment 10
[0316] The method of embodiment 8, wherein the starting dose is
administered in a titration period.
Embodiment 11
[0317] The method of embodiment 7 or 8, wherein the autoimmune
disease is selected from the group consisting of: PBC, multiple
sclerosis, rheumatoid arthritis, and type-I diabetes.
Embodiment 12
[0318] The method of any one of embodiments 1-2, 6 or 9, wherein
the titration period comprises 1 to 6 months.
Embodiment 13
[0319] The method of embodiment 11, wherein the titration period is
3 months.
Embodiment 14
[0320] The method of embodiment 11, wherein the titration period is
6 months.
Embodiment 15
[0321] The method of any one of embodiments 12 to 15, wherein the
starting dose is administered to the patient once daily.
Embodiment 16
[0322] The method of any one of embodiments 11 to 14, wherein the
starting dose is administered to the patient once daily.
Embodiment 17
[0323] The method of any one of embodiments 11 to 14, wherein the
starting dose is administered to the patient once weekly.
Embodiment 18
[0324] The method of any one of embodiments 11 to 14, wherein the
starting dose is administered to the patient once every other
day.
Embodiment 19
[0325] The method of any one of embodiments 11 to 17, wherein the
starting dose comprises about 1 mg to 50 mg.
Embodiment 20
[0326] The method of any one of embodiments 11 to 17, wherein the
starting dose comprises about 1 mg to 25 mg.
Embodiment 21
[0327] The method of any one of embodiments 11 to 17, wherein the
starting dose comprises about 1 mg to 10 mg.
Embodiment 22
[0328] The method of any one of embodiments 11 to 17, wherein the
starting dose comprises about 1 mg to 5 mg.
Embodiment 23
[0329] The method of any one of embodiments 11 to 17, wherein the
starting dose comprises about 5 mg.
Embodiment 24
[0330] The method of any one of embodiments 11 to 17, wherein the
starting dose comprises about 10 mg.
Embodiment 25
[0331] The method of any one of embodiments 11 to 17, wherein the
starting dose comprises about 25 mg.
Embodiment 26
[0332] The method of any one of embodiments 11 to 17, wherein the
starting dose comprises about 50 mg.
Embodiment 27
[0333] The method of any one of embodiments 1 to 26, further
comprising assessing or monitoring liver function before, during,
or after the titration period.
Embodiment 28
[0334] The method of embodiment 27, wherein the assessing or
monitoring comprises measuring a level of one or more liver
biomarkers compared to a control.
Embodiment 29
[0335] The method of embodiment 28, wherein the liver biomarker is
selected from the group consisting of: AST, ALT, alkaline
phosphatase (ALP), bilirubin, glycine conjugated obeticholic acid,
taurine conjugated obeticholic acid, a bile acid, a bile acid
glycine conjugate, or a bile acid taurine conjugate.
Embodiment 30
[0336] The method of embodiment 29, comprising detecting a level of
ALP in the patient.
Embodiment 31
[0337] The method of embodiment 29 or 30, comprising detecting a
level of bilirubin in the patient.
Embodiment 32
[0338] The method of any one of embodiments 27 to 31, further
comprising calculating a AST to platelet ratio (APRI) for the
patient.
Embodiment 33
[0339] The method of any one of embodiments 12 to 32, wherein the
obeticholic acid composition is administered to the patient as an
adjusted dose after the titration period.
Embodiment 34
[0340] The method of embodiment 33, wherein the adjusted dose is
equal to the titrated dose.
Embodiment 35
[0341] The method of embodiment 33, wherein the adjusted dose is
equal to the starting dose when the level of ALP is reduced
compared to a control.
Embodiment 36
[0342] The method of embodiment 33, wherein the adjusted dose is
greater than the titrated dose.
Embodiment 37
[0343] The method of any one of embodiments 33 to 36, wherein the
adjusted dose is administered more frequently than the titrated
dose.
Embodiment 38
[0344] The method of any one of embodiments 33 to 36, wherein the
adjusted dose is administered less frequently than the titrated
dose.
Embodiment 39
[0345] The method of any one of embodiments 33 to 38, wherein the
adjusted dose of the obeticholic acid composition is administered
to the patient once daily.
Embodiment 40
[0346] The method of any one of embodiments 33 to 38, wherein the
adjusted dose of the obeticholic acid composition is administered
to the patient once daily.
Embodiment 41
[0347] The method of any one of embodiments 33 to 38, wherein the
adjusted dose of the obeticholic acid composition is administered
to the patient once daily.
Embodiment 42
[0348] The method of any one of embodiments 33 to 38, wherein the
adjusted dose of the obeticholic acid composition is administered
to the patient once weekly.
Embodiment 43
[0349] The method of any one of embodiments 33 to 38, wherein the
adjusted dose of the obeticholic acid composition is administered
to the patient once every other day.
Embodiment 44
[0350] The method of any one of embodiments 33 to 38, wherein the
adjusted dose of the obeticholic acid composition is administered
to the patient twice a week.
Embodiment 45
[0351] The method of any one of embodiments 33 to 44, wherein the
adjusted dose comprises about 1 mg to 50 mg.
Embodiment 46
[0352] The method of any one of embodiments 33 to 44, wherein the
adjusted dose comprises about 1 mg to 25 mg.
Embodiment 47
[0353] The method of any one of embodiments 33 to 44, wherein the
adjusted dose comprises about 1 mg to 10 mg.
Embodiment 48
[0354] The method of any one of embodiments 33 to 44, wherein the
adjusted dose comprises about 1 mg to 5 mg.
Embodiment 49
[0355] The method of any one of embodiments 33 to 44, wherein the
adjusted dose comprises about 5 mg.
Embodiment 50
[0356] The method of any one of embodiments 33 to 44, wherein the
adjusted dose comprises about 10 mg.
Embodiment 51
[0357] The method of any one of embodiments 33 to 44, wherein the
adjusted dose comprises about 25 mg.
Embodiment 52
[0358] The method of any one of embodiments 33 to 44, wherein the
adjusted dose comprises about 50 mg.
Embodiment 53
[0359] The method of any one of embodiments 1 to 52, wherein the
method further comprises administering one or more active agents,
or combinations thereof.
Embodiment 54
[0360] The method of embodiment 53, wherein the active agent is
ursodeoxycholic acid (UDCA).
Embodiment 55
[0361] The method of embodiment 53, wherein the active agent is a
peroxisome proliferator-activated receptor alpha (PPAR.alpha.)
agonist, a peroxisome proliferator-activated receptor delta
(PPAR.delta.) agonist, a dual PPAR.alpha./.delta. agonist, a dual
PPAR.alpha./.gamma. agonist, or pan-PPAR agonist, an HMG CoA
reductase inhibitor, a GLP1 agonist, insulin, insulin mimetic,
metformin, a GTP4 agonist, an HST2 inhibitor, a DPP-IV inhibitor,
an SGLT2 inhibitor or a hydroxysteroid dehydrogenase (HSD)
inhibitor, such as an 11.beta.-HSD1 inhibitor, an ASK1 inhibitor,
an ACC1 inhibitor, a NOX1 and/or NOX4 inhibitor, an inhibitor or
antagonist of one or more chemokine receptors, such as, for
example, CCR2 and CCR5.
Embodiment 56
[0362] The method of any one of embodiments 1 to 55, wherein the
obeticholic acid composition is administered as a first line
therapy for the treatment of PBC.
Embodiment 57
[0363] The method of any one of embodiments 1 to 56, wherein the
patient is has renal impairment or hepatic impairment.
Embodiment 58
[0364] A method for treating primary biliary cirrhosis (PBC) in a
patient in need thereof, the method comprising:
[0365] administering a starting dose of a composition comprising
obeticholic acid, or a pharmaceutically acceptable salt, ester, or
amino acid conjugate thereof, in a titration period, wherein
obeticholic acid or a pharmaceutically acceptable salt, ester, or
amino acid conjugate thereof is in the form of particles, and
wherein at least 50% of the particles have a diameter of 200 .mu.m
or less;
assessing liver function of the patient before, during, and after
the titration period by: calculating an AST to platelet ratio
(APRI) score for the patient; or measuring the level of one or more
liver biomarker selected from ALP, bilirubin, AST, ALT, glycine
conjugated obeticholic acid, taurine conjugated obeticholic acid, a
bile acid, a bile acid glycine conjugate, or a bile acid taurine
conjugate; wherein a reduced APRI score compared to a control or a
reduced level of the one or more liver biomarkers compared to a
control indicates non-impaired liver function; assessing tolerance
of the patient to the starting dose by grading the severity of one
or more adverse effects, if present; and administering an adjusted
dose of the obeticholic acid composition, wherein the adjusted dose
comprises an amount equal to or greater than an amount of the
starting dose.
Embodiment 59
[0366] The method of embodiment 58, wherein the adjusted dose is
administered at an amount equal to an amount of the starting
dose.
Embodiment 60
[0367] The method of embodiment 58, wherein the adjusted dose is
administered at an amount greater than an amount of the starting
dose.
Embodiment 61
[0368] The method of embodiment 58, wherein the adjusted dose of
the obeticholic acid composition is administered at the same
frequency as the starting dose.
Embodiment 62
[0369] The method of embodiment 58, wherein the adjusted dose of
the obeticholic acid composition is administered at a decreased
frequency than the starting dose.
Embodiment 63
[0370] The method of embodiment 58, wherein the effective amount of
the obeticholic acid composition is administered at an increased
frequency than the starting dose.
Embodiment 64
[0371] The method of any one of embodiments 58 to 63, wherein the
starting dose is 5 mg.
Embodiment 65
[0372] The method of any one of embodiments 58 to 64, wherein the
starting dose is administered QD.
Embodiment 66
[0373] The method of any one of embodiments 58 to 64, wherein the
adjusted dose is 5 mg.
Embodiment 67
[0374] The method of any one of embodiments 58 to 64, wherein the
adjusted dose is 10 mg.
Embodiment 68
[0375] The method of any one of embodiments 58 to 67, wherein the
adjusted dose is administered QD or Q2D.
Embodiment 69
[0376] The method of any one of embodiments 58 to 68, further
comprising assessing the patient for tolerance to the adjusted
dose.
Embodiment 70
[0377] The method of embodiment 69, wherein the adjusted dose is
modified to a re-adjusted dose when the patient.
Embodiment 71
[0378] The method of embodiment 70, wherein the re-adjusted dose
comprises an equal amount compared to the adjusted dose and
administration at a reduced frequency.
Embodiment 72
[0379] The method of embodiment 71, wherein the re-adjusted dose
comprises a reduced amount compared to the adjusted dose and
administration at an equal frequency.
Embodiment 73
[0380] The method of embodiment 58, wherein the patient has hepatic
impairment.
Embodiment 74
[0381] The method of embodiment 73, wherein the starting dose is
administered QW.
Embodiment 75
[0382] The method of embodiment 74, wherein the starting dose is 5
mg.
Embodiment 75
[0383] The method of any one of embodiments 58 to 75, wherein the
adjusted dose is equivalent to the starting dose when the level of
ALP is reduced compared to a control.
Embodiment 76
[0384] The method of any one of embodiments 58 to 75, wherein the
adjusted dose comprises an amount equal to the starting dose and
wherein the adjusted dose is administered at a greater frequency
than the starting dose.
Embodiment 77
[0385] A composition comprising obeticholic acid, or a
pharmaceutically acceptable salt, ester, or amino acid conjugate
thereof, wherein obeticholic acid or a pharmaceutically acceptable
salt, ester, or amino acid conjugate thereof is in the form of
particles, and wherein at least 50% of the particles have a
diameter of 200 .mu.m or less, for use in treating primary biliary
cirrhosis (PBC) in a patient in need thereof.
Embodiment 78
[0386] A composition comprising obeticholic acid, or a
pharmaceutically acceptable salt, ester, or amino acid conjugate
thereof, wherein obeticholic acid or a pharmaceutically acceptable
salt, ester, or amino acid conjugate thereof is in the form of
particles, and wherein at least 50% of the particles have a
diameter of 200 .mu.m or less, for use in treating primary biliary
cirrhosis (PBC) in a patient in need thereof.
Embodiment 79
[0387] A composition comprising obeticholic acid, or a
pharmaceutically acceptable salt, ester, or amino acid conjugate
thereof, wherein obeticholic acid or a pharmaceutically acceptable
salt, ester, or amino acid conjugate thereof is in the form of
particles, and wherein at least 50% of the particles have a
diameter of 200 .mu.m or less, for use in treating primary
sclerosing cholangitis (PSC), chronic liver disease, nonalcoholic
fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH),
hepatitis C infection, alcoholic liver disease, liver damage due to
progressive fibrosis, or liver fibrosis in a patient in need
thereof in a patient in need thereof.
Embodiment 80
[0388] The composition of embodiment 79, for use in treating
NASH.
Embodiment 81
[0389] A composition comprising obeticholic acid, or a
pharmaceutically acceptable salt, ester, or amino acid conjugate
thereof, wherein obeticholic acid or a pharmaceutically acceptable
salt, ester, or amino acid conjugate thereof is in the form of
particles, and wherein at least 50% of the particles have a
diameter of 200 .mu.m or less, for use in treating a solid-tumor
cancer in a patient in need thereof.
Embodiment 82
[0390] The composition of embodiments 77, 79 or 81, wherein said
composition further comprises said obeticholic acid composition as
a starting dose.
Embodiment 83
[0391] The composition of embodiment 82, wherein said starting dose
is prepared to be administered in a titration period.
Embodiment 84
[0392] The composition of any one of embodiments 81 to 83, for use
in treating hepatocellular carcinoma (HCC), colorectal cancer,
gastric cancer, liver cancer, kidney cancer, or pancreatic
cancer.
Embodiment 85
[0393] A composition comprising obeticholic acid, or a
pharmaceutically acceptable salt, ester, or amino acid conjugate
thereof, wherein obeticholic acid or a pharmaceutically acceptable
salt, ester, or amino acid conjugate thereof is in the form of
particles, and wherein at least 50% of the particles have a
diameter of 200 .mu.m or less, for use in treating an autoimmune
disease in a patient in need thereof.
Embodiment 86
[0394] The composition of embodiment 85, wherein said composition
further comprises said obeticholic acid composition as a starting
dose.
Embodiment 87
[0395] The composition of embodiment 86, wherein said starting dose
is prepared to be administered in a titration period.
Embodiment 88
[0396] The composition of embodiment 85 or 86, for use in treating
multiple sclerosis, rheumatoid arthritis, or type-I diabetes.
Embodiment 89
[0397] The composition of any one of embodiments 78-79, 83 or 87,
wherein said titration period comprises 1 to 6 months.
Embodiment 90
[0398] The composition of embodiment 89, wherein said titration
period is 3 months.
Embodiment 91
[0399] The composition of embodiment 89, wherein said titration
period is 6 months.
Embodiment 92
[0400] The composition of any one of embodiments 89 to 91, wherein
said starting dose is prepared to be administered to said patient
once daily.
Embodiment 93
[0401] The composition of any one of embodiments 89 to 92, wherein
said starting dose is prepared to be administered to said patient
once daily.
Embodiment 94
[0402] The composition of any one of embodiments 89 to 92, wherein
said starting dose is prepared to be administered to said patient
once weekly.
Embodiment 95
[0403] The composition of any one of embodiments 89 to 92, wherein
said starting dose is prepared to be administered to said patient
once every other day.
Embodiment 96
[0404] The composition of any one of embodiments 89 to 95, wherein
said starting dose comprises about 1 mg to 50 mg.
Embodiment 97
[0405] The composition of any one of embodiments 89 to 95, wherein
said starting dose comprises about 1 mg to 25 mg.
Embodiment 98
[0406] The composition of any one of embodiments 89 to 95, wherein
said starting dose comprises about 1 mg to 10 mg.
Embodiment 99
[0407] The composition of any one of embodiments 89 to 95, wherein
said starting dose comprises about 1 mg to 5 mg.
Embodiment 100
[0408] The composition of any one of embodiments 89 to 95, wherein
said starting dose comprises about 5 mg.
Embodiment 101
[0409] The composition of any one of embodiments 89 to 95, wherein
said starting dose comprises about 10 mg.
Embodiment 102
[0410] The composition of any one of embodiments 89 to 95, wherein
said starting dose comprises about 25 mg.
Embodiment 103
[0411] The composition of any one of embodiments 89 to 95, wherein
said starting dose comprises about 50 mg.
Embodiment 104
[0412] The composition of any one of embodiments 78 to 103, wherein
said patient liver function assessed or monitored before, during,
or after said titration period.
Embodiment 105
[0413] The composition of embodiment 104, wherein said assessing or
monitoring comprises measuring a level of one or more liver
biomarkers compared to a control.
Embodiment 106
[0414] The composition of embodiment 105, wherein said liver
biomarker is selected from the group consisting of: AST, ALT,
alkaline phosphatase (ALP), bilirubin, glycine conjugated
obeticholic acid, taurine conjugated obeticholic acid, a bile acid,
a bile acid glycine conjugate, or a bile acid taurine
conjugate.
Embodiment 107
[0415] The composition of embodiment 106, wherein said liver
biomarker is ALP.
Embodiment 108
[0416] The composition of embodiment 106 or 107, wherein said liver
biomarker is bilirubin.
Embodiment 109
[0417] The composition of any one of embodiments 104 to 108,
further comprising calculating an AST to platelet ratio (APRI) for
said patient.
Embodiment 110
[0418] The composition of any one of embodiments 89 to 109, wherein
said obeticholic acid composition is prepared to be administered to
said patient as an adjusted dose after said titration period.
Embodiment 111
[0419] The composition of embodiment 110, wherein said adjusted
dose is equal to said titrated dose.
Embodiment 112
[0420] The composition of embodiment 110, wherein said adjusted
dose is equal to said starting dose when a level of ALP is reduced
compared to a control.
Embodiment 113
[0421] The composition of embodiment 110, wherein said adjusted
dose is greater than said titrated dose.
Embodiment 114
[0422] The composition of any one of embodiments 110 to 113,
wherein said adjusted dose is prepared to be administered more
frequently than said titrated dose.
Embodiment 115
[0423] The composition of any one of embodiments 110 to 113,
wherein said adjusted dose is prepared to be administered less
frequently than said titrated dose.
Embodiment 116
[0424] The composition of any one of embodiments 110 to 115,
wherein said adjusted dose of said obeticholic acid composition is
prepared to be administered to said patient once daily.
Embodiment 117
[0425] The composition of any one of embodiments 110 to 115,
wherein said adjusted dose of said obeticholic acid composition is
prepared to be administered to said patient once daily.
Embodiment 118
[0426] The composition of any one of embodiments 110 to 115,
wherein said adjusted dose of said obeticholic acid composition is
prepared to be administered to said patient once daily.
Embodiment 119
[0427] The composition of any one of embodiments 110 to 115,
wherein said adjusted dose of said obeticholic acid composition is
prepared to be administered to said patient once weekly.
Embodiment 120
[0428] The composition of any one of embodiments 110 to 115,
wherein said adjusted dose of said obeticholic acid composition is
prepared to be administered to said patient once every other
day.
Embodiment 121
[0429] The composition of any one of embodiments 110 to 115,
wherein said adjusted dose of said obeticholic acid composition is
prepared to be administered to said patient twice a week.
Embodiment 122
[0430] The composition of any one of embodiments 110 to 121,
wherein said adjusted dose comprises about 1 mg to 50 mg.
Embodiment 123
[0431] The composition of any one of embodiments 110 to 121,
wherein said adjusted dose comprises about 1 mg to 25 mg.
Embodiment 124
[0432] The composition of any one of embodiments 110 to 121,
wherein said adjusted dose comprises about 1 mg to 10 mg.
Embodiment 125
[0433] The composition of any one of embodiments 110 to 121,
wherein said adjusted dose comprises about 1 mg to 5 mg.
Embodiment 126
[0434] The composition of any one of embodiments 110 to 121,
wherein said adjusted dose comprises about 5 mg.
Embodiment 127
[0435] The composition of any one of embodiments 110 to 121,
wherein said adjusted dose comprises about 10 mg.
Embodiment 128
[0436] The composition of any one of embodiments 110 to 121,
wherein said adjusted dose comprises about 25 mg.
Embodiment 129
[0437] The composition of any one of embodiments 110 to 121,
wherein said adjusted dose comprises about 50 mg.
Embodiment 130
[0438] The composition of any one of embodiments 78 to 129, wherein
said obeticholic acid composition is prepared to be co-administered
one or more active agents, or combinations thereof.
Embodiment 131
[0439] The composition of embodiment 130, wherein said active agent
is ursodeoxycholic acid (UDCA).
Embodiment 132
[0440] The composition of embodiment 130, wherein the active agent
is a peroxisome proliferator-activated receptor alpha (PPAR.alpha.)
agonist, a peroxisome proliferator-activated receptor delta
(PPAR.delta.) agonist, a dual PPAR.alpha./.delta. agonist, a dual
PPAR.alpha./.gamma. agonist, or pan-PPAR agonist, an HMG CoA
reductase inhibitor, a GLP1 agonist, insulin, insulin mimetic,
metformin, a GTP4 agonist, an HST2 inhibitor, a DPP-IV inhibitor,
an SGLT2 inhibitor or a hydroxysteroid dehydrogenase (HSD)
inhibitor, such as an 11.beta.-HSD1 inhibitor, an ASK1 inhibitor,
an ACC1 inhibitor, a NOX1 and/or NOX4 inhibitor, an inhibitor or
antagonist of one or more chemokine receptors, such as, for
example, CCR2 and CCR5.
Embodiment 133
[0441] The composition of any one of embodiments 78 to 132, wherein
said obeticholic acid composition is prepared to be administered as
a first line therapy for the treatment of PBC.
Embodiment 134
[0442] The composition of any one of embodiments 78 to 133, wherein
said patient is has renal impairment or hepatic impairment.
Embodiment 135
[0443] A composition comprising a starting dose of obeticholic
acid, or a pharmaceutically acceptable salt, ester, or amino acid
conjugate thereof, wherein obeticholic acid or a pharmaceutically
acceptable salt, ester, or amino acid conjugate thereof is in the
form of particles, and wherein at least 50% of the particles have a
diameter of 200 .mu.m or less for use in treating primary biliary
cirrhosis (PBC) in a patient in need thereof wherein the
composition is prepared to be administered in a titration period
wherein
[0444] the liver function of the patient is assessed before,
during, and after said titration period by calculating an AST to
platelet ratio (APRI) score for said patient or by measuring the
level of one or more liver biomarker selected from ALP, bilirubin,
AST, ALT, glycine conjugated obeticholic acid, taurine conjugated
obeticholic acid, a bile acid, a bile acid glycine conjugate, or a
bile acid taurine conjugate, wherein a reduced APRI score compared
to a control or a reduced level of said one or more liver
biomarkers compared to a control indicates non-impaired liver
function; and
[0445] the tolerance of the patient to said starting dose is
assessed by grading the severity of one or more adverse effects, if
present; and the obeticholic acid composition is prepared to be
administered as an adjusted dose, wherein said adjusted dose
comprises an amount equal to or greater than an amount of said
starting dose.
Embodiment 136
[0446] The composition of embodiment 135, wherein said adjusted
dose is prepared to be administered at an amount equal to an amount
of said starting dose.
Embodiment 137
[0447] The composition of embodiment 135, wherein said adjusted
dose is prepared to be administered at an amount greater than an
amount of said starting dose.
Embodiment 138
[0448] The composition of embodiment 135, wherein said adjusted
dose of said obeticholic acid composition is prepared to be
administered at the same frequency as said starting dose.
Embodiment 139
[0449] The composition of embodiment 135, wherein said adjusted
dose of said obeticholic acid composition is prepared to be
administered at a decreased frequency than said starting dose.
Embodiment 140
[0450] The composition of embodiment 135, wherein said effective
amount of said obeticholic acid composition is prepared to be
administered at an increased frequency than said starting dose.
Embodiment 141
[0451] The composition of any one of embodiments 135 to 140,
wherein said starting dose is 5 mg.
Embodiment 142
[0452] The composition of any one of embodiments 135 to 141,
wherein said starting dose is prepared to be administered QD.
Embodiment 143
[0453] The composition of any one of embodiments 135 to 141,
wherein said adjusted dose is 5 mg.
Embodiment 144
[0454] The composition of any one of embodiments 135 to 141,
wherein said adjusted dose is 10 mg.
Embodiment 145
[0455] The composition of any one of embodiments 135 to 144,
wherein said adjusted dose is prepared to be administered QD or
Q2D.
Embodiment 146
[0456] The composition of any one of embodiments 135 to 145,
wherein said patient is assessed for tolerance to said adjusted
dose.
Embodiment 147
[0457] The composition of embodiment 146, wherein said adjusted
dose is modified to a re-adjusted dose.
Embodiment 148
[0458] The composition of embodiment 147, wherein said re-adjusted
dose comprises an equal amount compared to said adjusted dose and
is prepared to be administrated at a reduced frequency.
Embodiment 149
[0459] The composition of embodiment 148, wherein said re-adjusted
dose comprises a reduced amount compared to said adjusted dose and
is prepared to be administrated at an equal frequency.
Embodiment 150
[0460] The composition of embodiment 135, wherein said patient has
hepatic impairment.
Embodiment 151
[0461] The composition of embodiment 150, wherein said starting
dose is prepared to be administered QW.
Embodiment 152
[0462] The composition of embodiment 151, wherein said starting
dose is 5 mg.
Embodiment 153
[0463] The composition of any one of embodiments 135 to 152,
wherein said adjusted dose is equivalent to said starting dose when
said level of ALP is reduced compared to a control.
Embodiment 154
[0464] The composition of any one of embodiments 135 to 152,
wherein said adjusted dose comprises an amount equal to said
starting dose and wherein said adjusted dose is prepared to be
administered at a greater frequency than said starting dose.
Embodiment 155
[0465] Use of a composition comprising obeticholic acid, or a
pharmaceutically acceptable salt, ester, or amino acid conjugate
thereof, wherein obeticholic acid or a pharmaceutically acceptable
salt, ester, or amino acid conjugate thereof is in the form of
particles, and wherein at least 50% of the particles have a
diameter of 200 .mu.m or less, for the manufacture of a medicament
for use in treating primary biliary cirrhosis (PBC) in a patient in
need thereof.
Embodiment 156
[0466] Use of a composition comprising obeticholic acid, or a
pharmaceutically acceptable salt, ester, or amino acid conjugate
thereof, wherein obeticholic acid or a pharmaceutically acceptable
salt, ester, or amino acid conjugate thereof is in the form of
particles, and wherein at least 50% of the particles have a
diameter of 200 .mu.m or less, for the manufacture of a medicament
for use in treating primary sclerosing cholangitis (PSC), chronic
liver disease, nonalcoholic fatty liver disease (NAFLD),
nonalcoholic steatohepatitis (NASH), hepatitis C infection,
alcoholic liver disease, liver damage due to progressive fibrosis,
or liver fibrosis in a patient in need thereof in a patient in need
thereof.
Embodiment 157
[0467] The use of embodiment 156, for use in treating NASH.
Embodiment 158
[0468] Use of a composition comprising obeticholic acid, or a
pharmaceutically acceptable salt, ester, or amino acid conjugate
thereof, wherein obeticholic acid or a pharmaceutically acceptable
salt, ester, or amino acid conjugate thereof is in the form of
particles, and wherein at least 50% of the particles have a
diameter of 200 .mu.m or less, for the manufacture of a medicament
for use in treating a solid-tumor cancer in a patient in need
thereof.
Embodiment 159
[0469] The use of embodiments 155, 156 or 158, wherein said
composition further comprises said obeticholic acid composition as
a starting dose.
Embodiment 160
[0470] The use of embodiment 159, wherein said starting dose is
prepared to be administered in a titration period.
Embodiment 161
[0471] The use of any one of embodiments 158 to 160, wherein said
cancer is hepatocellular carcinoma (HCC), colorectal cancer,
gastric cancer, liver cancer, kidney cancer, or pancreatic
cancer.
Embodiment 162
[0472] Use of a composition comprising obeticholic acid, or a
pharmaceutically acceptable salt, ester, or amino acid conjugate
thereof, wherein obeticholic acid or a pharmaceutically acceptable
salt, ester, or amino acid conjugate thereof is in the form of
particles, and wherein at least 50% of the particles have a
diameter of 200 .mu.m or less, for the manufacture of a medicament
for use in treating an autoimmune disease in a patient in need
thereof.
Embodiment 163
[0473] The use of embodiment 162, wherein said said obeticholic
acid composition is prepared to be administered as a starting
dose.
Embodiment 164
[0474] The use of embodiment 163, wherein said starting dose is
prepared to be administered in a titration period.
Embodiment 165
[0475] The use of embodiment 162 or 163, wherein said autoimmune
disease is multiple sclerosis, rheumatoid arthritis, or type-I
diabetes.
Embodiment 166
[0476] The use of any one of embodiments 155-156, 160 or 164,
wherein said titration period comprises 1 to 6 months.
Embodiment 167
[0477] The use of embodiment 166, wherein said titration period is
3 months.
Embodiment 168
[0478] The use of embodiment 166, wherein said titration period is
6 months.
Embodiment 169
[0479] The use of any one of embodiments 166 to 168, wherein said
starting dose is prepared to be administered to said patient once
daily.
Embodiment 170
[0480] The use of any one of embodiments 166 to 169, wherein said
starting dose is prepared to be administered to said patient once
daily.
Embodiment 171
[0481] The use of any one of embodiments 166 to 169, wherein said
starting dose is prepared to be administered to said patient once
weekly.
Embodiment 172
[0482] The use of any one of embodiments 166 to 169, wherein said
starting dose is prepared to be administered to said patient once
every other day.
Embodiment 173
[0483] The use of any one of embodiments 166 to 172, wherein said
starting dose comprises about 1 mg to 50 mg.
Embodiment 174
[0484] The use of any one of embodiments 166 to 172, wherein said
starting dose comprises about 1 mg to 25 mg.
Embodiment 175
[0485] The use of any one of embodiments 166 to 172, wherein said
starting dose comprises about 1 mg to 10 mg.
Embodiment 176
[0486] The use of any one of embodiments 166 to 172, wherein said
starting dose comprises about 1 mg to 5 mg.
Embodiment 177
[0487] The use of any one of embodiments 166 to 172, wherein said
starting dose comprises about 5 mg.
Embodiment 178
[0488] The use of any one of embodiments 166 to 172, wherein said
starting dose comprises about 10 mg.
Embodiment 179
[0489] The use of any one of embodiments 166 to 172, wherein said
starting dose comprises about 25 mg.
Embodiment 180
[0490] The use of any one of embodiments 166 to 172, wherein said
starting dose comprises about 50 mg.
Embodiment 181
[0491] The use of any one of embodiments 155 to 180, wherein liver
function of said patient is assessed or monitored before, during,
or after said titration period.
Embodiment 182
[0492] The use of embodiment 181, wherein said assessing or
monitoring comprises measuring a level of one or more liver
biomarkers compared to a control.
Embodiment 183
[0493] The use of embodiment 182, wherein said liver biomarker is
selected from the group consisting of: AST, ALT, alkaline
phosphatase (ALP), bilirubin, glycine conjugated obeticholic acid,
taurine conjugated obeticholic acid, a bile acid, a bile acid
glycine conjugate, or a bile acid taurine conjugate.
Embodiment 184
[0494] The use of embodiment 183, wherein said liver biomarker is
ALP.
Embodiment 185
[0495] The use of embodiment 183 or 184, wherein said liver
biomarker is bilirubin.
Embodiment 186
[0496] The use of any one of embodiments 181 to 185, further
comprising calculating an AST to platelet ratio (APRI) for said
patient.
Embodiment 187
[0497] The use of any one of embodiments 166 to 186, wherein said
obeticholic acid composition is prepared to be administered to said
patient as an adjusted dose after said titration period.
Embodiment 188
[0498] The use of embodiment 187, wherein said adjusted dose is
equal to said titrated dose.
Embodiment 189
[0499] The use of embodiment 187, wherein said adjusted dose is
equal to said starting dose when a level of ALP is reduced compared
to a control.
Embodiment 190
[0500] The use of embodiment 187, wherein said adjusted dose is
greater than said titrated dose.
Embodiment 191
[0501] The use of any one of embodiments 187 to 190, wherein said
adjusted dose is prepared to be administered more frequently than
said titrated dose.
Embodiment 192
[0502] The use of any one of embodiments 187 to 190, wherein said
adjusted dose is prepared to be administered less frequently than
said titrated dose.
Embodiment 193
[0503] The use of any one of embodiments 187 to 192, wherein said
adjusted dose of said obeticholic acid composition is prepared to
be administered to said patient once daily.
Embodiment 194
[0504] The use of any one of embodiments 187 to 192, wherein said
adjusted dose of said obeticholic acid composition is prepared to
be administered to said patient once daily.
Embodiment 195
[0505] The use of any one of embodiments 187 to 192, wherein said
adjusted dose of said obeticholic acid composition is prepared to
be administered to said patient once daily.
Embodiment 196
[0506] The use of any one of embodiments 187 to 192, wherein said
adjusted dose of said obeticholic acid composition is prepared to
be administered to said patient once weekly.
Embodiment 197
[0507] The use of any one of embodiments 187 to 192, wherein said
adjusted dose of said obeticholic acid composition is prepared to
be administered to said patient once every other day.
Embodiment 198
[0508] The use of any one of embodiments 187 to 192, wherein said
adjusted dose of said obeticholic acid composition is prepared to
be administered to said patient twice a week.
Embodiment 199
[0509] The use of any one of embodiments 187 to 198, wherein said
adjusted dose comprises about 1 mg to 50 mg.
Embodiment 200
[0510] The use of any one of embodiments 187 to 198, wherein said
adjusted dose comprises about 1 mg to 25 mg.
Embodiment 201
[0511] The use of any one of embodiments 187 to 198, wherein said
adjusted dose comprises about 1 mg to 10 mg.
Embodiment 202
[0512] The use of any one of embodiments 187 to 198, wherein said
adjusted dose comprises about 1 mg to 5 mg.
Embodiment 203
[0513] The use of any one of embodiments 187 to 198, wherein said
adjusted dose comprises about 5 mg.
Embodiment 204
[0514] The use of any one of embodiments 187 to 198, wherein said
adjusted dose comprises about 10 mg.
Embodiment 205
[0515] The use of any one of embodiments 187 to 198, wherein said
adjusted dose comprises about 25 mg.
Embodiment 206
[0516] The use of any one of embodiments 187 to 198, wherein said
adjusted dose comprises about 50 mg.
Embodiment 207
[0517] The use of any one of embodiments 155 to 206, wherein said
obeticholic acid composition is prepared to be administered in
combination with one or more active agents, or combinations
thereof.
Embodiment 208
[0518] The use of embodiment 207, wherein said active agent is
ursodeoxycholic acid (UDCA).
Embodiment 209
[0519] The use of embodiment 207, wherein the active agent is a
peroxisome proliferator-activated receptor alpha (PPAR.alpha.)
agonist, a peroxisome proliferator-activated receptor delta
(PPAR.delta.) agonist, a dual PPAR.alpha./.delta. agonist, a dual
PPAR.alpha./.gamma. agonist, or pan-PPAR agonist, an HMG CoA
reductase inhibitor, a GLP1 agonist, insulin, insulin mimetic,
metformin, a GTP4 agonist, an HST2 inhibitor, a DPP-IV inhibitor,
an SGLT2 inhibitor or a hydroxysteroid dehydrogenase (HSD)
inhibitor, such as an 11.beta.-HSD1 inhibitor, an ASK1 inhibitor,
an ACC1 inhibitor, a NOX1 and/or NOX4 inhibitor, an inhibitor or
antagonist of one or more chemokine receptors, such as, for
example, CCR2 and CCR5.
Embodiment 210
[0520] The use of any one of embodiments 155 to 209, wherein said
obeticholic acid composition is prepared to be administered as a
first line therapy for the treatment of PBC.
Embodiment 211
[0521] The use of any one of embodiments 155 to 210, wherein said
patient is has renal impairment or hepatic impairment.
Embodiment 212
[0522] The use of a composition comprising a starting dose of
obeticholic acid, or a pharmaceutically acceptable salt, ester, or
amino acid conjugate thereof, wherein obeticholic acid or a
pharmaceutically acceptable salt, ester, or amino acid conjugate
thereof is in the form of particles, and wherein at least 50% of
the particles have a diameter of 200 .mu.m or less for use in
treating primary biliary cirrhosis (PBC) in a patient in need
thereof wherein the composition is prepared to be administered in a
titration period wherein:
the liver function of the patient is assessed before, during, and
after said titration period by calculating an AST to platelet ratio
(APRI) score for said patient or by measuring the level of one or
more liver biomarker selected from ALP, bilirubin, AST, ALT,
glycine conjugated obeticholic acid, taurine conjugated obeticholic
acid, a bile acid, a bile acid glycine conjugate, or a bile acid
taurine conjugate, wherein a reduced APRI score compared to a
control or a reduced level of said one or more liver biomarkers
compared to a control indicates non-impaired liver function; and
the tolerance of the patient to said starting dose is assessed by
grading the severity of one or more adverse effects, if present;
and the obeticholic acid composition is prepared to be administered
as an adjusted dose, wherein said adjusted dose comprises an amount
equal to or greater than an amount of said starting dose.
Embodiment 213
[0523] The use of embodiment 212, wherein said adjusted dose is
prepared to be administered at an amount equal to an amount of said
starting dose.
Embodiment 214
[0524] The use of embodiment 212, wherein said adjusted dose is
prepared to be administered at an amount greater than an amount of
said starting dose.
Embodiment 215
[0525] The use of embodiment 212, wherein said adjusted dose of
said obeticholic acid composition is prepared to be administered at
the same frequency as said starting dose.
Embodiment 216
[0526] The use of embodiment 212, wherein said adjusted dose of
said obeticholic acid composition is prepared to be administered at
a decreased frequency than said starting dose.
Embodiment 217
[0527] The use of embodiment 212, wherein said effective amount of
said obeticholic acid composition is prepared to be administered at
an increased frequency than said starting dose.
Embodiment 218
[0528] The use of any one of embodiments 212 to 217, wherein said
starting dose is 5 mg.
Embodiment 219
[0529] The use of any one of embodiments 212 to 218, wherein said
starting dose is prepared to be administered QD.
Embodiment 220
[0530] The use of any one of embodiments 212 to 218, wherein said
adjusted dose is 5 mg.
Embodiment 221
[0531] The use of any one of embodiments 212 to 218, wherein said
adjusted dose is 10 mg.
Embodiment 222
[0532] The use of any one of embodiments 212 to 221, wherein said
adjusted dose is prepared to be administered QD or Q2D.
Embodiment 223
[0533] The use of any one of embodiments 212 to 222, wherein said
patient is assessed for tolerance to said adjusted dose.
Embodiment 224
[0534] The use of embodiment 223, wherein said adjusted dose is
modified to a re-adjusted dose.
Embodiment 225
[0535] The use of embodiment 224, wherein said re-adjusted dose
comprises an equal amount compared to said adjusted dose and is
prepared to be administrated at a reduced frequency.
Embodiment 226
[0536] The use of embodiment 225, wherein said re-adjusted dose
comprises a reduced amount compared to said adjusted dose and is
prepared to be administrated at an equal frequency.
Embodiment 227
[0537] The use of embodiment 212, wherein said patient has hepatic
impairment.
Embodiment 228
[0538] The use of embodiment 227, wherein said starting dose is
prepared to be administered QW.
Embodiment 229
[0539] The use of embodiment 228, wherein said starting dose is 5
mg.
Embodiment 230
[0540] The use of any one of embodiments 212 to 229, wherein said
adjusted dose is equivalent to said starting dose when said level
of ALP is reduced compared to a control.
Embodiment 231
[0541] The use of any one of embodiments 212 to 229, wherein said
adjusted dose comprises an amount equal to said starting dose and
wherein said adjusted dose is prepared to be administered at a
greater frequency than said starting dose.
EXAMPLES
[0542] The disclosure is further illustrated by the following
examples, which are not to be construed as limiting this disclosure
in scope or spirit to the specific procedures herein described. It
is to be understood that the examples are provided to illustrate
certain embodiments and that no limitation to the scope of the
disclosure is intended. It is to be further understood that resort
may be had to various other embodiments, modifications, and
equivalents thereof which may suggest themselves to those skilled
in the art without departing from the spirit of the present
disclosure and/or scope of the appended claims.
Example 1: Particle Size Analysis
[0543] 5 mg tablet and 10 mg tablet formulations of obeticholic
acid (OCA or INT-747) demonstrated a slow dissolution release
profile. Particle size of agglomeration was identified as playing a
primary role in the release rate and dissolution and variability in
the blend uniformity and content uniformity of the tablet
formulations. In order to obtain an appropriate particle size
distribution (PSD), milling of obeticholic acid was investigated.
The particle size of the formulations was reduced using comilling
and jet milling to improve its dissolution release profile.
Particle size analysis was performed using a dry dispersion method
and analyzed by laser diffraction using Sympatec equipment.
[0544] Particle size distribution was assessed using a dry
dispersion method analyzed by laser diffraction using a Sympatec
Laser Helos/KF-Magic F71000 with Rodos Dispersing Unit. The OCA
sample (0.5 g sample) was tested as a dry powder. The parameters
for the validated particle size analysis method are described
below:
[0545] Apparatus: Sympatec Laser Helos/KF-Magic F71000 with Rodos
Dispersing Unit, Vibri sampling unit with Sniffer rotation, Nilfisk
exhaustion or equivalent.
[0546] Deionization apparatus: Sartorius or equivalent.
[0547] Measuring range: R3: 0.5/0.9 to 175 m.
[0548] Dispersing principle: Dry.
[0549] Pressure: 1.0 bar.
[0550] Feed rate: 80%.
[0551] Feed height: 2 mm.
[0552] Sniffer rotation: 20%.
[0553] Trigger conditions: Time base: 100 ms; Start:
Ka.28.gtoreq.1%; Stop: 1 s c.opt.ltoreq.1%.
[0554] Comilling. The use of a comil with different screen sizes
was evaluated. Three comil screens were utilized: 1.14 mm, 0.61 mm,
and 0.46 mm. The milled active pharmaceutical ingredient (API) was
evaluated for appearance, particle size distribution as well as
process yield. The process yield was difficult to determine
accurately, but as expected, a larger amount of milled drug product
was recovered from the larger screen sizes. The particle size
distribution of unmilled and comilled obeticholic acid is shown
below in Table 1.
TABLE-US-00001 TABLE 1 Particle size distribution of unmilled and
comilled obeticholic acid. Sample Description D.sub.10 D.sub.25
D.sub.50 D.sub.75 D.sub.90 D.sub.95 Unmilled API (no comil) 4.8
105.1 218.6 335.7 427.6 472.6 Unmilled API (no comil) 3.3 36.4
167.7 273.7 355.6 398.2 Comilled with 0.46 mm 5.7 122.9 217.5 283.0
335.1 360.3 screen Comilled with 0.61 mm 4.1 102.2 263.1 351.0
410.9 447.9 screen Comilled with 0.61 mm 5.5 106.6 223.2 320.8
393.8 429.8 screen Comilled with 1.14 mm 7.9 73.9 239.3 340.8 412.0
452.7 screen
[0555] After the comil, the material visually appeared to have a
lower particle size and be more uniform in size when compared to
unmilled (API). However, the measured particle size distribution of
the material by dry dispersion described above did not show a
difference between the comilled and the unmilled OCA. The PSD data
demonstrate a more robust milling technique is required to
significantly reduce the particle size of the material.
[0556] Jet Milling Using Hosokawa AFG 100 Jet Mill
[0557] Jet milling studies were performed using a Hosokawa AFG 100
jet mill. The results showed a significant reduction in the
particle size distribution (PSD). Jet milling was carried out with
various classifier speeds to determine the optimum set of jet mill
parameters. The jet mill parameters used in the Hosokawa AFG 100
jet mill are provided below:
[0558] Hosokawa AFG 100 jet mill parameters: [0559] Pressure in the
mill: -0.2.about.-0.3 mm Aq. [0560] Nozzle diameter/number: 1.9
.phi.mm.times.3 [0561] Consumption of compressed air: 0.7
Nm3/min
[0562] Classification parameters [0563] Rotor rotation speed: 4000
rpm [0564] Current rating of motor: 4.2 Amp [0565] Current
operating: 2.4 Amp [0566] Rotor seal pressure: 0.1 MPa (1 bar)
[0567] Bearing seal pressure: 0.1 MPa (1 bar) [0568] Rotor type:
SUS
[0569] Powder collector [0570] Filter material/length/number:
Gore/2 ft/4
[0571] The particle size distribution of unmilled and jet milled
OCA (API) is shown below in Table 2.
TABLE-US-00002 TABLE 2 Particle size distribution of unmilled and
jet milled obeticholic acid. Sample Description D.sub.10 D.sub.16
D.sub.50 D.sub.84 D.sub.90 D.sub.99 Unmilled API 4.8 -- 218.6 --
427.6 -- Jet mill, classifier speed 1.7 2.3 10.9 57.2 69.3 97.9
2000 rpm Jet mill, classifier speed 1.3 1.7 4.2 15.2 18.9 55.8 5000
rpm Jet mill, classifier speed 1.1 1.4 2.7 4.7 5.6 9.0 10000 rpm
Jet mill, classifier speed 1.3 1.6 3.8 17.0 21.7 36.0 4000 rpm
[0572] The results above show that jet milling at high classifier
speeds (i.e., 4000 rpm, 5000 rpm and 10,000 rpm) showed a
significant reduction in the PSD.
[0573] Jet milling using spiral jet mill. Jet milling studies were
performed using a spiral jet mill. The results showed a significant
reduction in the particle size distribution (PSD). Jet milling was
carried out with various a range of parameters to determine the
optimal settings. The jet mill parameters used in the spiral jet
mill are provided below:
[0574] Spiral jet mill parameters controlling the final PSD
are:
[0575] Feed rate: Product amount fed into the milling chamber per
unit time
[0576] Pressure: Fluid pressure through the nozzle section which
influences the speed at which the particles collide
TABLE-US-00003 TABLE 3 Milling Parameters Used During Development
at JetPharma Lot Batch Number Size Feed Rate Nitrogen Pressure PSD
JP1307001 10.0 kg Evaluated range: 200-400 g/30'' Evaluated range:
2.0-4.0 bar X.sub.10: 1 .mu.m Target range: 300 .+-. 10 g/30''
Target range: 3.0 .+-. 0.2 bar X.sub.50: 5 .mu.m X.sub.90: 20 .mu.m
JP1408001 5.6 kg Evaluated range: 200-400 g/30'' Evaluated range:
2.0-4.0 bar X.sub.10: 1 .mu.m Target range: 290 .+-. 10 g/30''
Target range: 3.2 .+-. 0.2 bar X.sub.50: 5 .mu.m X.sub.90: 19 .mu.m
JP1408002 4.8 kg Evaluated range: 200-400 g/30'' Evaluated range:
2.0-4.0 bar X.sub.10: 1 .mu.m Target range: 290 .+-. 10 g/30''
Target range: 3.2 .+-. 0.2 bar X.sub.50: 4 .mu.m X.sub.90: 14 .mu.m
JP1408003 6.3 kg Evaluated range: 200-400 g/30'' Evaluated range:
2.0-4.0 bar X.sub.10: 1 .mu.m Target range: 290 .+-. 10 g/30''
Target range: 3.2 .+-. 0.2 bar X.sub.50: 4 .mu.m X.sub.90: 15
.mu.m
[0577] The impact of jet-milling on API particle size and surface
area is detailed in Table 4-1 and Table 4-2, respectively. Surface
area was tested per a BET (Brunauer, Emmett, and Teller theory).
The BET method for analyzing surface area is based on adsorption of
gas on a surface. The amount of gas adsorbed at a given pressure
allows a determination of the surface area.
[0578] As can be observed from Table 2, the API particle size
distribution after jet-milling undergoes a dramatic shift towards
much smaller, more uniformly-sized particles within a tighter
distribution, while surface area increases approximately 3-fold.
FIG. 1 and FIG. 2 illustrate the typical particle size distribution
of unmilled and jet-milled API, respectively.
TABLE-US-00004 TABLE 4-1 Impact of jet-milling (micronization) on
particle size distribution of OCA drug substance Particle Size
Distribution of Unmicronized and Micronized OCA Drug Substance OCA
Example # 1 2 3 Before After Before After Before After D.sub.v (10)
2.6 0.7 1.8 0.6 5.3 0.7 D.sub.v (50) 26 6.1 19 4.4 39 4.9 D.sub.v
(90) 162 18.8 231 17.8 221 14.1 D.sub.v (99) 419 30.8 509 34.6 513
25.9
TABLE-US-00005 TABLE 4-2 Impact of jet-milling (micronization) on
surface area of OCA drug substance Surface Area of Unmicronized and
Micronized OCA Drug Substance OCA Example # 1 2 3 Before After
Before After Before After Surface Area 1557 3178 1854 3848 809 3412
(m.sup.2/kg)
Example 2: Improved Manufacturing Process of Obeticholic Acid (OCA)
Tablets
[0579] The manufacturing process of 5 mg and 10 mg obeticholic acid
(OCA) tablets uses dry granulation by roller compaction followed by
tablet compression and coating. The process steps used to
manufacture OCA tablets include: pre-blending; dry granulation,
final blending, compression, coating, and packaging. The equipment
used to manufacture OCA tablets are shown in Table 5.
TABLE-US-00006 TABLE 5 Equipment Used to Manufacture OCA Tablets
Process Step Equipment Sieving 0.5 mm and 1.0 mm aperture sieve
Pre-blending Drum and Bin blender, appropriately sized drum and bin
Roller Roller compactor, Alexanderwerk PP150 (or WP120) or
compaction equivalent fitted with upper and lower mill screens
Final blending Bin blender, appropriately sized bin Compression
Rotary tablet press, Kilian T300 or equivalent Coating Perforated
pan coater, Manesty Accelacota 150 or equivalent 48-inch coating
pan
[0580] Microcrystalline cellulose was added to the intra-granular
portion of the tablet mixture which produced tablets of moderate
hardness. Modification to the manufacturing process to add
microcrystalline cellulose to both the intra-granular and
extra-granular portions of the tablet for both the 5 mg and 10 mg
tablet generated more robust tablets (harder tablets). The
compression challenges observed were overcome by redistributing a
portion of microcrystalline cellulose in the 5 mg and 10 mg OCA
formulation blends. This change in the manufacturing process
impacted the quality attributes, specifically the dissolution
profile, of the OCA tablets.
[0581] OCA drug substance and excipients were added in specific
quantities and order during pre- and final blending. Prior to
manufacture, the materials were dispensed in the appropriate
portions as shown in Table 6. Microcrystalline cellulose (MCC) and
sodium starch glycolate (SSG) were sieved with a 1.0 mm aperture
sieve before use. Magnesium stearate was sieved using a 0.5 mm
aperture sieve immediately before use.
TABLE-US-00007 TABLE 6 Material Dispensing Summary for OCA Tablets
Quantity Quantity for 5 mg for 10 mg Quantity OCA Tablet OCA Tablet
for 25 mg Formulation Formulation OCA Tablet Component (kg) (kg)
Formulation (kg) Intra-granular (Pre Blending) OCA drug substance
2.5.sup.a 5.0.sup.a 12.5.sup.a MCC-for-Premix 7.5 10.0 25.0
MCC-for-Rinse 7.5 10.0 12.5 MCC-1 25.5.sup.a 33.0.sup.a 41.0.sup.a
SSG-1 4.0 4.0 4.0 Silicon dioxide-1 -- -- 1.0 Magnesium stearate-1
0.5 0.5 0.5 Extra-granular (Final Blending) MCC-2 50.0.sup.b
35.0.sup.b -- SSG-2 2.0.sup.b 2.0.sup.b 2.0.sup.b Silicon dioxide-2
-- -- 1.0.sup.b Magnesium stearate-2 0.5.sup.b 0.5.sup.b 0.5.sup.b
Coating Opadry .RTM. II Yellow 6.0.sup.c 6.0.sup.c 6.0.sup.c
85F32351 Purified water.sup.d 24.0 24.0 24.0 Total 104.0 104.0
104.0 MCC = Microcrystalline cellulose; SSG = Sodium starch
glycolate; .sup.aOCA drug substance amount assumes the drug
substance content is 100%; actual amount added is adjusted for
based on the potency of the drug substance lot used; the amount of
microcrystalline cellulose is correspondingly decreased. .sup.bThe
amounts of extra-granular excipients are adjusted based on the
yield of the process through roller compaction. The dispensing
summary presented assumes a 100% yield through roller compaction.
.sup.cThe amount of coating material prepared during the process is
150% of target. Excess coating material is discarded. .sup.dWater
is removed during processing.
[0582] Preblending Process. To an appropriately sized blender drum
was added OCA and a microcrystalline cellulose (MCC) for premix
(MCC-for-Premix: a portion of the total MCC added to the tablet
formulation) to produce OCA premix. The resulting mixture was
blended 90 to 120 revolutions (approximately for 3 minutes at a
blender speed of about 30 rpm) and discharged. For the 5 mg
tablets, OCA was pre-mixed with approximately 3 parts MCC (to 1
part OCA). For the 10 mg tablets, OCA was pre-mixed with
approximately 2 parts MCC (to 1 part OCA).
[0583] After unloading the API/MCC premix (OCA premix) from the
drum, the drum was rinsed with a further portion of MCC
(MCC-for-Rinse: same amount as used for the premix), to recover any
API retained on the drum surfaces to provide the MCC-rinse portion.
A blend time of 3 minutes (i.e., about 90 to 120 revolutions) was
used for this rinse process, i.e., MCC-rinse process. The API/MCC
premix and MCC drum rinse (MCC-rinse portion) were passed through a
1.0 mm aperture sieve on addition to the larger drum used for the
Pre-RC (roller compaction) blending process (i.e., 150 liter drum
for 5 mg tablets and 70 liter drum for 10 mg tablets). The sieve
removed any soft agglomerates of OCA, and ensured good blend
uniformity was achieved before roller compaction.
[0584] An appropriately sized bin was then charged with the
following components: approximately 1/4 (one-fourth) of MCC-1, 1/2
(half) of OCA Premix, MCC drum rinse (MCC Rinse), 1/2 of OCA
Premix, and 1/4 of MCC-1 in the order specified. The resulting
mixture was then blended for 300 to 360 revolutions (about 20
minutes for 5 mg tablets, about 10 minutes for 10 mg tablets) in a
Pharmatech MB400 drum blender or a Tumblemix drum blender or
V-blender. The SSG-1 and the remaining 1/2 of MCC-1 was added to
the bin and the mixture was then blended for 300 to 360 revolutions
(about 10 to 20 minutes). Magnesium stearate-1 was then added to
the bin via a 0.5 mm aperture sieve and the mixture was blended for
70 to 90 revolutions (about 3 minutes). For the 25 mg tablet,
silicon dioxide was added via a 0.5 mm aperture sieve together with
SSG-1 and the remaining 1/2 of MCC-1 to the bin and the mixture was
then blended for 300 to 360 revolutions (about 10 to 20 minutes).
The blender revolutions for the various preblending steps provide
homogeneity of the pre-blend formulation.
[0585] Dry granulation. The pre-blend was transferred from the bin
blender to the roller compactor hopper. The pre-blend was roller
compacted to provide flakes which were milled into granules through
an in-line dual screen milling system. The granules were then
collected in a suitable container. Roller compaction parameters
used in the commercial production are shown in Table 7. This
process provided the roller compacted active granules
(intra-granular portion) for use in the final blending step. Roll
pressure (compaction force), roll gap, and screen size (lower mill)
are meaningful process parameters in the roller compaction process.
The roll pressure, roll gap, and screen size provided granules with
consistent physical characteristics and particle-size
distribution.
TABLE-US-00008 TABLE 7 Roller Compactor Settings Used for
Commercial Production Attribute Setting Roll pressure (bar) 40 to
48 Roll gap (mm) 2.5 to 4.0 Upper mill screen size (mm) 2.0 Lower
mill screen size (mm) 0.8
[0586] Final Blending. The final blending of the OCA tablet
formulation was performed in 2 steps. First, an appropriately sized
bin was charged with the roller-compacted active granules
(intra-granular portion), extra-granular sodium starch glycolate-2
(SSG-2) and extra-granular MCC-2, and the resulting mixture was
blended for 450 to 540 revolutions. For the 25 mg tablet, silicon
dioxide was added via a 0.5 aperture sieve together with SSG-2 and
extra-granular MCC-2. Magnesium stearate-2 was then added to the
bin and the mixture was blended for 70 to 90 revolutions. Blender
revolution is a meaningful process parameter in the final blending
process providing a final blend with acceptable homogeneity.
[0587] Compression Process. The final blend prepared in the
blending process was used to supply the rotary tablet press fitted
with the appropriate OCA tablet tooling. OCA tablet tooling is
specific to the tablet strength. During equipment start-up, the
tablet press was set up by adjusting compression parameters to
produce tablets that meet the in-process control targets for tablet
weight, hardness, thickness, and friability. Tablet press speed
(about 70 rpm) and feeder speed (about 30 rpm to about 40 rpm) were
set to achieve satisfactory tablet weight variation. The tablet
press depth of fill was set to achieve the target tablet weight.
The main compression pressure (rollers) was set to achieve the
target hardness and thickness (compression force of about 8 kN). A
small amount of pre-compression force (about 0.5 kN) was applied
before the main compression to expel air from the blend to ensure
satisfactory tablet friability. Adjustments were made throughout
the compression operation to continuously meet the in-process
control targets. After the tablets were ejected from the press,
they were passed through a tablet deduster and metal detector prior
to collection in tablet containers.
[0588] In-process control testing for appearance, tablet weight,
hardness, thickness, friability, and disintegration time is
conducted at specific internals throughout the tablet compression
process and are provided in Table 8. Press speed and compression
are meaningful process parameters in the tablet compression
process. The specified press speed provided tablets with the target
tablet weight. Compression, including both pre- and main
compression, provided tablets that met the tablet hardness,
thickness and firability limits. In addition, the provided tablets
showed fast disintegration time.
TABLE-US-00009 TABLE 8 In-Process Tests for Compression Step 5 mg
OCA Tablets 10 mg OCA Tablet 25 mg OCA Tablet In-process Test
Acceptance Criteria Appearance White, round tablets White,
triangular White, oval tablets with with 5 debossed on tablets with
10 25 debossed on one one side and INT on debossed on one side side
and INT on the the other side and INT on the other other side side
Weight of 20 3.92 g to 4.08 g (Target 4.00 g) tablets Individual
weight 200 mg, NMT 2 individual tablets deviate from mean by more
of 20 tablets than 7.5% and none by more than 15% Hardness (mean) 7
kP to 13 kP 8 kP to 14 kP 9 kP to 15 kP (target 10 kP) (target 11
kP) (target 12 kP) Thickness (mean) 3.5 mm to 4.1 mm 4.0 mm to 4.6
mm 4.3 mm to 4.9 mm (target: 3.8 mm) (target: 4.3 mm) (target: 4.6
mm) Friability (6.5 g/ NMT 0.5% 100 rotations) Disintegration NMT 2
min time (6 tablets) NMT = not more than
[0589] Tablet Coating. The 5 mg and 10 mg OCA tablets were coated
with a non-functional immediate release coating material. Tablet
cores were coated with Opadry.RTM. II coating material using a
perforated pan coater and a 48-inch pan. A 20% w/w coating solution
was prepared by mixing Opadry.RTM. II with purified water. An
excess of coating solution was prepared to ensure sufficient
coating material is available for the coating process.
[0590] The tablet cores were loaded into the pan of the perforated
pan coater (i.e., O'Hara Labcoat MX coating machine and 1.times.
Schlick Model 930/7-1 S35 with 1.2 mm nozzle spray gun) and the
coating process was initiated. The pan rotation speed (about 12
rpm) was monitored and maintained in the appropriate range to
ensure the tablet cores flowed consistently throughout the coating
process. Pan speed is a meaningful process parameter, as this can
affect tablet appearance (too high a pan speed can damage the
tablets). Tablet bed temperature is a meaningful process parameter,
as this can affect tablet water content and protects the tablets
from over-wetting (which causes tablet appearance defects). Exhaust
air temperature is linked to tablet bed temperature and is a
meaningful process parameter if tablet bed temperature is not
recorded.
[0591] The supply air temperature of about 60 to 72.degree. C. and
an exhaust air temperature of about 45 to 55.degree. C. was used to
maintain tablet bed temperature at about 45 to 48.degree. C. Supply
and exhaust air temperatures were monitored throughout the coating
step to maintain the bed temperature range of about 45 to
48.degree. C. After the desired 4% weight gain was achieved, the
pan speed and supply air temperature were reduced (to about 4 rpm
and 45.degree. C.) to ensure dry tablets. The heater was then
turned off and tablets were further cooled while jogging the pan.
Tablet weight gain (target 4% gain) and appearance were checked
periodically during the tablet coating process as in-process
controls. The in-process tests conducted during the coating process
are shown below in Table 9.
TABLE-US-00010 TABLE 9 In-Process Tests for Coating Process 5 mg
OCA Tablets 10 mg OCA Tablets 25 mg OCA Tablets In-process Test
Acceptance Criteria Appearance Off-white to yellow, Off-white to
yellow, Off-white to yellow, round tablets with 5 triangular
tablets with oval tablets with 25 debossed on one side 10 debossed
on one debossed on one side and INT on the other side and INT on
the and INT on the other side other side side Tablet weight 3.0% to
5.0% 3.0% to 5.0% 3.0% to 5.0% gain
[0592] Packaging. Tablets were packaged in the commercial primary
packaging configuration using a standard automated bottling
operation. The primary packaging configuration utilized a white
high-density polyethylene bottle (40 cc) and child resistant cap
with an induction seal. The commercial bottle will contain 30 OCA
tablets. Tablet quantity, induction seal, cap torque, print
quality, and appearance control testing was conducted at specific
intervals throughout the packaging process. Induction sealing is a
meaningful process parameter in the packaging process providing a
completely sealed bottle. The in-process testing parameters for the
packaging process is provided in Table 10 below.
TABLE-US-00011 TABLE 10 In-Process Tests for Packaging Process
In-process Test Acceptance Criteria Tablet quantity Correct tablet
fill quantity (30 count) Induction seal integrity Totally sealed
bottle Cap torque test 15 lb/in.sup.2 to 25 lb/in.sup.2 Print
quality Print is present and correct Appearance (AQL inspection)
Satisfactory AQL = Acceptable quality limit
Example 3: Dissolution Testing of Obeticholic Acid Film-Coated
Tablets
[0593] Unmilled 5 mg tablet and 10 mg tablet formulations of OCA
were observed to release the drug slowly. The formulation of the 5
mg and 10 mg tablets are shown below in Table 11.
TABLE-US-00012 TABLE 11 5 mg, 10 mg, and 25 mg film-coated tablets
formulations mg/tablet Material 5 mg 10 mg 25 mg Intragranular OCA
Drug Substance.sup.a 5.0 10.0 25.0 Microcrystalline Cellulose.sup.a
81.0 106.0 157.0 Sodium Starch Glycolate 8.0 8.0 8.0 Colloidal
Silicon Dioxide -- -- 2.0 Magnesium Stearate 1.0 1.0 1.0 Granule
Mass 95.0 125.0 193.0 Ratio of Microcrystalline Cellulose to OCA
about about about 6:1 16:1 11:1 Extragranular Microcrystalline
Cellulose 100.0 70.0 -- Sodium Starch Glycolate 4.0 4.0 4.0
Colloidal Silicon Dioxide -- -- 2.0 Magnesium Stearate 1.0 1.0 1.0
Final Blend/Tablet Core 200.0 200.0 200.0 Tablet Coating Opadry II
Coating Material 8.0 8.0 8.0 Coated Tablet 208.0 208.0 208.0
.sup.aOCA quantity presented assumes drug substance is anhydrous
and 100% pure; actual amount is adjusted based on potency of the
drug substance lot used, and amount of microcrystalline cellulose
is correspondingly decreased.
[0594] Upon testing, the tablets containing unmilled OCA
demonstrated a slow dissolution release profile. For the
dissolution method, both RI and Corona detectors were initially
evaluated for analysis of the dissolution media. Considering the
need to quantify OCA (INT-747) at levels as low as 10% of a 5 mg
strength tablet dissolved in the dissolution media (1 .mu.g/mL),
the Corona CAD detector was chosen for the dissolution tests
because it has a better sensitivity to OCA than the RI
detector.
[0595] Tablet dissolution for both the 5 mg and 10 mg tablets was
conducted in 900 mL of 50 mM Disodium Hydrogen Phosphate Buffer
(Na.sub.2HPO.sub.4), pH 6.8 at 37.degree. C. using USP II paddle
apparatus at a paddle speed of 75 rpm. Samples were assayed
undiluted by filtering through a 0.2 m PVDF syringe filter using a
gradient RP-HPLC method with CAD detection. This method utilized an
Agilent Zorbax SB-C18 4.6 mm.times.150 mm, 3.5 .mu.m HPLC column. A
50 .mu.L sample was separated by a 20 minute gradient program, at a
temperature of 40.degree. C. and a flow rate of 1.5 mL per minute.
Two mobile phases were used in the program; one consisted of a
degassed Acidified Water pH 3.0/Acetonitrile (45:55) mixture and
the other degassed Acetonitrile. The OCA drug substance eluted with
an approximate retention time of 10 minutes.
[0596] The dissolution methodology is summarized below in Table
12.
TABLE-US-00013 TABLE 12 Parameters for the obeticholic acid 5 mg
and 10 mg tablet dissolution method. Parameter Value Apparatus USP
Apparatus II (paddles) Dissolution Media 50 mM sodium phosphate
dibasic buffer, pH 6.8 Dissolution Volume 900 mL Rotation Speed 75
rpm Temperature 37.degree. C. .+-. 0.5.degree. C. Sample Volume 10
mL with medium replacement Sample Pull Times 10, 15, 30, 45, 60
minutes Sample Analysis HPLC/Corona CAD Abbreviations: HPLC = high
performance liquid chromatography; rpm = revolutions per minute;
USP = United States Pharmacopeia; CAD = charged aerosol
detector
[0597] Obeticholic acid was comilled with a 0.61 mm screen or
jet-milled as described above to reduce the particle size of the
material. Jet-milling (i.e., micronization) resulted in material
that had a smaller, more uniform particle size and increased
surface area, leading to faster drug release from tablets
containing jet-milled OCA. The dissolution release rate of tablets
containing comilled and jet-milled OCA is shown below in Table
13.
TABLE-US-00014 TABLE 13 Dissolution release rates of comilled and
jet-milled OCA 5 mg tablets containing 5 mg tablets comilled 10 mg
tablets containing Dissolution OCA containing comilled Jet-milled
time Dissolution OCA OCA (min) rate (%) Dissolution rate (%)
Dissolution rate (%) 15 42 51 83 30 57 66 89 45 68 79 91 60 77 85
94 75 89 92 95
[0598] Table 13 shows that reduction in particle size of the OCA
drug product improves elution properties.
[0599] As shown in FIG. 3 and FIG. 4, the particle size
distribution of the OCA impacted the drug dissolution rate, even in
media where OCA is freely soluble (pH 6.8). It is therefore
possible that differences in particle size could impact OCA
bioavailability if dissolution becomes rate-limiting for
absorption. For this reason, the particle size distribution of the
active is considered a critical process parameter.
[0600] The dissolution profiles of 10 mg tablets containing either
unmilled (a batch of unmilled OCA with smaller particle size;
D.sub.50>about 100 .mu.M), unmilled/agglomerated, or jet-milled
OCA is compared in FIG. 3.
[0601] Drug release was compared for 5 mg tablets containing
unmilled (agglomerated) and jet-milled OCA. The difference in
release profiles was more dramatic for the 5 mg tablets than the 10
mg tablets. This is likely due to coning effects in the smaller
dissolution volume of 500 mL which may have contributed to the
slower/incomplete dissolution due to the non-favorable
hydrodynamics in the test vessel. The dissolution profiles of 5 mg
tablets containing either unmilled/agglomerated, or jet-milled OCA
is compared in FIG. 4.
Example 4: Content Uniformity Testing of Obeticholic Acid
Tablets
[0602] The content uniformity of 5 mg and 10 mg tablets containing
comilled OCA and jet-milled OCA was evaluated by RP-HPLC. The
results are shown below in Table 14.
TABLE-US-00015 TABLE 14 Content uniformity of 5 mg and 10 mg
tablets of unmilled, comilled and jet-milled OCA 5 mg tablets
containing 10 mg tablets 5 mg tablets comilled containing comilled
containing jet-milled OCA OCA OCA Content 104 (AV = 18, 104 (AV =
14, 105.2 (AV = 8, Uniformity 89.0%-110.6%) 97.4%-111.5%)
101.4%-109.2%) (%)
[0603] The results in Table 14 show the content uniformity data for
tablets containing comilled and jet-milled OCA. Tablets containing
comilled OCA showed a higher variability in content uniformity. The
smaller particle size of the jet-milled material provides better
content uniformity of the OCA tablets.
Example 5: Stability Studies of 5 mg and 25 mg Obeticholic Acid
Tablets
[0604] The stability of 5 mg and 25 mg tablets were tested in
accelerated stability studies. The stability test was conducted at
40.degree. C. and 75 relative humidity (RH) for 6 months. The
formulation of the 5 mg and 25 mg tablets are shown above in Table
11.
[0605] 5 mg and 25 mg OCA tablets were placed on stability at the
40.degree. C./75% RH storage conditions. Samples stored at the
accelerated condition were pulled from storage at 1, 2, 3, and 6
months for assessment of stability. The tests performed for
stability evaluations include appearance, assay for OCA by HPLC,
and related substances by HPLC Corona.
[0606] Obeticholic acid and formulations of obeticholic acid were
tested for stability. An unknown impurity at relative retention
time (RRT) 1.75 was observed during stability studies of the
tablets containing different batches of the 5 mg and 25 mg tablet
formulation. The stability test using uncoated tablets showed an
increase of a new impurity at about 0.05% with the test conducted
at 25.degree. C., 60% RH for 4 weeks, and about 0.2% with the test
conducted at 40.degree. C., 75% RH for 4 weeks. A study was
conducted to identify the structure of the impurity, clarify the
origin for the generation of the impurity, and adopt measures to
ensure that quality was not compromised during storage of the
tablet. The structure of OCA and the identified structure of the
impurity are respectively shown below:
##STR00004##
[0607] An analysis was conducted with LC/HRMS using LTQ-Orbitrap
Discovery. The LC/HRMS Test conditions used are outlined in Table
15 below:
TABLE-US-00016 TABLE 15 LC/HRMS conditions for identifying
impurities found in OCA after stability testing Equipment: [HPLC]
Shimadzu prominence (LC-20A series) [MS] Thermo Fisher Scientific
LTQ Orbitrap Discovery Ionization ESI (negative and positive mode)
method: HPLC [Column] Phenomenex, Kinetex C-18, 2.6 .mu.m, 4.6 mm
I.D. .times. 100 mm conditions: [Mobile phase] A: AcOH aqueous
solution*.sup.1 containing 15% MeOH B: MeCN containing 15% MeOH
Gradient conditions Time (min.) B (%) 0.0 .fwdarw. 25.0 40 .fwdarw.
65 25.0 .fwdarw. 35.0 65 .fwdarw. 95 35.0 .fwdarw. 50.0 95 50.0
.fwdarw. 50.1 95 .fwdarw. 40 50.1 .fwdarw. 60.0 40 60.1 stop
[Measurement time] 60 min [Detection] Total Ion Current
Chromatogram (TICC) [Flow rate] 1.0 mL/min. [Column temperature]
Approximately 40.degree. C. [Sample drug product Mobile phase B
solvent] [Injection] 5 .mu.l Sample*.sup.2 OCA drug product
(product stored for 4 weeks at 60.degree. C.) solution (OCA
concentration 500 .mu.g/mL)*.sup.3 Drug product placebo solution
(prepared in the same way as (1)) Impurity 1-5 and OCA mixed
solution (5 .mu.g/mL each) OCA powder (5000 rpm) OCA unground
product OCA drug product (stored at 50.degree. C., 85% RH for 4
weeks) solution
[0608] Based on the results, it was determined that the impurity is
an ethyl ester of obeticholic acid (OCA). Subsequently, an
authentic sample of the ethyl ester was synthesized by dissolving
obeticholic acid in ethanol, adding concentrated sulfuric acid and
heating the mixture. The retention time and mass spectrometry of
the authentic sample matched those of the impurity and thus the
structure of the impurity was confirmed as an ethyl ester of
obeticholic acid (FIG. 7A and FIG. 7B). Comparison of the retention
time and the mass spectrum of the ethy ester impurity and authentic
sample is shown in FIG. 7A and FIG. 7B.
[0609] Bottom row: TICC of ethyl ester (positive mode)
[0610] The structure of the ethyl ester impurity (shown above) was
determined through mass spectrometry analysis combined with
analysis of OCA fragmentation, and was confirmed by mass
spectrometry analysis of synthesized OCA ethyl ester (the above
authentic sample having the same retention time as the ethyl ester
impurity).
[0611] Since the ethyl ester impurity can be formed in the presence
of ethanol, the formulation was examined to determine if any
excipient could be a possible source of the ethanol. It was found
that sodium starch glycolate from two different manufacturers,
sodium starch glycolate (Glycolys.RTM.) from Roquette Pharma
containing no more than 6% ethanol and sodium starch glycolate
(Explotab.RTM.) from JRS Pharma containing no more than 3% ethanol,
were used to make the tablet formulations. A comparison of
accelerated stability data at 40.degree. C./75% RH of batches are
shown below in Table 16.
TABLE-US-00017 TABLE 16 OCA Ethyl Ester Impurity (RRT 1.75) Content
in Accelerated (40.degree. C./75% RH) Stability Studies Lot Number
(Manufacturer) Time 0 1 Month 3 Months 6 Months DNSY, 5 mg ND ND ND
ND Patheon (Explotab .RTM.) DNSZ, 25 mg ND ND ND ND Patheon
(Explotab .RTM.) PDS0048-03, 5 mg ND NT 0.35% 0.44% Piramal
(Glycolys .RTM.) PDS0048-10, 25 mg ND NT 0.17% 0.25% Piramal
(Glycolys .RTM.) ND = Not detected; NT = Not tested
[0612] The results in Table 16 show that the ethyl ester impurity
is not observed after 6 months in samples containing low ethanol
sodium starch glycolate (i.e., Explotab.RTM.). However, the ethyl
ester impurity in samples containing high ethanol sodium starch
glycolate (i.e., Glycolys.RTM.) was observed as early as three
months into the stability study. This data indicates that the
ethanol content of the sodium starch glycolate is critical to the
stability of the OCA formulation.
[0613] Stability Testing of Film Coated Tablets. Furthermore, in
the film coated tablet stability test an increase in a specific
impurity was confirmed at a rate of approximately 0.09% with the
test conducted at 40.degree. C., 75% RH for 4 weeks. Given that the
generation of this impurity only occurred in film coated tablets,
it was surmised that the impurity was a reactant with a film
coating component. Also, based on the structure of ethyl ester
impurity it is known that the carboxylic acid of OCA reacted easily
with alcohol. Of the film coating components, it was possible that
2 components, polyvinyl alcohol (PVA) and polyethylene glycol (PEG)
4000 could be the cause of the impurity.
[0614] Subsequently, when a blending combination change test was
conducted the specific impurity was generated and it was discovered
that PEG4000 was the cause. Therefore, it was estimated that the
structure of this impurity was an ester produced by a reaction
between a PEG4000 hydroxyl group and the OCA carboxylic acid. The
structure of OCA and PEG ester impurity are shown below:
##STR00005##
[0615] High resolution mass spectrometry (HRMS) was conducted to
confirm the structure. The mean molecular weight of PEG ester
impurity was expected to exceed 4000. micrOTOF-QII (Bruker
Daltonics) was used to measure high molecular weight compounds.
When measured with the APCI technique in positive mode, an m/z was
obtained that supported the structure of PEG ester impurity shown
above. (FIGS. 8A, 8B, and 8C). Enlargement of the mass spectrum of
a sample containing the specific impurity showed peak spacing
characteristic of PEG (FIG. 9).
[0616] The LC/HRMS Test conditions used are outlined in Table 17
below:
TABLE-US-00018 TABLE 17 LC/HRMS test conditions for the
identification of the impurity found in film coated OCA tablets
after stability testing. Equipment: [HPLC] Agilent 1200 [MS]
micrOTOF-QII (Bruker Daltonics) Ionization APCI positive mode
method: HPLC [Column] Phenomenex, Kinetex C-18, 2.6 .mu.m, 4.6 mm
I.D. .times. 100 mm conditions: [Mobile phase] A: AcOH aqueous
solution*.sup.2 containing 15% MeOH B: MeCN containing 15% MeOH
Gradient conditions. Time (min.) B (%). 0.0 .fwdarw. 25.0 40
.fwdarw. 65 25.0 .fwdarw. 35.0 65 .fwdarw. 95 35.0 .fwdarw. 50.0 95
50.0 .fwdarw. 50.1 95 .fwdarw. 40 50.1 .fwdarw. 60.0 40 60.1 stop
[Measurement time] 60 min [Detection] Total Ion Current
Chromatogram (TICC) [Flow rate] 1.0 mL/min. [Column temperature]
Approximately 40.degree. C. [Sample drug product Mobile phase B
solvent] [Injection] 5 .mu.l Sample OCA film coated tablet (product
stored for 4 weeks at 60.degree. C.) extract solution*.sup.3
*.sup.2pH 3.0 *.sup.3The 500 .mu.l sample prepared was concentrated
to dryness under a stream of nitrogen, dissolved in 50 .mu.l of
mobile phase B and used as the sample (OCA concentration: 5
mg/mL).
[0617] The extract from the film coated tablets was measured using
the APCI technique in positive mode. Analysis of the retention
time, the mass spectra, and the m/z value confirmed the structure
of PEG ester impurity (shown above and in FIGS. 8A, 8B, and
8C).
Example 6: Solubility Studies of OCA in Various Buffers and
Biological Media
[0618] Solubility Studies of OCA in Various Buffers. A study was
performed to screen different media of various pH over the pH range
1.2-10.0, incorporating the physiological pH range (1.2-6.8) for
immediate release tablets. The solubility of OCA was measured at
37.degree. C. in various buffers from pH 1.2 to 10.0. The
equilibrium solubility results for OCA in various aqueous buffer
solutions are presented in Table 18 below.
TABLE-US-00019 TABLE 18 Equilibrium solubility and recovery for OCA
at 37.degree. C. in various buffers from pH 1.2 to 10.0 Solubility
USP Solubility pH, Media (Buffer) (mg/mL) % Recovery Rating pH 1.2
Hydrochloric acid N/A <1 Practically insoluble pH 2.0
Hydrochloric acid N/A <1 Practically insoluble pH 3.0 Acid
Phthalate N/A <1 Practically insoluble pH 4.1 Acetate 0.003
<1 Slightly soluble pH 5.1 Acetate 0.023 5 Sparingly soluble pH
6.0 Phosphate 0.050 10 Soluble pH 6.8 Phosphate.sup.a 0.220 94
Freely soluble pH 7.0 Phosphate 0.462 92 Freely soluble pH 8.0
Phosphate 0.486 97 Freely soluble pH 9.0 Alkaline Borate 0.462
.sup. 92.sup.b Freely soluble pH 10.0 Alkaline Borate 0.056 .sup.
11.sup.b Soluble .sup.aDissolution media (50 mM sodium phosphate
dibasic buffer, pH 6.8) .sup.bBasic decomposition of drug substance
suspected.
[0619] OCA is a weak acid (pKa=4.82) and exhibits a pH-solubility
profile consistent with that of a weak acid. As expected, the
solubility of the free acid form is highest when deprotonated and
lowest when protonated.
[0620] OCA drug substance was observed to precipitate out of
solution in those acidic buffers in the pH range 1.2 to 3.0.
Solutions at pH 4.1 to 6.0 also had some precipitation resulting in
a cloudy solution. Solutions at pH 6.8 to 10 produced clear
solutions. The recovery of OCA steadily diminishes at pH higher
than 8.0, indicating basic decomposition of the drug substance.
[0621] The nominal concentration for dissolved 5 mg and 10 mg
tablets in the typical dissolution volume of 900 mL is
approximately 0.006 & 0.01 mg/mL, respectively. Above pH 6.8
the solubility is well above 0.01 mg/mL, the minimum concentration
required to dissolve a 5 mg or 10 mg tablet in 900 mL of
dissolution medium (i.e., sink conditions).
[0622] As demonstrated in FIG. 5, solubility of OCA increases as a
function of increasing pH, plateauing just above approximately pH
7. The dramatic increase in solubility observed between
approximately pH 4 and pH 7 indicates that this pH region is
less-than-ideal for use in the dissolution media. However, given
that OCA is freely soluble at pH 6.8 and that this pH is
physiologically relevant to the site of absorption, it was selected
for use in diligent pursuit of a discriminating and relevant
dissolution method.
[0623] Solubility Studies of OCA in Biological Media. A solubility
study was performed in physiologically relevant dissolution media
at 37.degree. C. and pH of 1.2, 4.5, and 6.8 along with fasted
state simulated gastric fluid (FaSSGF, pH 1.2), fed state simulated
intestinal fluid (FeSSIF, pH 5.0) and fasted state simulated
intestinal fluid (FaSSIF, pH 6.5). The solubility results for OCA
in physiologically relevant buffers are presented in Table 19.
TABLE-US-00020 TABLE 19 Solubility of OCA in biologically relevant
media at 37.degree. C. Solubility pH (Medium) (mg/mL) USP
Solubility Rating 1.2 (0.1N HCl) <LOQ Practically insoluble 1.2
(FaSSGF).sup.a <LOQ Practically insoluble 4.5 <LOQ
Practically insoluble 5.0 (FeSSIF).sup.b 0.82 Freely soluble 6.5
(FaSSIF).sup.c 0.64 Freely soluble 6.8.sup.d 0.22 Freely soluble
6.8 with surfactant.sup.e 0.59 Freely soluble .sup.aFaSSGF is
de-ionized water containing sodium taurocholate (80 .mu.M) and NaCl
(34.2 mM), pH 1.6. .sup.bFeSSIF is de-ionized water containing
sodium taurocholate (15 mM) and lecithin (3.75 mM) with an
osmolarity of 635 .+-. 10 mOsmol, pH 5.0. .sup.cFaSSIF is
de-ionized water containing sodium taurocholate (3 mM) and lecithin
(0.75 mM) with an osmolarity of 270 .+-. 10 mOsmol, pH 6.5.
.sup.dProposed dissolution medium; 0.5 mM sodium phosphate dibasic,
pH 6.8. .sup.eSurfactant is polysorbate 80 (Tween 80 .RTM.)
Abbreviation: USP = United States Pharmacopeia
[0624] As shown in Table 19 and FIG. 6, from a Biopharmaceutical
Classification System (BCS) perspective, OCA is poorly soluble
below pH 4.5 and highly soluble above pH 5.0 in biologically
relevant media. This provides further support and justification for
selecting pH 6.8 phosphate buffer as the dissolution medium. A
35-fold increase in OCA solubility is evident at pH 5.0 in the
presence of the taurocholate bile acid and lecithin emulsifier vs.
pH 5.1 acetate buffer alone. This is likely due to the formation of
highly soluble micelles in the presence of the amphipathic
surfactant lecithin. One would expect similar solubility
enhancement in vivo, as taurocholic acid and lecithin are typically
present in the gastric and intestinal milieu.
Example 7
[0625] This example describes a study of two doses of OCA (10 mg
and 50 mg) vs. placebo for a period of 12 weeks (85 days). The
study was completed by 48 patients and PK data are available for 34
patients. All patients returned to the study site for 4 visits (Day
15, Day 29, Day 57, and Day 85) for evaluations of efficacy,
safety, tolerability, and compliance with investigational
product.
[0626] Key Inclusion criteria: [0627] Age >18 years, [0628] Both
male and female had to use one effective method of contraception,
[0629] Proven or likely PBC demonstrated by patient presenting with
at least 2 of the 3 diagnostic criteria [0630] History of increased
ALP [0631] Positive AMA [0632] Liver biopsy consistent with PBC
[0633] Screening ALP value between 1.5 and 10.times.ULN.
[0634] Key Exclusion Criteria [0635] 1. The following drugs were
contraindicated: ursodeoxycholic acid (UDCA), colchicine,
methotrexate, azathioprine, or systemic corticosteroids [0636] 2.
Conjugated bilirubin >2.times.ULN; ALT or AST>5.times.ULN and
serum creatinine >133 .mu.mol/L (1.5 mg/dL) [0637] 3. History or
presence of hepatic decompensation [0638] 4. History of presence of
concomitant liver diseases such as Hepatitis B or C; HIV; primary
sclerosing cholangitis, alcoholic liver disease, definite
autoimmune liver disease or biopsy proven nonalcoholic
steatohepatitis (NASH).
[0639] The percent change (%) in serum ALP from Baseline to End of
Study (EOS) was monitored. The baseline value was the mean of the
pretreatment screening and day 0 evaluations. The EOS value was Day
85/ET or the last observed ALP value on treatment.
[0640] Absolute changes in serum ALP levels were monitored from
Baseline to Day 15, Day 29, Day 57, Day 85/ET and Follow-Up (Day
99). The percentage of patients was calculated who met the
definition of PBC responder criteria applying the Paris I, Toronto
I, Toronto II, Toronto III, Toronto IV, Mayo II, and Barcelona
disease prognostic risk criteria at Day 85/ET. Each patient was
tested for absolute and percent change in serum aspartate
aminotransferase (AST), alanine aminotransferase (ALT),
gamma-glutamyl transferase (GGT), and conjugated (direct) bilirubin
values from Baseline to Day 15, Day 29, Day 57, Day 85/ET and
Follow-Up (Day 99). Efficacy results are shown in Table 20
below.
TABLE-US-00021 TABLE 20 Percent Change in ALP from Baseline - ITT
population. Placebo OCA 10 mg OCA 50 mg Percent Change (n = 23) (n
= 20) (n = 16) Mean (SD) 0.4 (15.3) -44.5 (24.4) -37.6 (21.0)
Median -0.8 -53.9 -37.2 p-value.sup.a,b NA <0.0001
<0.0001
[0641] Reductions in GGT and ALT and AST. GGT levels decreased,
relative to placebo, at all-time points from day 15 to Day 85/ET in
both the OCA 10 mg and OCA 50 mg groups. In the ITT Population, the
mean (SD) GGT levels decreased from 653 (370) U/L at baseline to
184 (203) U/L at Day 85/ET in the OCA 10 mg group, and from 455
(418) U/L at baseline to 202 (300) U/L at day 85/ET in the OCA 50
mg group. Placebo GGT levels were 466 (321) U/L at Baseline and 502
(383) U/L at Day 85/ET.
[0642] ALT levels decreased, relative to placebo, from baseline to
Day 85/ET in both OCA 10 mg and OCA 50 mg groups. The mean (SD) ALT
levels decreased from 86 (44) U/L at baseline to 54 (41) U/L at Day
85/ET in the OCA 10 mg group, and similarly decreased from 71 (38)
U/L at baseline to 49 (29) U/L at Day 85/ET in the OCA 50 mg group.
There was no change in the levels of ALT in the placebo group from
baseline to Day 85/ET.
[0643] The mean (SD) AST levels at Day 85/ET were 54 (40) U/L and
56 (28) U/L in OCA 10 mg and OCA 50 mg groups compared to baseline
levels of 67 (33) U/L and 66 (29) U/L, respectively. There was no
change in the levels of AST in the placebo group from Baseline to
Day 85/ET.
[0644] Changes in serum lipids were observed across all treatment
groups including placebo, but the magnitude of HDL-C change was
greater in the OCA treatment groups. Mean HDL-C levels decreased
from 1.73 (0.45) mmol/L at baseline to 1.57 (0.46) mmol/L at the
end of treatment (ET) in the OCA 10 mg arm. In the OCA 50 mg arm,
the mean (SD) HDL-C decreased from 1.95 (0.55) mmol/L at baseline
to 1.86 (0.56) mmol/L at ET. In the placebo arm the mean HDL-C
decreased from 1.84 (0.52) mmol/L at baseline to 1.70 (0.44) mmol/L
at ET. The effect of HDL-C lowering is not as prominent in the OCA
50 mg treatment group, perhaps due to a 44% dropout rate which
occurred early in treatment (<1 month). At Day 85/ET, a mean
change in LDL-C of -0.08 (0.43) mmol/L was observed in the placebo
group compared to mean changes of +0.10 (0.58) mmol/L and +0.23
(0.52) mmol/L in the OCA 10 mg and OCA 50 mg groups,
respectively.
[0645] Patients with early stage PBC demonstrated ALP reductions
with OCA 10 mg and 50 mg monotherapy, which were greater than
placebo (on average approximately 40% for each OCA dose vs. minimal
change in placebo). The adverse events reported were consistent
with the known safety profile of the drug, with pruritus and
headache being the most frequent AEs reported. Fatigue was reported
infrequently.
TABLE-US-00022 TABLE 21 ALP Levels (U/L) at Baseline and Day 85/ET:
ITT Population (N = 59). Placebo OCA 10 mg OCA 50 mg (n = 23) (n =
20) (n = 16) Baseline Mean (SD) 408.4 (223.0) 461.6 (298.7) 431.1
(177.2) Median 320.5 366.3 379.0 Day 85/ET Mean (SD) 420.1 (253.5)
228.1 (117.0) 269.8 (158.9) Median 288.0 196.5 197.5 Change from
11.7 (63.0) -233.5 (212.3) -161.3 (129.7) Baseline to Day 85/ET,
Mean (SD)
Example 8
[0646] This example describes a study conducted using an
international, multi-center, randomized, double-blind,
placebo-controlled, multi-dose, parallel group to determine
efficacy and safety of obeticholic acid (OCA) in combination with
ursodeoxycholic acid (UDCA) in subjects with primary biliary
cirrhosis.
[0647] Key Inclusion Criteria [0648] Male or female age 18-75 years
and on a stable dose of UDCA for at least 6 months prior to
screening [0649] Screening ALP level between 1.5.times. upper limit
of normal (ULN) and 10.times.ULN [0650] Proven or likely PBC, as
demonstrated by the subject presenting with at least 2 of the
following 3 diagnostic factors: [0651] History of increased ALP
levels for at least 6 months prior to Day 0 [0652] Positive
antimitochondrial antibody (AMA) titer (>1:40 titer on
immunofluorescence or M2 positive by enzyme-linked immunosorbent
assay) or PBC-specific antinuclear antibodies (antinuclear dot and
nuclear rim positive) [0653] Liver biopsy consistent with PBC
[0654] Key Exclusion criteria [0655] Use of colchicine,
methotrexate, azathioprine, or systemic corticosteroids [0656]
Screening conjugated (direct) bilirubin >2.times.ULN; ALT or
AST>5.times.ULN; serum creatinine >1.5 mg/dL (133 .mu.mol/L)
[0657] History or presence of hepatic decompensation (e.g.,
variceal bleeds, encephalopathy, or poorly controlled ascites)
[0658] History or presence of other concomitant liver diseases or
human immunodeficiency virus (HIV) or other viral hepatitis
infection [0659] Clinically significant medical condition, and
gastrointestinal conditions affecting drug ADME
[0660] The percent change (%) in serum ALP from Baseline to End of
Study (EOS) was tested where [EOS=Day 85 or last observed ALP value
on treatment]
[0661] Also observed were the absolute and percent changes in serum
ALP levels from Baseline to Day 15, Day 29, Day 57, Day 85/ET and
Follow-Up (Day 99). Patients were examined for the absolute and
percent change in serum gamma-glutamyl transferase (GGT), alanine
aminotransferase (ALT), and aspartate aminotransferase (AST) values
from Baseline to Day 15, Day 29, Day 57, Day 85/ET and Follow-Up
(Day 99). Patients were examined for absolute and percent changes
in serum albumin and conjugated (direct) bilirubin values from
Baseline to Day 15, Day 29, Day 57, Day 85/ET and Follow-Up (Day
99). Patients' Enhanced liver fibrosis (ELF) score and change in
levels of its components, hyaluronic acid, aminoterminal peptide of
pro-collagen III, and tissue inhibitor of matrix
metalloproteinase-1 from Baseline to Day 85/ET were performed. The
absolute and percent changes in levels of C-reactive protein,
non-esterified fatty acid, tumor necrosis factor alpha, tumor
necrosis factor beta, tumor growth factor beta, bile acids,
glutathione, immunoglobulin M, and osteopontin from Baseline to Day
85/ET were taken.
[0662] Bile acid analysis: Absolute and percent changes in the
levels of total bile acids and OCA plasma concentrations, and their
conjugates, from Baseline to Day 85/ET.
[0663] The absolute and percent change in fibroblast growth
factor-19 (FGF-19) levels from Baseline to Day 85/ET were
taken.
[0664] Overall, 165 subjects (100%) received at least 1 dose of
investigational product (ITT and Safety Populations) and 136
subjects comprised the Completer Population. One hundred sixty-one
subjects (98%) were included for the analysis of the mITT
Population as measured by the percent change in ALP from Baseline
to EOS; the mITT Population for sensitivity analysis of the primary
endpoint included 163 subjects. It should be noted that the mITT
population was defined for the primary analysis as all patients
randomized who received at least one dose of study medication and
had at least one post-baseline ALP evaluation which was taken at
most seven days after their last dose of study medication. (See
FIG. 10). The mITT Population for the sensitivity analysis included
ALP assessments obtained up to 15 days after the last
investigational product use (unlike 7 days for primary endpoint).
The number of subjects was balanced across all groups in all
analysis populations with the exception of the Completer Population
due to the higher proportion of discontinuations with OCA 50
mg.
TABLE-US-00023 TABLE 22 ALP (U/L) at Baseline to Day 85/ET: ITT
Population (N = 165) and Completer Population (N = 136). Placebo
OCA 10 mg OCA 25 mg OCA 50 mg ITT Population (n = 38) (n = 38) (n =
48) (n = 41) Baseline Mean (SD) 275.2 (102.7) 294.4 (149.4) 290.0
(123.6) 289.5 (106.2) Median 249.5 234.8 255.8 262.5 Day 85/ET Mean
(SD) 270.7 (118.7) 219.0 (113.5) 225.0 (169.1) 227.9 (115.9) Median
234.5 177.5 187.5 197.0 Mean (SD) Change -4.6 (34.9) -75.4 (81.5)
-65.0 (91.3) -62.9 (101.9) Median Change -6.3 -47.5 -69.3 -56.5
Mean (SD) -2.6 (12.4) -23.3 (17.1) -24.0 (18.8) -20.0 (27.4)
Percent Change Median Percent Change -3.2 -21.0 -27.8 -22.7 P-value
NA <0.0001 <0.0001 <0.0001 Completer Population (n = 37)
(n = 32) (n = 42) (n = 25) Baseline Mean (SD) 276.4 (103.8) 298.6
(159.5) 274.9 (80.2) 279.3 (110.5) Median 250.0 234.8 255.8 236.5
Day 85/ET Mean (SD) 272.1 (120.0) 212.3 (120.2) 199.0 (59.8) 179.1
(63.6) Median 235.0 175.0 187.5 158.5 Mean (SD) Change -4.3 (35.3)
-86.3 (83.7) -76.0 (48.8) -101.8 (85.5) Median Change -6.0 -61.3
-71.3 -76 Mean (SD) Percent -2.5 (12.6) -26.7 (16.0) -26.6 (14.7)
-32.5 (20.1) Change Median Percent Change -3.1 -23.5 -28.2
-33.9
Example 9
[0665] This example describes a randomized, double-blind,
placebo-controlled, parallel-group, 12-month trial evaluating OCA
in patients with PBC as a monotherapy. The study was performed
using a randomized, double-blind, placebo-controlled,
parallel-group, in patients with PBC who either: (1) were on
ursodeoxycholic acid (UDCA) for at least 12 months (and on stable
dose for 3 months), or (2) were unable to tolerate UDCA, and did
not receive UDCA for 3 months prior to Day 0.
[0666] Where all eligibility criteria (see below) were met,
participants were stratified into one of four groups, i.e., two
factors each with two sub-categories (specified in parentheses):
[0667] pre-treatment ALP3.0.times.ULN and/or aspartate
aminotransferase (AST)2.0.times.ULN and/or TBULN; (`no` for all
three conditions, `yes` to at least one of the three conditions)
[0668] intolerance to UDCA; (`no` hence UDCA usage for at least 12
months, with a stable dose for at least 3 months, prior to study
start with the assumption of continued stable usage of UDCA
throughout the study; `yes` hence no UDCA usage for at least 3
months prior to study start with the assumption of continued
non-usage of UDCA throughout the study).
[0669] Key inclusion criteria [0670] Definite or probable PBC
diagnosis as demonstrated by the presence of 2 of the following 3
diagnostic factors: [0671] History of elevated ALP levels for at
least 6 months [0672] Positive anti-mitochondrial antibody (AMA)
titer or if AMA negative or in low titer (<1:80) PBC specific
antibodies (anti-GP210 and/or anti-SP100 and/or antibodies against
the major M2 components [PDC-E2, 2-oxo-glutaric acid dehydrogenase
complex]) [0673] Liver biopsy consistent with PBC [0674] At least 1
of the following qualifying biochemistry values: [0675]
ALP1.67.times.ULN or [0676] Total bilirubin >ULN but
<2.times.ULN [0677] Age18 years [0678] Taking UDCA for at least
12 months (stable dose for 3 months) prior to Day 0, or unable to
tolerate UDCA (no UDCA for 3 months) prior to Day 0. [0679]
Contraception: Female patients had to be postmenopausal, surgically
sterile, or if premenopausal, had to use 1 effective (1% failure
rate) method of contraception during the trial and for 30 days
after the EOT Visit.
[0680] Key exclusion criteria [0681] Any hepatic decompensation
[0682] Portal hypertension, cirrhosis and complications of
cirrhosis/portal hypertension [0683] History of liver
transplantation, current placement on a liver transplant list or
current Model for End Stage Liver Disease (MELD) score 15 [0684]
Cirrhosis with complications, including history or presence of:
spontaneous bacterial peritonitis, hepatocellular carcinoma,
bilirubin >2.times.ULN [0685] Hepatorenal syndrome (type I or
II) or Screening serum creatinine >2 mg/dL (178 .mu.mol/L)
[0686] Competing etiology for liver disease (e.g., hepatitis C,
active hepatitis B, nonalcoholic steatohepatitis (NASH), alcoholic
liver disease (ALD), autoimmune hepatitis, primary sclerosing
cholangitis, Gilbert's Syndrome) [0687] Severe pruritus (Intense or
widespread and interfering with activities of daily living) or
pruritus requiring treatment with bile acid sequestrants,
rifampicin within 2 months of day 0 [0688] On prohibited
medications (such as fenofibrates, budesonide, corticosteroids,
valproate, isoniazid etc.); please see the list of prohibited
medications in protocol review. [0689] Patients who had previously
participated in a clinical trial of OCA were not allowed to
participate [0690] Prolonged QT interval, pregnancy or lactation.
[0691] If female: known pregnancy, or had a positive urine
pregnancy test (confirmed by a positive serum pregnancy test), or
lactating [0692] Known history of human immunodeficiency virus
infection [0693] Presence of any other disease or condition that
was interfering with the absorption, distribution, metabolism, or
excretion of drugs including bile salt metabolism in the intestine.
Patients with inflammatory bowel disease or who had undergone
gastric bypass procedures were excluded (gastric lap band was
acceptable). [0694] Medical conditions that could cause non-hepatic
increases in ALP (e.g., Paget's disease)
[0695] One goal of the study was to demonstrate the efficacy of
OCA, relative to placebo, based on its effects on ALP and TB. Other
objectives included assessing safety, histological, bile acid, and
biomarker (i.e., not including ALP and TB) parameters.
[0696] ALP and TB composite response criteria were measured; a
patient was designated as a responder if all three of the following
conditions were met: [0697] A value of ALP<1.67.times.ULN [0698]
ALP reduction from baseline 15% [0699] A value of TB<ULN
[0700] The absolute and percent change from Baseline in ALP,
gamma-glutamyl transferase (GGT), alanine aminotransferase (ALT),
AST, total bilirubin, conjugated (direct) bilirubin, albumin,
prothrombin time and international normalized ratio (INR) at
all-time points was measured. The percentage of patients with a
decrease in ALP of 10%, 15%, 20%, and 40% from Baseline or ULN at
month 12 was measured. The percentage of patients achieving the
following biochemical response criteria was also measured: [0701]
ALP3.times.ULN and AST2.times.ULN and bilirubinULN ((Corpechot
2008); Paris I) [0702] ALP1.5.times.ULN and AST1.5.times.ULN and
bilirubin ULN ((Corpechot 2011), Paris II) [0703] ALP1.67.times.ULN
and bilirubin ULN ((Momah 2012), Mayo II) [0704] ALP1.76.times.ULN
((Kumagi 2010b), Toronto II) [0705] Normal bilirubin (values ULN)
and/or normal albumin (values lower limit of normal [LLN]; (Kuiper
2009) [Rotterdam criteria])
[0706] The absolute change from Baseline for enhanced liver
fibrosis (ELF) and hepatic stiffness (at select sites) as
assessments of end stage liver failure. The absolute and percent
change from Baseline on: C-reactive protein (CRP), tumor necrosis
factor-alpha (TNF-.alpha.), tumor necrosis factor-beta
(TGF-.beta.), fibroblast growth factor-19 (FGF-19) levels,
interleukin-6 (IL-6), and CK-18 was measured. The absolute and
percent change from Baseline on PBC-40 domains was measured.
[0707] Absolute and percent change from Baseline on PBC
autoantibodies (IgA, IgG, IgM) and interleukins (IL-12 [p40],
IL-23) were measured.
[0708] Measuring the plasma OCA concentrations including OCA
(unconjugated), conjugates (glyco-OCA and tauro-OCA), and total OCA
(the sum of OCA unconjugated, glyco-OCA, and tauro-OCA).
[0709] Measuring the absolute change from Baseline for total bile
acids, endogenous bile acids, and individual total and unconjugated
bile acids (UDCA, deoxycholic acid, cholic acid and lithocholic
acid), glyco-conjugate, and tauro-conjugate; proportion of each of
the individual bile acids to total bile acids
[0710] Bile acid sequestrant (BAS) concomitant exposure. The
primary analysis set used for all efficacy analyses, along with the
summarization of disposition along with demographics and baseline
characteristics, was the `Intent-to-Treat` (ITT) analysis set. This
analysis set included all randomized patients who received at least
one dose of blinded study drug. When utilizing this analysis set,
patients were analyzed according to the treatment group that they
were randomized to regardless of the actual treatment received. It
should be noted that all but one randomized patient received at
least one dose of blinded study drug.
[0711] For sensitivity analysis purposes, all efficacy analyses
were repeated utilizing a `Completer` analysis set. This analysis
set was comprised of all ITT patients who participated through the
end of the double-blind period (i.e., through the Month 12 visit).
When utilizing this analysis set, patients were analyzed according
to the treatment group that they were randomized to, regardless of
the actual treatment received.
[0712] For additional sensitivity analysis purposes, all efficacy
analyses were again repeated utilizing an `Efficacy Evaluable` (EE)
analysis set. This analysis set was comprised of all `Completer`
patients who did not have any major protocol deviations that would
potentially affect the efficacy of the study drug. This analysis
set definition was finalized in a blinded manner prior to database
lock.
[0713] For population pharmacokinetic (PK) analysis purposes, the
PK analysis set was utilized, which consisted of all patients who
had at least 1 confirmed fasted analyzable sample at and who did
not have any major protocol deviations that could potentially
affect exposure levels.
[0714] To control the overall study-wise type I error rate, a
step-down/closed sequential testing procedure was pre-specified to
adjust for the multiple comparisons of the two OCA dose groups
individually to placebo on the primary study endpoint alone.
Starting with the 10 mg OCA comparison to placebo on the primary
endpoint, the step-down could only be carried to the OCA Titration
comparison to placebo (on the primary endpoint), if and only if the
10 mg OCA comparison to placebo was found to be statistically
significant (i.e., p-value less than 0.05). If the 10 mg OCA
comparison to placebo was not statistically significant (i.e.,
p-value greater than or equal to 0.05), then the hypothesis test
for the OCA Titration comparison to placebo on the primary endpoint
would be deemed as exploratory.
[0715] This pre-specified multiplicity adjustment procedure was
narrow in scope in that it only pertained to the individual OCA
dose comparisons with placebo on the primary endpoint alone. Hence
even if both OCA dose comparisons were found to be statistically
significant, then any other hypothesis test would still be deemed
as exploratory in nature.
[0716] A Cochran-Mantel-Haenszel (CMH) test which adjusted for both
randomization stratification variables as described above, was used
for pre-specified analysis. In tandem with the CMH test, a
Breslow-Day test was also conducted, to test for the homogeneity of
the treatment effect across the different randomization strata.
[0717] The PK population was used to summarize OCA and bile acid
concentrations. The change from Baseline concentrations within each
treatment group was compared using a paired t-test. Descriptive
statistics of OCA plasma concentrations and the extent of BAS
concomitant exposure were provided by treatment group. Initial
evaluation of the effects of BAS on OCA, total bile acid
concentrations, and ALP was performed using a correlation
analysis.
[0718] It can be observed from Table 23 that both OCA treatment
groups showed a superior difference in the proportion/percentage of
patients achieving response at Month 12 when individually compared
to placebo using the CMH test. The corresponding Breslow-Day test
result shows that the treatment effects were homogeneous across the
different randomization strata. This analysis was repeated
utilizing the Completer and EE analysis sets and the conclusions
were consistent. The ultra-worse-case imputation strategy,
implemented by the FDA statistical reviewer as described above, did
not impact the study conclusions. In regards to ALP or TB values at
Month 12, there were no patients who were designated as outliers
(i.e., by having studentized residual values greater than three),
and there was no impact on study conclusions between corrected 30
laboratory values (as presented) and original (i.e., uncorrected)
laboratory values. All of the previously presented analyses were
re-conducted utilizing a baseline value that was the median of all
pre-first dose measurements, and, separately, a traditional
baseline definition (both approaches as described above); there was
no impact on study conclusions with either approach. Considering
the pre-specified step-down/closed sequential testing procedure as
previously described, formal hypothesis testing is stopped at this
point. Any subsequent inferential statistic reported below should
be considered exploratory
TABLE-US-00024 TABLE 23 Proportion of Patients who Achieved
Response 10 mg OCA OCA Titration Placebo Statistics (N = 73) (N =
70) (N = 73) Response at Month 37 (50.7%) 24 (34.3%) 5 (6.9%) 6 - n
(%) [1] Corresponding 95% 39.2%, 62.2% 23.2%, 45.4% 1.1%, 12.6%
Wald Cl Response at 34 (46.6%) 32 (45.7%) 7 (9.6%) Month 12 - n (%)
[1] Corresponding 95% 36.5%, 59.4% 34.0%, 57.4% 2.8%, 16.3% Wald CI
CMH Test p-value [2] <0.0001 <0.0001 Corresponding 0.9072
0.5045 Breslow-Day Test p-value
[0719] It can be observed from Table 24 that both OCA treatment
arms reduced ALP relative to placebo. It should be noted that the
continuous descriptive statistics pertaining to the baseline
absolute change from baseline 12 and percentage change from
baseline utilized only the available data at those time points
(i.e., no missing data were imputed). The categorical descriptive
statistics (i.e., frequencies and corresponding proportions)
utilized the worse-case (i.e., non-response) imputation
strategy.
[0720] Patients from the OCA Titration and OCA 10 mg groups,
respectively, achieved an ALP reduction from Baseline 40% compared
with 1 (1%) placebo patient. The numbers of patients normalizing
ALP values i.e., 118 U/L in females and 124 U/L males are as
follows: 1 (1%) patient from OCA titration group, 5 (7%) patients
from the OCA 10 mg group, and zero placebo-treated patients.
[0721] It can be seen that ALP concentration levels are reduced in
both OCA treatment groups, and during the first three months; these
reduced levels remain stable during the long-term safety and
efficacy (LTSE) period, signifying durability of response.
TABLE-US-00025 TABLE 24 Total Bilirubin (TB) Summary. 10 mg OCA OCA
Titration Placebo Time Point/Statistics (N = 73) (N = 70) (N = 73)
Baseline ALP Concentration (U/L) N 73 70 73 Mean (SD) 316.3
(103.88) 325.9 (116.24) 327.5 (115.01) Median 271.3 281.3 311.9
Min, Max 207, 620 187, 811 144, 746 Month 12 ALP Concentration
(U/L) N 63 64 70 Mean (SD) 191.2 (61.38) 219.5 (99.76) 321.3
(142.88) Median 181.7 196.6 270.5 Min, Max 95, 444 116, 690 149,
733 Absolute Change from Baseline to Month 12 (U/L) N 63 64 70 Mean
(SD) -117.1 (72.84) -103.5 (87.03) -7.7 (87.96) Median -99.0 -85.5
-15.8 Min, Max -346, 0.3 -402, 127 -208, 308 Percentage Change from
Baseline to Month 12 (%) N 63 64 70 Mean (SD) -36.4 (14.88) -30.5
(18.97) -2.5 (23.82) Median -38.3 -31.5 -4.7 Min, Max -72, 0.1 -74,
23 -45, 80 Decrease in ALP .gtoreq.10% at Month 12 - n (%) 61
(83.6%) 55 (78.6%) 29 (39.7%) Decrease in ALP .gtoreq.15% at Month
12 - n (%) 57 (78.1%) 54 (77.1%) 21 (28.8%) Decrease in ALP
.gtoreq.20% at Month 12 - n (%) 54 (74.0%) 49 (70.0%) 17 (23.3%)
Decrease in ALP .gtoreq.40% at Month 12 - n (%) 25 (34.3%) 21
(30.0%) 1 (1.4%) Baseline ALP Concentraton (.times.ULN) N 73 70 73
Mean (SD) 2.658 (0.878) 2.747 (0.9851) 2.760 (0.9732) Median 2.293
2.378 2.607 Min, Max 1.68, 5.23 1.58, 6.86 1.22, 6.31 Month 12 ALP
Concentration (.times.ULN) N 63 64 70 Mean (SD) 1.606 (0.5161)
1.851 (0.8449) 2.705 (1.1987) Median 1.527 1.661 2.286 Min, Max
0.80, 3.75 0.98, 5.84 1.26, 6.19 ALP < 1.0 .times. ULN at Month
12 - n (%) 5 (6.9%) 1 (1.4%) 0 ALP < 1.67 .times. ULN at Month
12 - n (%) 40 (54.8%) 33 (47.1%) 12 (16.4%)
[0722] After completing the treatment period, 193 out of the 216
ITT patients (64 on 10 mg OCA, 63 on OCA Titration, and 66 Placebo
patients) continued on open-label OCA treatment during the LTSE
period (note: that all placebo patients were switched to OCA 5 mg
and then all patients were switched to OCA 10 mg). FIG. 11 presents
ALP concentrations over time, organized by originally randomized
treatment group.
[0723] It can be observed from Table above that reductions from
baseline in TB were greater in both OCA treatment groups than in
the placebo group. It should be noted that the continuous
descriptive statistics pertaining to the baseline, absolute change
from baseline and percentage change from baseline values utilized
only the available data at those time points (i.e., no missing data
was imputed). The categorical descriptive statistics (i.e.,
frequencies and corresponding proportions) utilized the worse-case
imputation strategy. FIG. 12 illustrates TB concentrations over
time, organized by originally randomized treatment group for the
193 ITT patients continuing on open-label OCA treatment during the
LTSE period.
[0724] Dose Titration: A total of 69 of 70 ITT patients from the
OCA titration group completed month 6. Of these, 36 (52%) remained
at 5 mg for the duration of the treatment period and 33 (48%) who
did not meet the primary composite endpoint at Month 6, but,
because they tolerated the investigational product, were titrated
to 10 mg. Thirteen (39%) of the patients who up-titrated met the
composite endpoint suggesting that a benefit can be gained with
titration of OCA from 5 mg to 10 mg in those patients who did not
respond to the 5 mg dose.
[0725] Because for some patients, a response can be achieved with
OCA 5 mg, initiating treatment on OCA 5 mg and titrating
subsequently to 10 mg if needed and if tolerated appears to be a
reasonable dosing strategy. For patients who do not achieve an
optimal response within 6 months of treatment with OCA 5 mg,
additional benefit may be gained by titrating to OCA 10 mg.
[0726] Effect of Bile Acid Sequestrants (BAS) Exposure on Efficacy.
For patients receiving BAS, OCA 5 mg and 10 mg trough
concentrations were slightly lower compared to those patients who
did not receive BAS. The decreased trough concentrations resulted
in a modest attenuation in efficacy in patients receiving OCA 5 mg
(despite instruction to dose BS at least 4 hours apart from OCA),
but did not appear to affect efficacy in patients receiving OCA 10
mg.
[0727] ALP and total bilirubin, were evaluated in relation to age
at baseline, age at time of diagnosis, and years since diagnosis.
The effect of OCA was consistent independent of age at diagnosis,
duration of PBC, or years since diagnosis. In general, the
subgroups were consistent with the observed effect in the overall
ITT population. Greater improvements were observed in OCA-treated
subjects, compared with placebo subjects.
[0728] It can be observed from Table 25 that both OCA treatment
groups showed a difference in the proportion/percentage of patients
achieving response when individually compared to placebo. This
analysis was repeated utilizing the Completer and EE analysis sets
and the conclusions were consistent. The ultra-worse-case
imputation strategy, implemented by the FDA statistical reviewer as
described above, did not impact the results. All of the previously
presented analyses were re-conducted utilizing a baseline value
that was the median of all pre-first dose measurements, and,
separately, a traditional baseline definition (both approaches as
described above); there was no impact on the results with either
approach.
TABLE-US-00026 TABLE 25 Proportion of Patients who Achieved
Response 10 mg OCA OCA Titration Placebo Statistics (N = 60) (N =
60) (N = 61) Response at Month 6 - n (%) [1] 25 (41.7%) 21 (35.0%)
1 (1.6%) Corresponding 95% Wald Cl 29.2%, 54.1% 22.9%, 47.1% 0.0%,
4.8% Baseline ALP .gtoreq. 2.0 .times. ULN - n (%) 42 (70.0%) 47
(78.3%) 46 (75.4%) ALP <2.0 .times. ULN at Month 6 - n (%) [2]
30 (71.4%) 24 (51.1%) 8 (17.4%) Decrease in ALP .gtoreq.40% at
Month 6 - n (%) [2] 10 (23.8%) 13 (27.7%) 0 ALP < 2.0 .times.
ULN and Decrease .gtoreq.40% at Month 6 - n (%) [2] 9 (21.4%) 11
(23.4%) 0 Baseline ALP .gtoreq.1.67 .times. ULN but <2.0 .times.
ULN - n (%) 18 (30.0%) 13 (21.7%) 15 (24.6%) ALP < 1.67 .times.
ULN at Month 6 - n (%) [3] 17 (94.4%) 10 (76.9%) 3 (20.0%) Decrease
in ALP .gtoreq.15% at Month 6 - n (%) [3] 16 (88.9%) 11 (84.6%) 1
(6.7%) ALP <1.67 .times. ULN and Decrease .gtoreq.15% at Month 6
- n (%) [3] 16 (88.9%) 10 (76.9%) 1 (6.7%) Response at Month 12 - n
(%) [1] 26 (43.3%) 23 (38.3%) 3 (4.9%) Corresponding 95% Wald CI
30.8%, 55.9% 26.0%, 50.6% 0.0%, 10.3% Baseline ALP .gtoreq.2.0
.times. ULN - n (%) 42 (70.0%) 47 (78.3%) 46 (75.4%) ALP <2.0
.times. ULN at Month 12 - n (%) [2] 29 (69.1%) 28 (59.6%) 9 (19.6%)
Decrease in ALP .gtoreq.40% at Month 12 - n (%) [2] 13 (31.0%) 16
(34.0%) 1 (2.2%) ALP <2.0 .times. ULN and Decrease .gtoreq.40%
at Month 12 - n (%) [2] 12 (28.6%) 13 (27.7%) 1 (2.2%) Baseline ALP
.gtoreq.1.67 .times. ULN but <2.0 .times. ULN - n (%) 18 (30.0%)
13 (21.7%) 15 (24.6%) ALP <1.67 .times. ULN at Month 12 - n (%)
[3] 16 (88.9%) 11 (84.6%) 6 (40.0%) Decrease in ALP .gtoreq.15% at
Month 12 - n (%) [3] 14 (77.8%) 10 (76.9%) 2 (13.3%) ALP <1.67
.times. ULN and Decrease .gtoreq.15% at Month 12 - n (%) [3] 14
(77.8%) 10 (76.9%) 2 (13.3%)
[0729] Treatment with OCA (10 mg) in a cohort of subjects with
early stage PBC who were enrolled with incomplete biochemical
response to UDCA resulted in statistically significant improvement
from baseline in alkaline phosphatase for the pre-specified
endpoint of reduction of ALP to <1.67.times.ULN and 15%,
relative to placebo. The percentage of patients achieving response
was statistically significantly different than placebo [34 of 73
(46.6%) in the OCA 10 mg arm, 32 of 70 (45.7%) in the titration arm
and 7 of 73 (9.6%) in the placebo arm]. The effect of OCA on
achieving a reduction in ALP was independent of age at diagnosis,
duration of PBC, and baseline ALP.
[0730] Secondary analysis showed that patients from the OCA
Titration and OCA 10 mg groups achieved an ALP reduction from
Baseline 40% compared with 1 (1%) placebo patient. The numbers of
patients normalizing ALP values i.e., 118 U/L in females and 124
U/L males are as follows: 1 (1%) patient from OCA titration group,
5 (7%) patients from the OCA 10 mg group, and zero placebo-treated
patients.
Example 10
[0731] This example describes clinical pharmacology and dosing of
obeticholic acid (OCA--including obeticholic acid compositions
described herein). The starting dosage of OCA is 5 mg orally once
daily in adult patients who have failed to achieve an adequate
reduction in alkaline phosphatase on a stable dose of UDCA for an
adequate duration or who were intolerant to UDCA. OCA can be
supplied as an oral tablet containing obeticholic acid in a
formulation as described herein.
[0732] If an adequate reduction in alkaline phosphatase has not
been achieved after 3 months of OCA 5 mg once daily, and the
patient is tolerating the drug, the dose of OCA can be increased to
10 mg once daily.
[0733] For patients experiencing intolerability due to pruritus,
one of the following modifications was considered: [0734] Reduce
the dosage to: [0735] 5 mg every other day, for patients intolerant
to 5 mg once daily or [0736] 5 mg once daily, for patients
intolerant to 10 mg once daily [0737] Alternative dosing schedules,
such as dosing every other day, every third day or every seventh
day. [0738] Interruption of dosing for up to 2 weeks followed by
restarting at a reduced dose or on an alternative dosing schedule.
[0739] hepatic decompensation. [0740] Addition of an antihistamine
or a bile acid sequestrants.
[0741] OCA may be taken with or without food. Food does not have a
clinically relevant effect on the PK of 10 mg OCA.
[0742] Bile acid binding resins may be taken at least 4 hours
before or 4 hours after (or at as great an interval as possible)
OCA. Bile acid binding resins such as cholestyramine, colestipol,
or colesevelam affect bile acid absorption and may reduce the
absorption, systemic exposure, and efficacy of OCA.
[0743] No dose adjustment is believed to beneeded when OCA is used
in patients with serum creatinine clearance >50 mL/min/1.73
m.sup.2. No data are available as to how severe impairment would
impact the systemic exposure to OCA and its conjugates.
[0744] Dose adjustment may be needed in patients with hepatic
impairment. Dose adjustment may not be needed in patients with mild
hepatic impairment (Child-Pugh Class A). In some examples, the
starting dosage is 5 mg once weekly for patients with moderate or
severe hepatic impairment (Child-Pugh Class B or C). If an adequate
reduction in alkaline phosphatase has not been achieved after 3
months of OCA 5 mg once weekly, and the patient is tolerating the
drug, the OCA dose should be increased to 5 mg twice weekly and
then to 5 mg every day depending on response and tolerability.
[0745] Obeticholic acid is absorbed with peak plasma concentrations
(Cmax) occurring at a median time (tmax) of approximately 2 hours.
Co-administration with food does not alter the extent of absorption
of obeticholic acid. Following multiple-dose administration of 5,
10, and 25 mg once daily for 14 days, systemic exposures of
obeticholic acid increase dose proportionally. Exposures to
glyco-obeticholic acid and tauro-obeticholic acid, and total
obeticholic acid increase more than proportionally with dose.
[0746] Following multiple oral doses of OCA 10 mg once daily, peak
plasma concentrations (Cmax) of OCA occurring at a median time
(Tmax) of approximately 1.5 hours. Median Tmax for glyco-OCA and
tauro-OCA is 10 hours.
[0747] Distribution. Human plasma protein binding of obeticholic
acid and its conjugates is greater than 99%. The volume of
distribution of OCA is 613L. The volume of distributions of glycol-
and tauro-obeticholic acid has not been determined.
[0748] Elimination and Metabolism. Obeticholic acid is conjugated
with glycine or taurine in the liver and secreted into bile. These
glycine and taurine conjugates of obeticholic acid are absorbed in
the small intestine leading to enterohepatic recirculation. The
conjugates can be deconjugated in the ileum and colon by intestinal
microbiota, leading to the conversion to obeticholic acid that can
be reabsorbed or excreted in feces, the principal route of
elimination.
[0749] After daily administration of obeticholic acid, there is
accumulation of the glycine and taurine conjugates of obeticholic
acid which have in vitro pharmacological activities similar to the
parent drug, obeticholic acid. The metabolite-to-parent ratios of
the glycine and taurine conjugates of obeticholic acid were 13.8
and 12.3, respectively, after daily administration. An additional
third obeticholic acid metabolite, 3-glucuronide is formed but is
considered to have minimal pharmacologic activity.
[0750] Excretion. After administration of radiolabeled obeticholic
acid, greater than 85% is excreted in feces. Urinary excretion is
less than 3%.
[0751] The proposed human metabolic pathways are shown in FIG.
13.
[0752] Following an oral administration of 25 mg [.sup.14C]-OCA,
about 87% of the dose is excreted in feces through biliary
secretion. Less than 3% of the dose is excreted in the urine with
no detection of OCA.
[0753] The effective half-life of OCA is about 24 hours.
[0754] Gender, age, and race had no impact on the pharmacokinetics
of OCA based on the population-PK analysis. Population PK analysis
dataset consisted of 301 female and 505 male subjects, age ranging
from 18 to 71 years and had 10 Asian, 233 Black, 554 White and 9
Other subj ects.
[0755] In vitro studies: Obeticholic acid is not an inhibitor of
CYP2C8 and did not cause a significant change in the expression of
CYP2B6, CYP2C8, CYP2D.sub.6, MRP2, MRP3, MRP4, MATE1, and OATP2B 1.
Obeticholic acid showed either no or weak effects on these
metabolizing enzymes and transporters.
[0756] Concomitant administration of 20 mg omeprazole once daily
with obeticholic acid 10 mg once daily resulted in a less than
1.2-fold increase in obeticholic acid exposure.
[0757] Treatment with obeticholic acid 10 mg or obeticholic acid
titration (5 mg to 10 mg) resulted in clinically meaningful and
statistically significant increases (p<0.0001) relative to
placebo, in the number of patients achieving the primary composite
endpoint at all study time points (see Table 26). Responses
occurred as early as 2 weeks and were dose dependent (obeticholic
acid 5 mg compared with obeticholic acid 10 mg at 6 months,
p=0.04).
TABLE-US-00027 TABLE 26 Percentage of Patients Achieving
Response..sup.A Obeticholic acid .+-. UDCA.sup.B Obeticholic acid
Obeticholic acid Placebo .+-. Titration.sup.C 10 mg UDCA.sup.B (N =
70) (N = 73) (N = 73) Month 6 Dose 5 mg 10 mg Responders, n (%) 24
(34) 37 (51) 5 (7) p-value.sup.D <0.0001 <0.0001 NA Month 12
Dose 5 mg or 10 mg 10 mg Responders, n (%) 32 (46) 34 (47) 7 (10)
p-value.sup.D <0.0001 <0.0001 NA NA = not applicable
.sup.APercentage of Subjects Achieving an ALP less than 1.67
.times. ULN and Total Bilirubin less than or equal to the ULN and
an ALP decrease of 15% or greater. Missing values were considered a
non-response. .sup.BThe majority of patients received treatment in
combination with UDCA and a small number of patients unable to
tolerate UDCA received obeticholic acid as monotherapy.
.sup.CSubjects randomized to obeticholic acid titration received
obeticholic acid 5 mg for the initial 6-month period. At Month 6,
patients who did not achieve the composite endpoint and did not
have evidence of tolerability issues were titrated from 5 mg to 10
mg for the final 6 months of the double-blind phase. .sup.Dp-values
for comparing obeticholic acid versus placebo are obtained using
CMH General Association test stratified by double-blind Baseline
UDCA usage (yes/no) and double-blind Baseline total bilirubin (less
than or equal to the ULN/greater than the ULN).
[0758] In one example, 77% of patients on both titration and 10 mg
obeticholic acid achieved a reduction of at least 15% in ALP at 12
months compared to 29% of patients on placebo (see FIG. 14A, FIG.
14B, FIG. 14C). In addition, 36% of patients treated with placebo
experienced an increase in ALP associated with worsening of disease
compared to 5% of patients on titration obeticholic acid and 2% on
10 mg obeticholic acid.
[0759] Treatment with obeticholic acid also resulted in clinically
meaningful and statistically significant improvements versus
placebo (p<0.0001) in ALP levels as early as 2 weeks and at all
timepoints thereafter (see FIG. 15A, FIG. 15B). During the
double-blind, 12 month period, bilirubin levels increased in the
placebo patients and remained stable in patients taking obeticholic
acid.
[0760] Patients randomized to the obeticholic acid titration group
received obeticholic acid 5 mg for the initial 6-month period. At
Month 6, patients who did not yet meet the criteria for the
composite endpoint and did not have evidence of tolerability issues
were titrated from obeticholic acid 5 mg to obeticholic acid 10 mg
for the final 6 months of the double-blind phase. SE=standard
error.
[0761] The above dosing regimen including a 5 mg QD starting dose,
followed by up-titration to 10 mg QD at 3 months was based on
response and tolerability for the overall population. Based on the
dose dependent increase in incidences of pruritus and better
tolerability profile with time with a lower starting dose, 5 mg QD
(once daily) is an effective starting dose for the general
population.
[0762] The increase in dose from 5 mg to 10 mg QD resulted in
additional responders from month 6 to month 12. There were also 19%
patients (out of patients on 5 mg QD dosing) who were responders
(as per the primary composite endpoint criteria), but became
non-responders, possibly due to disease progression, with continued
dosing of 5 mg QD. These patients also benefit from up-titration to
10 mg QD.
[0763] In the dedicated hepatic impairment study with a single dose
of 10 mg, the systemic exposure (AUC0-9 days) to total OCA was
1.1-, 4.2-, and 17.3-fold in subjects with mild, moderate and
severe hepatic impairment, respectively, when compared to normal
healthy volunteers. The mean total OCA concentration-time profiles
in this study are shown in FIG. 16 and the mean PK parameters (Cmax
and AUCt) for total OCA in plasma for normal healthy volunteers and
subjects with various categories of hepatic impairment are
quantified in Table 27.
TABLE-US-00028 TABLE 27 Mean (SD) PK parameters of plasma total
OCA. Normal Hepatic Mild Parameters Function (N = 8) (N = 8)
Moderate (N = 8) Severe (N = 8) Cmax (ng/mL) 68.3 (27.6) 107 (65.1)
348 (377) 674 (281) AUC0-t 2480 (1810) 2770 (2060) 15700 (19100)
41000 (21900) (hr * ng/mL)
[0764] There was no apparent association of change of unbound free
fraction percentage (% Fu) of OCA and tauro-OCA with the increased
degree of hepatic impairment. Mean % Fu of glyco-OCA increased in
patients with severe hepatic impairment.
Example 11
[0765] Obeticholic acid (OCA) is a farnesoid X receptor (FXR)
agonist and as shown, inter alia, useful for the treatment of
primary biliary cholangitis/cirrhosis (PBC), nonalcoholic
steatohepatitis (NASH), and other liver diseases. OCA is the
6.alpha.-ethyl derivative of chenodeoxycholic acid (CDCA). Patients
with cirrhosis have systemic bile acid exposure higher than those
in healthy subjects (.times.18) while hepatic bile acid exposure is
only .about.2.times. higher. Thus systemic OCA exposure may not be
reflective of OCA concentrations in the liver or intestine, the
primary sites of action.
[0766] Plasma levels of OCA and its conjugates were measured in
healthy subjects and cirrhotic patients with varying degrees of
hepatic impairment. A physiologic pharmacokinetic model for OCA was
developed to quantitatively describe the absorption, distribution,
metabolism, and excretion of OCA in patients with and without
hepatic impairment. The model was based on a published
multi-compartment PK model for CDCA, and consisted of systemic,
hepatobiliary, and intestinal systems. The model was used to
simulate the pathophysiological abnormalities caused by cirrhosis
including decreased hepatic uptake, portal-systemic shunting,
decreased liver volume, and differences in amino acid
conjugation.
[0767] There was good agreement between predicted and observed
increases in systemic OCA exposure after a single 10 mg dose in
subjects with mild (.times.1.4), moderate (.times.8), and severe
(.times.13) hepatic impairment relative to healthy subjects. The
predicted increases in liver exposure for subjects with mild,
moderate, and severe hepatic impairment were increased only 1.1-,
1.5-, and 1.7-fold, relative to healthy participants. Hepatic
exposure of OCA, the primary site of pharmacological activity, is
increased marginally (.about.2-fold) in patients with
cirrhosis.
[0768] Bile acids are the natural endogenous ligand for the
famesoid X receptor (FXR) which is a nuclear receptor with high
expression levels in the liver and intestine. Nuclear receptors
constitute a family of ligand-activated transcription factors which
can either activate or repress target genes, including those
involved in bile acid homeostasis. FXR activation appears to lead
to decreased bile acid synthesis via CYP7A1 suppression, decreased
conjugated bile acid uptake, and increased excretion from the
hepatocytes via induction of transporters. Obeticholic acid (OCA,
6-ethyl chenodeoxycholic acid) is a FXR agonist. OCA is a
modification of chenodeoxycholic acid (CDCA), the most potent
endogenous agonist of FXR and differs from CDCA by the addition of
an ethyl group at the 6 carbon position. The addition of this ethyl
group to CDCA confers approximately 100-fold greater potency
compared to CDCA.
[0769] PBC is a rare chronic autoimmune disease characterized by
T-cell mediated destruction of the intrahepatic bile ducts,
decreased bile secretion, bile acid retention in the liver,
inflammation, fibrosis, cirrhosis, and liver failure, followed by
either liver transplantation or death. NASH is a chronic liver
disease often associated with type 2 diabetes or metabolic syndrome
which is defined by presence of hepatic steatosis, inflammation,
and cytological ballooning with eventual varying degrees of
fibrosis and possible cirrhosis leading to liver transplantation,
hepatocellular carcinoma or death. In general, chronic injury to
the liver can lead to the formation of regenerative nodules and
fibrous bands in the liver that form after an extended process of
fibrosis. Cirrhosis causes the interface between the sinusoids and
the hepatocytes to fill with fibrotic tissue leading to increased
resistance to hepatic blood flow causing portal hypertension and
its associated complications. Previous reports have shown that
patients with cirrhosis have systemic bile acid exposure markedly
higher than those in healthy subjects (18-fold higher) while
hepatic bile acid exposure was only .about.2-fold higher.
[0770] There are 4 primary mechanisms of hepatic impairment that
are related to the pharmacokinetics of endogenous bile acids and
OCA: reduced hepatic uptake (caused in part by capillarization of
the sinusoids), portal systemic shunting (both hepatic and
extrahepatic), decreased functional liver volume, and increased
taurine conjugation. Mild liver disease may be associated with
little or no change in the hepatic uptake of bile acids but severe
cirrhosis and/or jaundice causes large decreases in the extraction
ratio that affects all bile acids similarly. Healthy control
subjects have hepatic uptakes of bile acids of at least 70%. In
contrast, values in cirrhotic patients were reduced over a wide
range of values with some less than 10%.
[0771] Portosystemic shunting appears to occur secondary to the
development of portal hypertension. With ongoing liver injury,
resultant fibrogenesis and the occurrence of nodular regeneration,
intrahepatic resistance increases. When coupled with increased
splanchnic blood flow into the liver that occurs as a result of
splanchnic vasodilation in cirrhotics, portal pressures can become
elevated and blood is shunted through collateral vessels, away from
the liver. Portosystemic shunting can occur via either diversion of
blood through newly developed veins or via anastomoses ("shunts")
formed between existing portal and hepatic veins and is associated
with higher systemic bile acid concentrations. Relative to normal
controls, the portal blood flow was 91%, 64%, and 55%, for
Child-Pugh scores-A, -B, and -C, respectively. In response to the
decreased portal blood flow to the liver, the hepatic arterial
blood flow increased by 41%, 63%, and 92% for Child Pugh-A, --B,
and --C, relative to normal controls. This increase in arterial
blood flow in response to decreased portal blood flow is termed
hepatic arterial buffer response and allows for relatively constant
blood flow to the liver regardless of portosystemic shunting. The
SimCYP library for cirrhotic subjects uses a decrease of 89%, 71%,
and 61% in functional liver size relative to control subjects in
subjects with Child-Pugh Score-A, -B, and -C, respectively, based
on meta-analyses (SimCYP simulator Version 11; Simcyp Limited,
Sheffield, UK).
[0772] Bile acids are metabolized in the liver, primarily by
conjugation (N-acylamidation) to the amino acids glycine or
taurine. In healthy humans, a normal adult ratio of glycine to
taurine bile acid conjugation ("G/T ratio") is 3:1 with a range of
1:1 to 5:1. Dietary intake of taurine increases the proportion of
bile acids conjugated with taurine. In contrast, oral ingestion of
glycine does not change the G/T ratio. The G/T ratio in healthy and
disease states appears to be governed by the liver as opposed to
intestinal control via preferential deconjugation of glycine
conjugated bile acids by bacteria or preferential conjugate uptake
into the enterocytes. It has been reported in the literature that
the G/T ratio is decreased in patients with cirrhosis.
[0773] A physiologic pharmacokinetic model exists describing the
metabolism and enterohepatic circulation of CDCA. The CDCA model
included 9 spaces based on anatomical and physiological
considerations (systemic circulation, portal circulation,
sinusoidal circulation, liver, bile duct, gallbladder,
duodenum-jejunum, ileum, and colon) with each space possessing a
compartment of either CDCA, glycine-conjugated CDCA (glyco-CDCA),
or taurine-conjugated CDCA (tauro-CDCA). The model included
transfer coefficients describing fluid flow, biotransformation of
chemical entities, and transport across membranes.
[0774] Without being bound by any particular theory, due to the
similar structure of CDCA, OCA was considered to have comparable
pharmacokinetic properties when compared to CDCA. This examples
describes development of a physiologic PK model to quantitatively
describe the absorption, distribution, metabolism, and excretion of
OCA. In addition, the model was used to define the effects of
hepatic impairment to predict the systemic and liver exposure to
OCA in subj ects with various degrees of liver impairment relative
to healthy subj ects with normal liver function. The model was
developed based on 3 studies in healthy volunteers and 2 studies in
patients with varying degrees of hepatic impairment (N=399).
[0775] All participants in each of the studies were over 18 years
of age and provided informed consent for willing participation. The
studies were conducted in accordance with the Declaration of
Helsinki (Seoul 2008 Revision) and adhered to guidelines for Good
Clinical Practices and were approved by all relevant ethics
committees.
[0776] Data from was used to develop the model in healthy subjects
(n=160) and then adjust for hepatic impairment (n=32) using the
data from the above Examples. After development, the model was
validated with data sourced from healthy subjects and cirrhotic
patients.
[0777] The data used in model development included subject
identifiers, time of dosing and sample collection, plasma drug
concentrations (OCA, glyco-OCA, and tauro-OCA), dose amount,
disease status (e.g., Child-Pugh score), and meal consumption
information. Study participants received standardized meals at
specified times during inpatient observation. Gallbladder
contraction was assumed to last 90 minutes after the start of a
meal. Drug concentrations below the limit of quantification (BLQ)
were imputed to half of the lower limit of quantification
(LLOQ).Observed and BLQ concentrations of OCA, glyco-OCA, and
tauro-OCA associated with samples drawn prior to the first dose
were excluded from the analyses. As the glyco- and tauro-conjugates
are nearly equipotent relative to OCA on FXR, total OCA
concentrations were calculated as the sum of OCA, glyco-OCA, and
tauro-OCA.
[0778] Concentrations of OCA (420.6 g/mol), glyco-OCA (477.7
g/mol), and tauro-OCA (527.8 g/mol) were measured from human plasma
samples using high performance liquid chromatography tandem mass
spectrometry (LC-MS/MS) (Shimadzu 10AVP HPLC System, Kyoto, Japan;
AB MDX Sciex API-4000 LC-MS/MS System, Framingham, Mass.). The LLOQ
for OCA, glyco-OCA, and tauro-OCA was 0.594 nM, 0.523 nM, and 0.474
nM, respectively.
[0779] The PK model developed for CDCA used 27 compartments
consisting of 9 spaces with anatomical and physiological
considerations, each requiring three compartments to accommodate
CDCA, glyco-CDCA, and tauro-CDCA. Division of each space into 3
compartments was necessary because while flow rates (e.g., blood
flow) were independent of chemical structure, biotransformation
rates (e.g., conjugation and deconjugation) and transport rates
(e.g., hepatic uptake) differed based on chemical structure. Values
for the physiologic compartment volumes and transfer rates used in
the model were obtained from the literature. To construct the PK
model for OCA, the physiologic PK model for CDCA was structurally
modified to accurately reflect the interaction of human physiology
and OCA.
[0780] A number of structural modifications were made to the base
CDCA model in order to adapt it for use with OCA. For
simplification, a single space was used to represent the gut (small
and large intestines). Since OCA is an exogenous molecule, it was
assumed that there was no endogenous synthesis and an absorption
compartment with a first-order transfer coefficient (K.sub.a) was
included to represent the administration and absorption kinetics of
an oral OCA dose. Based on steric hindrance by the 6-ethyl group of
OCA, no bacterial 7-alpha dehydroxylation biotransformation
activity (i.e., CDCA to lithocholic acid) was included in the
model. Compartment volumes in the model were fixed to physiological
values from the base CDCA model. The OCA model used the
physiological flow values for blood, bile and gastrointestinal
transit from the original physiologic PK model for CDCA, with the
exception of flows from bile duct to gallbladder and from bile duct
to gut. The physiological values from the base model led to poor
predictions and may not be applicable due to the simplification of
the enteral system into a unified gut compartment. The
biotransformation and transport rates in the model, being dependent
on chemical entity structure, were estimated by fitting the model
to the plasma concentration time profiles of OCA, glyco-OCA, and
tauro-OCA.
[0781] The PK model was first developed using the OCA, glyco-OCA,
and tauro-OCA plasma concentration time profiles from healthy
volunteers with normal hepatic function. Model parameter estimates
related to healthy physiology were then held constant while the PK
model was further developed using OCA, glyco-OCA, and tauro-OCA
plasma concentration time profiles from patients with hepatic
impairment (Child-Pugh scores A, B, and C). Only parameters
specific to hepatic impairment were estimated during this
process.
[0782] Four mechanisms of hepatic impairment were incorporated into
the OCA PK model and included (1) reduction of hepatic uptake, (2)
portal systemic shunting, (3) decreased functional volume, and (4)
preferential conjugation to taurine. These parameters were
incorporated in the model in a manner allowing the parameter
estimates in subjects with mild, moderate, and severe hepatic
impairment to progressively deviate relative to the parameter
values estimated in healthy volunteers. These deviations for the
portal systemic shunting and decreased functional liver volume
mechanisms used physiological values from the Simcyp library for
cirrhotic subjects (SimCYP simulator Version 11; Simcyp Limited,
Sheffield, UK). The deviations for the reduced hepatic uptake and
change in OCA conjugation mechanisms were estimated based on
fitting of the plasma drug concentration time profiles from
subjects with hepatic impairment. Table 28 lists the model
parameters and coding modifications associated with the four
mechanisms of hepatic impairment.
TABLE-US-00029 TABLE 28 Model Parameters and Coding Modification
associated with mechanism of Hepatic Impairment.
Anatomical/Physiological Change Equations Decreased hepatic uptake
t.sub.10-Mild = t.sub.10 * exp(Effect in Mild hepatic impairment in
hepatic uptake of OCA and conjugates) t.sub.10-Moderate = t.sub.10
* exp(Effect in Moderate hepatic impairment in hepatic uptake of
OCA and conjugates) t.sub.10-Severe = t.sub.10 * exp(Effect in
Severe hepatic impairment in hepatic uptake of OCA and conjugates)
Portal-systemic f.sub.4-Mild = f.sub.4 * 1.408 for mild hepatic
impairment shunting/Arterial buffer f.sub.4-Moderate = f.sub.4 *
1.625 for moderate hepatic impairment response f.sub.4-Severe =
f.sub.4 * 1.915 for severe hepatic impairment f.sub.8-Mild =
f.sub.8 * 0.91 for mild hepatic impairment f.sub.8-Moderate =
f.sub.8 * 0.635 for moderate hepatic impairment f.sub.8-Severe =
f.sub.8 * 0.554 for severe hepatic impairment Decreased
V.sub.liver-Mild = V.sub.liver-healthy * 0.891 for mild hepatic
impairment functional/anatomical liver V.sub.liver-Moderate =
V.sub.liver-healthy * 0.71 for moderate hepatic impairment volume
V.sub.liver-Severe = V.sub.liver-healthy * 0.61 for severe hepatic
impairment Changes in b.sub.16-Mild = b.sub.16 * exp(Effect of Mild
hepatic impairment on OCA tauro-conjugation) for mild hepatic
metabolism/conjugation impairment b.sub.16-Moderate = b.sub.16 *
exp(Effect of Moderate hepatic impairment on OCA tauro-conjugation)
for moderate hepatic impairment b.sub.16-Severe = tb.sub.10 *
exp(Effect of Severe hepatic impairment on OCA tauro-conjugation)
for severe hepatic impairment
[0783] For the portal systemic shunting mechanism, the coefficient
for portal to sinusoidal flow was progressively decreased as
hepatic impairment worsened and was matched by a progressive
increase in flow from the portal to systemic circulation of equal
magnitude. The latter flow does not occur in healthy individuals.
To compensate for reduced blood flow to the liver, the coefficient
for hepatic arterial flow from the systemic circulation to the
sinusoids was progressively increased with worsening hepatic
impairment (i.e., hepatic arterial buffer response).
[0784] The biotransformation coefficient for conjugation of taurine
to OCA was allowed to change for mild, moderate, and severe hepatic
impairment relative to the coefficient in healthy subjects while
the coefficient for conjugation to glycine was fixed at the value
for healthy individuals.
[0785] The OCA physiologic PK model used a population PK approach
and consisted of a description of the relationships between plasma
drug concentrations and time as well as components for between
subject and residual variability. Between subject variability (BSV)
was modeled assuming a log-normal distribution as follows:
.theta..sub.in=.theta..sub.Tvn exp(.eta..sub.in)
(.eta..sub.1 . . . .eta..sub.m).about.MVN(0,.OMEGA.)
[0786] Where .theta..sub.Tvn is the population typical value for
the n.sup.th PK parameter (e.g., clearance) and .eta..sub.in (ETA)
is the random BSV on the n.sup.th parameter for subject i that
jointly follow a multivariate normal distribution (MVN) with a mean
of zero and variance of .OMEGA.. The BSV model assumes that PK
parameters are log-normally distributed. Due to the high level of
model complexity, BSV was only incorporated on K.sub.a and the flow
rate from gallbladder to gut, both parameters that analysis showed
had substantial impact on the plasma concentration time profiles.
Residual variability was assumed to have additive and proportional
components:
y.sub.ij=y.sub.ij.times.(1+.epsilon..sub.1ij)+.epsilon..sub.2ij
[0787] Where y.sub.ij and y.sub.ij represent the j.sup.th observed
and predicted plasma drug concentration for the i.sup.th subject
and .epsilon. is the random residual variability. Each .epsilon. is
normally distributed with a mean of zero and a variance of
.sigma..sup.2. Distinct residual variability components were
estimated for OCA, glyco-OCA, and tauro-OCA.
[0788] Model development was guided by feedback from various
diagnostic plots including: observed OCA, glyco-OCA, and tauro-OCA
versus population prediction (PRED) or individual prediction
(IPRED) with a line of unity and trend line, conditional weighted
residuals (CWRES) of OCA, glyco-OCA, and tauro-OCA versus PRED or
time, and prediction-corrected visual predictive checks (pcVPC; 200
iterations).
[0789] A simulation with 200 replicates was performed based on
subjects in the phase 1 hepatic impairment study using the OCA
physiologic PK model. Dosing and meal consumption history were used
to simulate rich 0 to 216 hour concentration-time profiles of OCA,
glyco-OCA, and tauro-OCA. Total OCA was calculated for each
observation by summing the molar-based concentrations for OCA,
glyco-OCA, and tauro-OCA. Total OCA concentrations from the
systemic circulation and liver were subjected to non-compartmental
analysis to calculate Cmax and AUC (0-216h).
[0790] Phoenix.RTM. NLME.TM. software version 1.3 (Certara Inc.,
Princeton, N.J.) was used for the physiologic population PK
analysis and simulations with Lindstrom-Bates First-order
Conditional Estimation (FOCE-LB). Analysis datasets,
visualizations, and exploratory analyses were created using R
software version 3.1 (The R Foundation) and SAS version 9.4 (SAS
Institute Inc., Cary, N.C.). GraphPad Prism software version 6.07
(Graphpad Software Inc., La Jolla, Calif.) was used for the
generation of some graphical analyses.
[0791] The OCA physiologic PK model was initially developed using
8248 plasma sample concentrations of OCA, glyco-OCA, and tauro-OCA
from 160 healthy volunteers administered 10 mg OCA in a cross-over
design. Each subject contributed PK samples from both study
periods. The healthy volunteer pool had normal hepatic function,
was primarily male (59%), mean (SD) age was 37.0 (9.8) years, and
mean (SD) weight was 76.4 (11.8) kg. Volunteers were 65.6% white,
32.5% black, 0.6% Asian, and 1.3% other. The percentage of BLQ
samples with imputed concentrations was 38.2%, 9.4%, and 24.4% for
OCA, glyco-OCA, and tauro-OCA, respectively.
[0792] The healthy PK model contained a total of 22 parameters: 7
flow parameters, 4 biotransformation parameters, and 11 transport
parameters (Table 29). Many of these were expected to have values
specific to exogenous OCA (e.g., hepatic uptake) or did not exist
in the base model (e.g., K.sub.a or K.sub.out) and thus required
estimation. Most of the flow parameters were fixed to physiological
values from the literature with the exception of bile duct to
gallbladder and from bile duct to gut. All structural parameters
(Table 29) were well estimated (.ltoreq.5.5% CV). The BSV for flow
from bile duct to gallbladder was 78.1% (19.3% CV) and for the oral
absorption of OCA was 195% (2.21% CV). The additive portion of
residual variability was .ltoreq.1 nM (15-50% CV) and the
proportional portion ranged from 72% to 88% (30-70% CV) for OCA and
its conjugates. The pcVPC results shown in FIG. 25A, FIG. 25B, FIG.
25C, and FIG. 25D and the goodness of fit plots shown in FIGS.
18A-18F and FIGS. 19A-19F indicate acceptable model
performance.
TABLE-US-00030 TABLE 29 Model Parameters in Normal Hepatic Function
Parameter Parameter Description Estimate CV % BSV (RSE %) f.sub.4
(L/h) Hepatic arterial flow 14.4 Fixed f.sub.3 (L/h) Hepatic portal
flow 39.6 Fixed t.sub.10 (h.sup.-1) OCA transport rate from liver
to sinusoidal space 1698 1.0 t.sub.9 (h.sup.-1) Glyco-OCA transport
rate from sinusoidal space to liver 1210 2.0 t.sub.11 (h.sup.-1)
Tauro-OCA transport rate from sinusoidal space to liver 1615 1.9 NA
t.sub.12 (h.sup.-1) OCA transport rate from sinusoidal space to
liver 1.62 Fixed t.sub.12 (h.sup.-1) Glyco-OCA and tauro-OCA
transport rate from liver to 1.62 Fixed sinusoidal space f.sub.24
(L/h) Flow from bile duct to gut 7.29 4.5 f.sub.22 (L/h) Flow from
bile duct to gallbladder 0.856 4.4 78.1% (19.3) f.sub.28 (h.sup.-1)
Rate of output from gallbladder to gut 1.2 Fixed K.sub.out (L/h)
Rate of fecal elimination of OCA 0.612 5.5 b.sub.16 (h.sup.-1) OCA
rate of conjugation with glycine 1.44 4.5 b.sub.18 (h.sup.-1) OCA
rate of conjugation with taurine 0.312 1.9 b.sub.38 (h.sup.-1)
Glyco-OCA rate of deconjugation to OCA 0.0431 4.5 NA b.sub.37
(h.sup.-1) Tauro-OCA rate of deconjugation to OCA 0.0200 1.8
f.sub.34 (h.sup.-1) OCA rate of absorption from gut to portal space
0.857 3.4 f.sub.33 (h.sup.-1) Glyco-OCA rate of absorption from gut
to portal space 0.904 1.1 f.sub.35 (h.sup.-1) Tauro-OCA rate of
absorption from gut to portal space 1.62 2.2 K.sub.9 (h.sup.-1) OCA
first order rate constant of oral absorption 5.32 1.0 195% (2.21)
t.sub.18 (h.sup.-1) Glyco-OCA transport rate from liver to bile
duct 7.44 0.7 NA t.sub.21 (h.sup.-1) Tauro-OCA transport rate from
liver to bile duct 9.28 1.0 Proportional Error OCA (%) 88.0 33.9 NA
Proportional Error Glyco-OCA (%) 62.6 32.7 Proportional Error
Tauro-OCA (%) 71.6 70.4 Additive Error OCA (nM) 0.546 18.5 Additive
Error Glyco-OCA (nM) 0.675 21.8 Additive Error Tauro-OCA (nM) 0.469
50.3
[0793] Development of the PK model for the physiological changes
associated with hepatic impairment used 928 plasma sample
concentrations of OCA, glyco-OCA, and tauro-OCA from 32 subjects-8
subjects each with mild, moderate, severe hepatic impairment and
normal hepatic function. Subjects were administered a single 10 mg
dose of OCA. The study subjects were primarily male (72%), had a
mean (SD) age of 55.0 (5.6) years, and mean (SD) body weight was
81.7 (16.9) kg. Participants were 90.6% white, 3.1% black, 3.1%
Asian, and 3.1% other. Mean Child-Pugh Score was 8.0 (2.0)
(Child-Pugh Score: Class A/Mild 5-6 points, Class B/Moderate 7-9
points, Class C/Severe 10-15 points). The percentage of BLQ samples
with imputed concentrations was 16.8%, 5.4%, and 9.6% for OCA,
glyco-OCA, and tauro-OCA, respectively.
[0794] The 22 PK parameters from the healthy PK model were held
fixed during the development of the model for hepatic impairment.
Portal systemic shunting and reduced functional liver volume
parameters were fixed to physiological values from the literature
while parameters associated with reduced hepatic uptake and changes
in OCA conjugation were estimated. Parameter estimates for hepatic
uptake and taurine conjugation obtained from the hepatic impairment
PK model are presented in Table 30. The structural parameters were
well estimated (<25% CV) with the exception of the change in
hepatic uptake in OCA and its conjugates in moderate hepatic
impairment (44% CV) and the change in OCA conjugation for severe
hepatic impairment (109% CV). The BSV for flow from bile duct to
gallbladder was 168% (299% CV) and for the oral absorption of OCA
was 246% (9.87% CV). The additive portion of residual variability
was .ltoreq.1 nM (>75% CV) and the proportional portion ranged
from 112% to 123% for OCA and its conjugates (>75% CV). This
magnitude of variability is consistent with a bile acid analog that
undergoes extensive enterohepatic recirculation. The pcVPC results
shown in FIGS. 26A-26D and the goodness of fit plots indicate
acceptable model performance.
TABLE-US-00031 TABLE 30 Modified Model Parameters in Impaired
Hepatic Function Parameter Estimate CV % Effect in Mild hepatic
impairment in hepatic uptake of OCA and conjugates -0.132 9.11
Effect in Moderate hepatic impairment in hepatic uptake of OCA and
conjugates -1.86 44.3 Effect in Severe hepatic impairment in
hepatic uptake of OCA and conjugates -2.37 24.9 Effect of Mild
hepatic impairment on OCA tauro-conjugation 0.00481 0.341 Effect of
Moderate hepatic impairment on OCA tauro-conjugation 1.05 15.8
Effect of Severe hepatic impairment on OCA tauro-conjugation 1.56
109 Proportional Error OCA (%) 122 77.1 Proportional Error
Glyco-OCA (%) 112 384 Proportional Error Tauro-OCA (%) 123 636
Additive Error OCA (nM) 0.993 77.1 Additive Error Glyco-OCA (nM)
0.273 383 Additive Error Tauro-OCA (nM) 0.532 627 BSV OCA first
order rate constant of oral absorption 246% 9.87 Flow from bile
duct to gallbladder 168% 299
[0795] The final OCA physiologic PK model, developed for both
normal and impaired hepatic function, was validated with external
PK data in subjects with normal (single doses of 10 mg and
multiple-dosing to steady-state with doses of 5 mg, 10 mg, or 25
mg) and hepatic impairment (cirrhosis and portal hypertension).
FIG. 27A to FIG. 27C and FIG. 28A to FIG. 28C show pcVPC-based
assessments of the model's ability to accurately predict the plasma
total OCA concentration time profiles under these varied
conditions. The model predicted the profiles well for subjects with
normal hepatic function (FIGS. 20A-20F, FIGS. 21A-21D) and for
subjects with moderate or severe hepatic impairment (FIGS.
22A-22F). For mild hepatic impairment, the model tended to
underestimate the total OCA concentrations.
[0796] Simulations of total OCA in the systemic circulation
(plasma) and in the liver after a single 10 mg dose were compared
to observed total OCA plasma concentrations from the hepatic
impairment clinical study in FIGS. 23A-22B. The total OCA exposures
are summarized as either the Cmax or the AUC over the 216 hour
sampling period. For both exposure measures, and across all levels
of hepatic function, there appeared to be agreement between the
exposures observed in the clinical trial and the exposures
predicted by the PK model. Simulation data in Table 31 reveals that
the systemic AUC of total OCA in subjects with mild, moderate, and
severe hepatic impairment increased 1.4-, 8.0-, and 13-fold
relative to subjects with normal hepatic function. However, in the
liver, the predicted AUC of total OCA in subjects with mild,
moderate, and severe hepatic impairment increased only 1.1-, 1.5-,
and 1.7-fold relative to subjects with normal hepatic function.
TABLE-US-00032 TABLE 31 Systemic AUC of total OCA in Patients with
mild, moderate, and severe hepatic impairment. Liver Impairment
Ratio (Liver Impairment/Normal) Exposure Metric Normal Mild
Moderate Severe Mild/Normal Moderate/normal Severe/normal Systemic
AUC (ng .times. h/mL) 2339 3156 18785 30986 1.35 8.03 13.2
C.sub.avg (ng/mL) 10.8 14.6 87 143 1.35 8.03 13.2 C.sub.max (ng/mL)
99.5 131 634 961 1.31 6.38 9.66 Liver AUC (ng .times. h/mL) 47427
53032 89540 82521 1.12 1.47 1.74 C.sub.avg (ng/mL) 220 248 322 382
1.12 1.47 1.74 C.sub.max (ng/mL) 2395 2665 2701 2651 1.11 1.13 1.11
Mean Simulated OCA Distribution (% Nanomoles Total OCA) Systemic
Circulation 1.03 10.36 Portal Circulation 0.77 2.33 Sinusoidal
Circulation 0.05 0.45 Liver 7.88 10.44 Bile Ducts 0.14 0.13
Gallbladder 39.94 37.74 Gut 50.20 36.56
[0797] This OCA physiologic PK model, derived from prior bile acid
models, provides valuable insights into the absorption,
distribution, metabolism, and excretion of the drug. Orally
administered OCA is absorbed from the intestines, conjugated with
glycine or taurine in the hepatocyte, and the conjugated OCA
circulates enterohepatically. Conjugation also results in most of
the OCA conjugates being poorly absorbed in the proximal small
intestine and reaching the terminal ileum, where bile acids are
actively conserved. The predominant pharmacodynamic activity of OCA
is thus mediated by its taurine and glycine amidates in the
hepatocyte and distal small intestine.
[0798] The PK model used a dosing compartment and first-order rate
constant (K.sub.a) to represent the cumulative processes from oral
intake of OCA through entry into the gut. The population mean
half-life for this process was 0.13 hours, but the high BSV on
K.sub.a indicated that the absorption process varied substantially
between subjects. Once in the gut, the model estimated the extent
of intestinal absorption for OCA at approximately 56%. This value
is likely an underestimation due to consolidation of the various
segments of the small and large intestine into a single gut
compartment wherein OCA gets absorbed and excreted from the same
compartment. The extent of intestinal absorption for glyco-OCA and
tauro-OCA was 95% and 99%, respectively. Simulations for healthy
subjects using the PK model showed that at steady-state, .about.90%
of total OCA mass is distributed to the gut and the gallbladder.
Approximately 8% of the total OCA mass resides in the liver while
.about.1% can be found in the plasma of the systemic circulation.
In contrast, the simulated total OCA mass increases to .about.10%
in the systemic circulation in patients with Child-Pugh C hepatic
impairment with the liver distribution being approximately equal to
healthy subjects (.about.10%). The simulated gut and gallbladder
distribution was 79% in patient with Child-Pugh C hepatic
impairment. The low systemic levels of total OCA would in part
explain the high variability observed in plasma.
[0799] The PK model estimated hepatic uptake, in healthy subjects,
at 79%, 73%, and 78% for OCA, glyco-OCA, and tauro-OCA,
respectively, are consistent with hepatic uptake values reported
for CDCA. Once in the liver, OCA was conjugated to glycine and
taurine in a ratio of 4.6:1, consistent with the normal range for
endogenous bile acids. Simulations from the PK model showed that
the half-life for OCA is approximately 4 days indicating a time to
steady-state or a post-treatment washout period of about 2 weeks.
The estimated OCA half-life is consistent with the half-life values
for CDCA reported in the literature.
[0800] Simulations using the PK model predicted changes in systemic
and liver OCA concentrations associated with changes in the
severity of hepatic impairment. Model simulations predicted that
for mild, moderate, and severe hepatic impairment, total OCA
concentrations in the plasma increase 1.4-, 8.0-, and 13-fold
relative to subjects with normal hepatic function while total OCA
concentrations in the liver increase 1.1-, 1.5-, and 1.7-fold,
respectively. The predicted changes in plasma OCA concentrations
were similar to the observed concentration of total endogenous bile
acids in subjects with alcoholic cirrhosis. The concentration of
total endogenous bile acids measured in the plasma were increased
1.6-, 6.4-, and 13-fold for mild, moderate, and severe hepatic
impairment relative to normal hepatic function, respectively.
Previously, soluble and tissue-bound hepatic bile acids were
measured by Fischer et al. from the livers of end-stage liver
disease patients and compared to measurements made from healthy
livers (resected for tumors but functionally and histologically
normal). It was shown that endogenous bile acid levels in the serum
of patients with end-stage liver disease prior to liver
transplantation were 18-fold greater than those in healthy
subjects; however, in the livers from patients with end-stage liver
disease bile acid levels were only approximately 2-fold higher
relative to healthy livers. The observed 2-fold increase in the
liver exposure of endogenous bile acids is in good agreement with
the predicted increase in total OCA exposure in subjects with
severe hepatic impairment (1.7-fold; Child-Pugh C). These results
suggest that the PK characteristics of OCA are very similar to
endogenous bile acids.
[0801] There were some differences between the observed and
predicted values in the external validation in patients with mild
hepatic impairment. The Child-Pugh score is based on total
bilirubin, serum albumin, prothrombin time, ascites, and hepatic
encephalopathy. While all of these parameters are indicators of
prognosis in liver disease, they do not all necessarily reflect
substantial changes in PK or flow mechanics in/around the liver.
Without being bound by any particular theory, the presence of
portal hypertension in the validation cohort for mild impairment
may be a reason for a discrepancy between predicted and observed
values in patients with mild hepatic impairment.
[0802] The OCA physiologic model predicted liver to plasma ratios
for OCA concentrations that were similar to the ratios previously
observed for endogenous bile acids. These results indicate that the
liver to plasma ratio is not consistent between healthy subjects
and patients with hepatic impairment. The liver is the primary site
of action for the safety and efficacy of OCA; therefore, it is
important to account for the differences in systemic and liver
exposure when assessing an effective dose. The hepatically-impaired
patients treated with OCA experienced plasma OCA exposures
>10-fold higher than those experienced by healthy subjects, yet
there was no apparent impact on the overall safety profile
experienced by these patients. The safety results are consistent
with only a modest increase in liver exposure of OCA associated
with hepatic impairment. Collectively, the results from these
analyses and those from literature for bile acids would suggest
that the dose of OCA administered to hepatically-impaired patients
should be modestly lower than those for patients with normal
hepatic function to achieve similar hepatic exposure.
Example 12
[0803] This example describes a clinical, double-blind study
examining the effect of daily 25 mg OCA on nonalcoholic
steatohepatitis (NASH). OCA lead to biopsy proven improvements in
liver fibrosis. Patients with NASH who have elevated NAFLD activity
scores (NAS) and fibrosis are at a higher risk of progression to
cirrhosis and liver related mortality.
[0804] The high risk subgroup was defined as patients with a
baseline NAS.gtoreq.4, baseline fibrosis stage 2 or 3 or baseline
fibrosis stage 1 with a comorbidity (type 2 diabetes, BMI.gtoreq.30
kg/m.sup.2 or ALT.gtoreq.60 U/L) (OCA n=114; Placebo n=112). The
Fibrosis-4 (FIB-4), the aspartate transaminase to platelet ratio
(APRI), and the NAFLD fibrosis score (NFS) were all examined
between baseline through 72 weeks of treatment and for an
additional 24 weeks of follow up.
[0805] Significant reductions were observed as early as week 24 and
persisted through the course of treatment. Patients receiving OCA
had significant improvements compared to placebo in all three
non-invasive measures of fibrosis at week 72 (FIB-4 OCA-Placebo LS
Mean change=-0.33, 95% CI=[-0.47, -0.19], p<0.0001; APRI
OCA-Placebo LS Mean change=-0.23, 95% CI=[-0.32, -0.15],
p<0.0001; NFS OCA-Placebo LS Mean change=-0.28, 95% CI=[-0.45,
-0.10], p<0.01). However, 24 weeks after concluding treatment,
all three scores had diminished improvement and trended toward
baseline values.
[0806] Treatment with OCA lead to significant early and sustained
improvements in FIB-4, APRI, and NFS in patients in a subgroup at
higher risk for liver related mortality in NASH. However, without
OCA, improvement in these non-invasive measures of fibrosis
diminished, possibly due to continuing underlying disease
pathogenesis.
* * * * *