U.S. patent application number 12/766051 was filed with the patent office on 2010-10-28 for method for improving pharmacokinetics.
Invention is credited to Jonathan Q. Tran.
Application Number | 20100272682 12/766051 |
Document ID | / |
Family ID | 42236685 |
Filed Date | 2010-10-28 |
United States Patent
Application |
20100272682 |
Kind Code |
A1 |
Tran; Jonathan Q. |
October 28, 2010 |
METHOD FOR IMPROVING PHARMACOKINETICS
Abstract
The object of the present invention is to elevate the blood
levels of a compound of formula I by co-administration with a
cytochrome P450 inhibitor.
Inventors: |
Tran; Jonathan Q.; (San
Francisco, CA) |
Correspondence
Address: |
Grant D. Green;M/S A2-250 Roche Palo Alto L.L.C.
Patent Law Department, 3431 Hillview Avenue
Palo Alto
CA
94304
US
|
Family ID: |
42236685 |
Appl. No.: |
12/766051 |
Filed: |
April 23, 2010 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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61172722 |
Apr 25, 2009 |
|
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|
Current U.S.
Class: |
424/85.5 ;
514/365; 514/4.3; 514/411 |
Current CPC
Class: |
A61K 31/407 20130101;
A61P 43/00 20180101; A61P 31/00 20180101; A61K 31/426 20130101;
A61K 31/404 20130101; A61K 45/06 20130101; A61P 31/12 20180101;
A61P 31/14 20180101; A61K 31/404 20130101; A61K 2300/00 20130101;
A61K 31/426 20130101; A61K 2300/00 20130101 |
Class at
Publication: |
424/85.5 ;
514/411; 514/365; 514/12 |
International
Class: |
A61K 31/407 20060101
A61K031/407; A61K 31/427 20060101 A61K031/427; A61K 38/21 20060101
A61K038/21; A61K 38/22 20060101 A61K038/22 |
Claims
1. A method for increasing the bioavailability of a Hepatitis C
virus NS3/4A protease inhibitor according to formula I in a patient
comprising co-administering to the patient a ##STR00003## compound
of formula I and a cytochrome P450 monooxygenase inhibitor wherein
the monooxygenase inhibitor is present sufficient amount to elevate
the blood levels of I.
2. A method according to claim 1 wherein the cytochrome P450
monooxygenase inhibitor is ritonavir.
3. The method according to claim 2 wherein the compound of formula
I and ritonavir are in separate dosage forms.
4. The method according to claim 3 wherein the separate dosage
forms are administered about simultaneously.
5. The method according to claim 2 wherein the compound of formula
I and ritonavir are administered in a single dosage form.
6. The method according to claim 2 wherein the dose of ritonavir is
50 to 400 mg/day and the dose of compound I was 25 to 600
mg/day.
7. A method according to claim 6 wherein the dose of ritonavir is
100 to 200 mg/day and the dose of compound I was 50 to 300
mg/day.
8. A method for treating a Hepatitis C virus infection in a patient
in need thereof comprising administering to the patient in need
thereof the compound of formula I, or free base or other
pharmaceutically acceptable salt thereof, and a cytochrome P450
monooxygenase inhibitor, or a pharmaceutically acceptable salt
thereof.
9. A method according to claim 11 wherein the cytochrome P450
monooxygenase inhibitor is ritonavir, or a pharmaceutically
acceptable salt thereof.
10. The method according to claim 9 which method comprises
co-administering along with a compound of formula I and ritonavir,
at least one additional agent selected from an immunomodulatory
agent and/or an antiviral agent and/or another inhibitor of HCV
NS3/4A protease and/or an inhibitor of NS5B polymerase and/or a
broad-spectrum viral inhibitor and/or another cytochrome P-450
inhibitor.
11. The method according to claim 10, wherein said immunomodulatory
agent is .alpha.-, .beta.- or .gamma.-interferon or thymosin, said
antiviral agent is ribavirin or said polymerase inhibitor is
R7128.
12. The method of claim 10 wherein the inhibitor of NS5B polymerase
is R7128.
13. A pharmaceutical composition comprising a compound of formula
I, or free base or other pharmaceutically acceptable salt thereof,
and a cytochrome P450 monooxygenase inhibitor or a pharmaceutically
acceptable salt thereof, and at least one pharmaceutically
acceptable excipient, diluent or carrier.
14. A pharmaceutical composition according to claim 13 wherein the
cytochrome P450 monooxygenase inhibitor is ritonavir, or a
pharmaceutically acceptable salt thereof.
15. A kit comprising a Hepatitis C virus NS3 protease inhibitor
according to formula I and ritonavir.
16. A pharmaceutical pack containing comprising a compound
according to formula I, ritonavir, and an information insert
containing directions for the use of the inhibitors.
Description
CROSS REFERENCE TO PRIOR APPLICATIONS
[0001] This application claims the benefit of priority to U.S.
Provisional Application 61/172,722 filed Apr. 25, 2009 the contents
of which is incorporated herein by reference in its entirety.
FIELD OF THE INVENTION
[0002] The present invention relates to a an improved method or
administering a compound according to formula I for treating HCV by
co-administration with ritonavir. The invention further relates to
a pharmaceutical compositions containing the compound of formula I
and ritonavir.
BACKGROUND
[0003] Hepatitis C virus (HCV) is the leading cause of chronic
liver disease throughout the world. (Boyer, N. et al., J. Hepatol.
2000 32:98-112). The World Health Organization (WHO) estimates that
more than 170 million people worldwide (or about 3% of the world's
population) are infected with the single-stranded ribonucleic acid
(RNA) HCV. (G. M. Lauer and B. D. Walker, N. Engl. J. Med. 2001
345:41-52) Approximately one-fifth of chronically infected patients
with HCV will eventually develop cirrhosis of the liver, suffering
considerable morbidity and mortality, including liver failure and
hepatocellular carcinoma (T. J. Liang et al. Ann. Intern. Med. 2000
132:296-305; M. W. Fried et al. N. Engl. J. Med. 2002 347:975-982),
HCV infection is the primary indication for liver transplantation
in the United States (NIH Consensus Statement on Management of
Hepatitis C. 2002 Jun. 10-12 19(3):146;
http://www.ncbi.nlm.nih.gov/pubmed/14768714).
[0004] HCV has been classified as a member of the virus family
Flaviviridae that includes the genera flaviviruses, pestiviruses,
and hapaceiviruses which includes hepatitis C viruses (Rice, C. M.,
Flaviviridae: The viruses and their replication. In: Fields
Virology, Editors: B. N. Fields, D. M. Knipe and P. M. Howley,
Lippincott-Raven Publishers, Philadelphia, Pa., Chapter 30,
931-959, 1996). HCV is an enveloped virus containing a
positive-sense single-stranded RNA genome of approximately 9.4 kb.
The viral genome consists of a highly conserved 5' untranslated
region (UTR), a long open reading frame encoding a polyprotein
precursor of approximately 3011 amino acids, and a short 3'
UTR.
[0005] Genetic analysis of HCV has identified six main genotypes
which diverge by over 30% of the DNA sequence. More than 30
subtypes have been distinguished. In the US approximately 70% of
infected individuals have Type 1a and 1b infection. Type 1b is the
most prevalent subtype in Asia. (X. Forms and 3. Bukh, Clinics in
Liver Disease 1999 3:693-716; 3. Bukh et al., Semin. Liv. Dis. 1995
15:41-63). Unfortunately type 1 infection is more resistant to
therapy than either type 2 or 3 genotypes (N. N. Zein, Clin.
Microbiol, Rev., 2000 13:223-235).
[0006] The HCV genome encodes a polyprotein of 3010-3033, amino
acids (Q. L. Choo, et al., Proc. Natl. Acad. Sci. USA, 1991
88:2451-2455; N. Kato et al., Proc. Natl. Acad. Sci. USA 1990
87:9524-9528; A. Takamizawa et al., J. Virol. 1991 65:1105-1113).
Viral structural proteins include a nucleocapsid core protein (C)
and two envelope glycoproteins, E1 and E2. HCV also encodes two
proteases, a zinc-dependent metalloproteinase encoded by the
NS2-NS3 region and a serine protease encoded in the NS3 region. The
HCV NS3 protease is a serine protease that helps process the
majority of the viral enzymes, and is thus considered essential for
viral replication and infectivity. These proteases are required for
cleavage of specific regions of the precursor polyprotein into
mature peptides. The carboxyl half of nonstructural protein 5,
NS5B, contains the RNA-dependent RNA polymerase.
[0007] Currently a limited number of approved therapies are
available for the treatment of HCV infection. New and existing
therapeutic approaches for treating HCV infection and inhibiting of
HCV NS5B polymerase activity have been reviewed: R. G. Gish, Sem.
Liver. Dis., 1999 19:5; Di Besceglie, A. M. and Bacon, B. R.,
Scientific American, October: 1999 80-85; G. Lake-Bakaar, Curr.
Drug Targ. Infect. Dis. 2003 3(3):247-253; P. Hoffmann et al, Exp.
Opin. They. Patents 2003 13(11):1707-1723; M. P. Walker et al.,
Exp. Opin. Investing. Drugs 2003 12(8):1269-1280; S.-L. Tan et al.,
Nature Rev. Drug Discov. 2002 1:867-881; J. Z. Wu and Z. Hong,
Curr. Drug Targ-Infect. Dis. 2003 3(3):207-219.
[0008] Ribavirin
(1-((2R,3R,4S,5R)-3,4-dihydroxy-5-hydroxymethyl-tetrahydro-furan-2-yl)-1H-
-[1,2,4]-triazole-3-carboxylic acid amide; Virazole.RTM.) is a
synthetic, non-interferon-inducing, broad-spectrum antiviral
nucleoside analog. Ribavirin has in vitro activity against several
DNA and RNA viruses including Flaviviridae (Gary L. Davis.
Gastroenterology 2000 118:S104-S114). Although, in monotherapy
ribavirin reduces serum amino transferase levels to normal in 40%
of patients, it does not lower serum levels of HCV-RNA. Ribavirin
also exhibits significant toxicity and is known to induce anemia.
Viramidine is a ribavirin prodrug converted ribavirin by adenosine
deaminase to in hepatocytes. (J. Z. Wu, Antivir. Chem. Chemother.
2006 17(1):33-9)
[0009] Interferons (IFNs) have been available for the treatment of
chronic hepatitis for nearly a decade. IFNs are glycoproteins
produced by immune cells in response to viral infection. Two
distinct types of interferon are recognized: Type 1 includes
several interferon alphas and one interferon beta, type 2 includes
interferon gamma. Type 1 interferons are produced mainly by
infected cells and protect neighboring cells from de novo
infection. IFNs inhibit viral replication of many viruses,
including HCV, and when used as the sole treatment for hepatitis C
infection, IFN suppresses serum HCV-RNA to undetectable levels.
Additionally, IFN normalizes serum amino transferase levels.
Unfortunately, the effects of IFN are temporary. Cessation of
therapy results in a 70% relapse rate and only 10-15% exhibit a
sustained virological response with normal serum alanine
transferase levels. (Davis, Luke-Bakaar, supra)
[0010] Combination therapy of HCV with ribavirin and
interferon-.alpha. currently is the standard of care for
treatment-naive patients HCV. Combining ribavirin and PEG-IFN
(infra) results in a sustained viral response (SVR) defined as
undetectable hepatitis C virus ribonucleic acid (HCV RNA) 24 weeks
after completion of therapy (M. W. Fried et al. supra) in 54-56% of
patients with type 1 HCV. The SYR approaches 80% for type 2 and 3
HCV. (Walker, supra) Furthermore, PEG-IFN is given by injection,
and the hematologic and constitutional toxicities of PEG-IFN and of
RBV are difficult for many patients to tolerate for the long (up to
48 weeks) duration of treatment required. Currently, there is no
SOC treatment for patients who either relapsed or did not respond
to (nonresponders) PEG-IFN/RBV therapy. Given the high prevalence
of CHC disease worldwide, the high treatment failure rate with the
current SOC, and tolerability issues with the current SOC, there is
a substantial unmet medical need to improve and expand therapeutic
options for these patient populations. The effectiveness of the
host defenses is hampered by the ability of HCV to disrupt, evade,
and antagonize the host immune response, not only ensuring
continued viral infection, but also quite often resisting the
antiviral action of IFN therapy (M. Gale, Jr. and E. M. Foy, Nature
2005.436:939-945). Therefore, a strategy that targets the virus
itself may improve the results of therapy in comparison with
current therapy options.
[0011] A number of potential new molecular targets for drug
development as anti-HCV therapeutics have now been identified
including, but not limited to, the NS2-NS3 autoprotease, the NS3
protease, the NS3 helicase and the NS5B polymerase. The
RNA-dependent RNA polymerase is absolutely essential for
replication of the single-stranded, positive sense, RNA genome.
This enzyme has elicited significant interest among medicinal
chemists.
[0012] HCV polymerase inhibitors are another target for drug
discovery and compounds in development include R-1626, R-7128,
IDX184/IDX102, PF-868554 (Pfizer), VCH-759 (ViroChem), GS-9190
(Gilead), A-837093 and A-848837 (Abbot), MK-3281 (Merck), GSK949614
and GSK625433 (Glaxo), ANA598 (Anadys), VBY 708 (ViroBay).
[0013] Inhibitors of the HCV NS3 protease also have been identified
as potentially useful for treatment of HCV. Protease inhibitors in
clinical trials include VX-950 (Telaprevir, Vertex), SCH503034
(Broceprevir, Schering), TMC435350 (Tibotec/Medivir) and ITMN-191
(Intermune). Other protease inhibitors in earlier stages of
development include MK7009 (Merck), BMS-790052 (Bristol Myers
Squibb), VBY-376 (Virobay), IDXSCA/IDXSCB (Idenix), BI12202
(Boehringer), VX-500 (Vertex), PHX1766 Phenomix).
SUMMARY OF THE INVENTION
[0014] In one aspect of the present invention there is provided a
method for increasing the bioavailability and or blood level of a
Hepatitis C virus NS3 protease inhibitor according to formula I in
a patient comprising co-administering to the patient the compound
of formula I and a cytochrome P450 monooxygenase inhibitor.
[0015] In another aspect of the present invention there is provided
a pharmaceutical composition comprising a compound of formula I and
a cytochrome P450 monooxygenase inhibitor.
DETAILED DESCRIPTION OF THE INVENTION
[0016] The phrase "a" or "an" entity as used herein refers to one
or more of that entity; for example, a compound refers to one or
more compounds or at least one compound. As such, the terms "a" (or
"an"), "one or more", and "at least one" can be used
interchangeably herein.
[0017] As used in this specification, whether in a transitional
phrase or in the body of the claim, the terms "comprise(s)" and
"comprising" are to be interpreted as having an open-ended meaning.
That is, the terms are to be interpreted synonymously with the
phrases "having at least" or "including at least". When used in the
context of a process, the term "comprising" means that the process
includes at least the recited steps, but may include additional
steps. When used in the context of a compound or composition, the
term "comprising" means that the compound or composition includes
at least the recited features or components, but may also include
additional features or components.
[0018] The term "optional" or "optionally" as used herein means
that a subsequently described event or circumstance may, but need
not, occur, and that the description includes instances where the
event or circumstance occurs and instances in which it does
not.
[0019] As used herein, the recitation of a numerical range for a
variable is intended to convey that the invention may be practiced
with the variable equal to any of the values within that range.
Thus, for a variable which is inherently discrete, the variable can
be equal to any integer value of the numerical range, including the
end-points of the range. Similarly, for a variable which is
inherently continuous, the variable can be equal to any real value
of the numerical range, including the end-points of the range. As
an example, a variable which is described as having values between
0 and 2, can be 0, 1 or 2 for variables which are inherently
discrete, and can be 0.0, 0.1, 0.01, 0.001, or any other real value
for variables which are inherently continuous.
[0020] There is a need for compositions and therapeutic
combinations for treating HCV. Combination chemotherapy has proven
effective in treatment of HCV, however, patient compliance improves
as the number of doses and frequency of administration decreases.
Improved compounds and dosage regimens would be useful in anti-HCV
therapies. The subject invention provides a method for
administering a compound of formula I (R7227) and a CYP 3A4
inhibitor that enhances the bioavailability of 87227 and reduces
the amount of R7227 n that must be administered.
[0021] Compound I (R7227) is a highly potent and selective
macrocyclic, peptidomimetic inhibitor of NS3/4A protease activity
selected for development as an oral agent for the treatment of HCV
infection due to the potency displayed in inhibiting NS3/4A
protease. R7227 displays significant exposure in the liver of
animal species, which is the primary or sole site of HCV
replication in humans, and has an acceptable toxicologic profile.
R7227 is a highly potent inhibitor of NS3/4A proteolysis with a 50%
inhibitory concentration (IC.sub.50).ltoreq.0.225 nM and a high
degree of specificity for the intended target. In cell-based
potency assays employing a genotype 1 HCV replicon, R7227 has an
IC.sub.50 of 1.77 nM. R7227 additionally displays synergistic
antiviral effects with polyethylene glycol conjugated ("pegylated")
interferon alfa-2a (PEG-IFN-.alpha.2a, Pegasys.RTM., Roche) in this
same cell-based assay that suggests R7227 will be useful in HCV
therapy.
##STR00001##
[0022] Cytochromes, especially the CYP3A4 isoform, have been found
to metabolize R7227 resulting in a requirement for more frequent
and higher dose levels to maintain therapeutically effective blood
levels.
[0023] In early preclinical studies, cytochrome P450 phenotyping
using chemical inhibitors suggests that multiple CYP isozymes
including 3A4, 2C19, 1A2, 2D6, and 2C9 participate in the
metabolism of (R7227). Further experiments with recombinant CYPs
show that only CYP3A4 metabolized R7227 to an extent that could
influence the pharmacokinetics. Therefore, a cytochrome P450
monooxygenase inhibitor in an amount effective to inhibit
metabolism of the protease inhibitor could increase the
bioavailability of R7227 compared to administration in the absence
of the CYP inhibitor.
[0024] Some drugs are metabolized by cytochrome P450 enzymes. These
enzymes typically oxidize the drugs resulting in unfavorable
pharmacokinetic characteristics (e.g., decreased blood levels,
decreased half-life). In these cases inhibition of drug metabolism
can lead to improvements in the pharmacokinetic profile of the
drug. (see, e.g., U.S. Pat. No. 6,037,157; D. E. Kempf et al.
Antimicrob. Agents Chemother., 1997 41:654-660; W. J. Curatolo and
G. Foulds, U.S. Patent Publication 2004/0091527 and M. G.
Cordingley, U.S. Patent Publication US2004/0152625). To ascertain
whether combination therapy with a cytochrome P450 antagonist will
improve the pharmacokinetics of a drug the metabolic pathways
involved must be elucidated.
[0025] Cytochrome P450 (CYP P450) is a very large and diverse
superfamily of hemoproteins. Both exogenous and endogenous
compounds as substrates for cytochrome P450 isoforms. Cytochrome
P450 3A4 (CYP3A4; EC 1.14.13.97), is one of the most important
enzymes involved in the metabolism of xenobiotics in the body.
CYP3A4 is involved in the oxidation of the largest range of
substrates of all the CYPs. Although CYP3A4 is predominantly found
in the liver, it is also present in other organs and tissues of the
body.
[0026] Any CYP inhibitor that improves the pharmacokinetics of the
relevant NS3 protease may be used in a method of this invention.
These CYP inhibitors include, but are not limited to, ritonavir (WO
94/14436), ketoconazole, troleandomycin, 4-methyl pyrazole,
cyclosporin, clomethiazole, cimetidine, itraconazole, fluconazole,
miconazole, fluvoxamine, fluoxetine, nefazodone, sertraline,
indinavir, nelfinavir, amprenavir, fosamprenavir, saquinavir,
lopinavir, delavirdine and erythromycin. A preferred CYP inhibitor
is ritonavir.
[0027] Ritonavir is a potent inhibitor of CYP3A4 activity and is
currently utilized at low non-therapeutic doses (e.g., 100 mg twice
daily) to enhance or "boost" the PK of other HIV protease
inhibitors (PIs). Given the high prevalence of HIV/HCV
co-infection, R7227 could be used for the treatment of HCV in
HIV/HCV co-infected patients who received ritonavir-boosted HIV
PIs, resulting in possible interactions between ritonavir-boosted
HIV PIs and R7227.
[0028] However, in addition to the inhibitory effect on 3A4,
ritonavir appears to induce the activities of other enzymes
including CYPs 1A2, 2C9, and 2C19. Although during acute dosing,
the inhibitory effect of ritonavir will be predominant resulting in
elevated levels of R7227, chronic dosing anticipated in HCV therapy
could induce other isoforms which could oxidize R7227 offsetting
the desired inhibitory effect.
[0029] In one embodiment of the present invention there is provided
a method for increasing the bioavailability of Hepatitis C virus
NS3/4A protease inhibitor R7227 in a patient in need thereof
comprising administering R7227 and a cytochrome P450 monooxygenase
inhibitor wherein the amount of the cytochrome P450 monooxygenase
inhibitor is sufficient to elevate the blood levels of R7227
compared to the blood levels R7227 in the absence of a cytochrome
P450 monooxygenase inhibitor.
[0030] In another embodiment of the present invention there is
provided a method for increasing the bioavailability of R7227 in a
patient comprising administering R7227 and ritonavir. Ritonavir is
marketed by Abbott Laboratories under the name of NORVIR.RTM. as an
HIV protease inhibitor (Chemical Abstract Registry Number
1555213-67-5).
[0031] In another embodiment of the present invention there is
provided a method for increasing the bioavailability of R7227 in a
patient comprising co-administering R7227 and ritonavir wherein
R7227 and ritonavir are in a separate dosage form. The doses of
each can be taken either at or about the same time or the doses may
be taken at different intervals.
[0032] In another embodiment of the present invention there is
provided a method for increasing the bioavailability of R7227 in a
patient comprising co-administering R7227 and ritonavir wherein
R7227 and ritonavir are administered simultaneously. R7227 and
ritonavir may be present in a single formulation for increased
patient convenience.
[0033] In another embodiment of the present invention there is
provided a method for increasing the bioavailability of R7227 in a
patient comprising co-administering 87227 and ritonavir wherein
R7227 and ritonavir are administered in a single dosage form.
[0034] In another embodiment of the present invention there is
provided a method for increasing the bioavailability of 87227 in a
patient comprising co-administering a dose of 25 to 600 mg/day of
R7227 and 50 to 400 mg/day of ritonavir.
[0035] In another embodiment of the present invention there is
provided a method for increasing the bioavailability of R7227 in a
patient comprising co-administering a dose of 50 to 300 mg/day of
R7227 and 100 to 200 mg/day of ritonavir.
[0036] In a another embodiment of the present invention there is
provided a method for treating HCV comprising administering to a
patient in need thereof the compound of formula I, or free base or
other pharmaceutically acceptable salt thereof, and a cytochrome
P450 monooxygenase inhibitor.
[0037] In a another embodiment of the present invention there is
provided a method for treating HCV comprising administering to a
patient in need thereof the compound of formula I, or free base or
other pharmaceutically acceptable salt thereof, and ritonavir.
[0038] Combination therapy has proven to be a valuable component of
antiviral therapy and therefore treatment of HCV with R7227 and
ritonavir may comprise administration of another component
comprising an additional agent selected from an immunomodulatory
agent; an antiviral agent; another HCV protease inhibitor; an
inhibitor of another target in the HCV life cycle; such as an HCV
polymerase inhibitor or combinations thereof.
##STR00002##
[0039] In another embodiment of the present invention there is
provided a method for treating HCV comprising co-administering
along with a compound of formula I and ritonavir at least one
additional agent selected from an immunomodulatory agent and/or an
antiviral agent and/or another inhibitor of HCV NS3/4A protease
and/or an inhibitor of NS5B polymerase and/or a broad-spectrum
viral inhibitor and/or another cytochrome P-450 inhibitor.
[0040] In another embodiment of the present invention there is
provided a method for treating HCV which method comprises
co-administering II (R7128) along with R7227 and ritonavir.
[0041] In still another embodiment of the present invention there
is provided a method for treating HCV which method comprises
co-administering .alpha.-, .beta.- or .gamma.-interferon and/or
thymosin and/or ribavirin and/or R7128 along with R7227 and
ritonavir.
[0042] In a another embodiment of the present invention there is
provided a pharmaceutical composition comprising R7227 or a
pharmaceutically acceptable salt thereof, a cytochrome P450
monooxygenase inhibitor or a pharmaceutically acceptable salt
thereof, and at least one pharmaceutically acceptable excipient,
diluent or carrier.
[0043] In a another embodiment of the present invention there is
provided a pharmaceutical composition comprising R7227, or free
base or other pharmaceutically acceptable salt thereof, a
cytochrome P450 monooxygenase inhibitor, and at least one
pharmaceutically acceptable excipient, diluent or carrier.
[0044] In yet another embodiment of the present invention there is
provided a comprising R7227, or free base or other pharmaceutically
acceptable salt thereof, a cytochrome P450 monooxygenase inhibitor,
the HCV polymerase inhibitor R7128 and at least one
pharmaceutically acceptable excipient, diluent or carrier.
[0045] In a another embodiment of the present invention there is
provided a pharmaceutical composition comprising R7227, or free
base or other pharmaceutically acceptable salt thereof, ritonavir,
or a pharmaceutically acceptable salt thereof, and at least one
pharmaceutically acceptable excipient, diluent or carrier.
[0046] In a fifteenth embodiment of the present invention there is
provided a kit comprising a Hepatitis C virus NS3 protease
inhibitor according to formula I and ritonavir.
[0047] In an embodiment of the present invention there is provided
a pharmaceutical pack containing comprising a compound according to
formula I, ritonavir, and optionally an informational insert
containing directions for the use of the inhibitors.
[0048] Ritonavir low dose was reported to increase the exposure of
midazolam, the most sensitive CYP3A probe substrate, by
approximately 7-fold. (A. A. Mathias et al., Clin. Pharmacol. Ther.
2009 85(1)64-70), SimCYP.RTM. simulation (SymCYP Limited, Blades
Enterprise Centre, John Street, Sheffield S2 4SU, UK) predicted
that ritonavir could increase R7227 exposure between ca. 2- and
4-fold, assuming the contribution of CYP3A to the overall
elimination of R7227 is 50% and 100%, respectively. When
co-administered with ritonavir in this study, the predicted 4-fold
increase in R7227 exposure is still significantly lower than that
observed at the highest safe and tolerable dose of 1600 mg in the
SAD study in healthy volunteers.
[0049] Multiple doses of ritonavir 100 mg every 12 hours
significantly increased R7227 AUC.sub.0.fwdarw..infin., C.sub.max,
and C.sub.12h by approximately 5.5-fold, 3.25-fold, and 27- to
42-fold, respectively. The multiple-dose effect of ritonavir on
R7227 C.sub.12h is less than that of the acute single-dose effect
of ritonavir possibly due to the induction of CYP enzymes by
ritonavir following multiple dosing offsetting some of the acute
inhibitory effect by ritonavir on CYP 3A4. Thus the
pharmacokinetics R7227 was substantially improved by the
co-administration of ritonavir.
Dosage and Administration
[0050] The compounds of the present invention may be formulated in
a wide variety of oral administration dosage forms and carriers.
Oral administration can be in the form of tablets, coated tablets,
dragees, hard and soft gelatin capsules, solutions, emulsions,
syrups, or suspensions. Compounds of the present invention are
efficacious when administered by other routes of administration
including continuous (intravenous drip) topical parenteral,
intramuscular, intravenous, subcutaneous and suppository
administration, among other routes of administration. The preferred
manner of administration is generally oral using a convenient daily
dosing regimen which can be adjusted according to the degree of
affliction and the patient's response to the active ingredient.
[0051] A compound or compounds of the present invention, as well as
their pharmaceutically useable salts, together with one or more
conventional excipients, carriers, or diluents, may be placed into
the form of pharmaceutical compositions and unit dosages. The
pharmaceutical compositions and unit dosage forms may be comprised
of conventional ingredients in conventional proportions, with or
without additional active compounds or principles, and the unit
dosage forms may contain any suitable effective amount of the
active ingredient commensurate with the intended daily dosage range
to be employed. The pharmaceutical compositions may be employed as
solids, such as tablets or filled capsules, semisolids, powders,
sustained release formulations, or liquids such as solutions,
suspensions, emulsions, elixirs, or filled capsules for oral use;
or in the form of suppositories for rectal or vaginal
administration; or in the form of sterile injectable solutions for
parenteral use. A typical preparation will contain from about 5% to
about 95% active compound or compounds (w/w). The term
"preparation" or "dosage form" is intended to include both solid
and liquid formulations of the active compound and one skilled in
the art will appreciate that an active ingredient can exist in
different preparations depending on the target organ or tissue and
on the desired dose and pharmacokinetic parameters.
[0052] The term "excipient" as used herein refers to a compound
that is useful in preparing a pharmaceutical composition, generally
safe, non-toxic and neither biologically nor otherwise undesirable,
and includes excipients that are acceptable for veterinary use as
well as human pharmaceutical use. The compounds of this invention
can be administered alone but will generally be administered in
admixture with one or more suitable pharmaceutical excipients,
diluents or carriers selected with regard to the intended route of
administration and standard pharmaceutical practice.
[0053] "Pharmaceutically acceptable" means that which is useful in
preparing a pharmaceutical composition that is generally safe,
non-toxic, and neither biologically nor otherwise undesirable and
includes that which is acceptable for human pharmaceutical use.
[0054] A "pharmaceutically acceptable salt" form of an active
ingredient may also initially confer a desirable pharmacokinetic
property on the active ingredient which were absent in the non-salt
form, and may even positively affect the pharmacodynamics of the
active ingredient with respect to its therapeutic activity in the
body. The phrase "pharmaceutically acceptable salt" of a compound
means a salt that is pharmaceutically acceptable and that possesses
the desired pharmacological activity of the parent compound. Such
salts include: (1) acid addition salts, formed with inorganic acids
such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric
acid, phosphoric acid, and the like; or formed with organic acids
such as acetic acid, propionic acid, hexanoic acid,
cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic
acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric
acid, tartaric acid, citric acid, benzoic acid,
3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid,
methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic
acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid,
4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,
4-toluenesulfonic acid, camphorsulfonic acid,
4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic
acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary
butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic
acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic
acid, and the like; or (2) salts formed when an acidic proton
present in the parent compound either is replaced by a metal ion,
e.g., an alkali metal ion, an alkaline earth ion, or an aluminum
ion; or coordinates with an organic base such as ethanolamine,
diethanolamine, triethanolamine, tromethamine, N-methylglucamine,
and the like.
[0055] Solid form preparations include powders, tablets, pills,
capsules, cachets, suppositories, and dispersible granules. A solid
carrier may be one or more substances which may also act as
diluents, flavoring agents, solubilizers, lubricants, suspending
agents, binders, preservatives, tablet disintegrating agents, or an
encapsulating material. In powders, the carrier generally is a
finely divided solid which is a mixture with the finely divided
active component. In tablets, the active component generally is
mixed with the carrier having the necessary binding capacity in
suitable proportions and compacted in the shape and size desired.
Suitable carriers include but are not limited to magnesium
carbonate, magnesium stearate, talc, sugar, lactose, pectin,
dextrin, starch, gelatin, tragacanth, methylcellulose, sodium
carboxymethylcellulose, a low melting wax, cocoa butter, and the
like. Solid form preparations may contain, in addition to the
active component, colorants, flavors, stabilizers, buffers,
artificial and natural sweeteners, dispersants, thickeners,
solubilizing agents, and the like.
[0056] Liquid formulations also are suitable for oral
administration include liquid formulation including emulsions,
syrups, elixirs, aqueous solutions, aqueous suspensions. These
include solid form preparations which are intended to be converted
to liquid form preparations shortly before use. Emulsions may be
prepared in solutions, for example, in aqueous propylene glycol
solutions or may contain emulsifying agents such as lecithin,
sorbitan monooleate, or acacia. Aqueous solutions can be prepared
by dissolving the active component in water and adding suitable
colorants, flavors, stabilizing, and thickening agents. Aqueous
suspensions can be prepared by dispersing the finely divided active
component in water with viscous material, such as natural or
synthetic gums, resins, methylcellulose, sodium
carboxymethylcellulose, and other well known suspending agents.
[0057] The compounds of the present invention may be formulated for
parenteral administration (e.g., by injection, for example bolus
injection or continuous infusion) and may be presented in unit dose
form in ampoules, pre-filled syringes, small volume infusion or in
multi-dose containers with an added preservative. The compositions
may take such forms as suspensions, solutions, or emulsions in oily
or aqueous vehicles, for example solutions in aqueous polyethylene
glycol. Examples of oily or nonaqueous carriers, diluents, solvents
or vehicles include propylene glycol, polyethylene glycol,
vegetable oils (e.g., olive oil), and injectable organic esters
(e.g., ethyl oleate), and may contain formulatory agents such as
preserving, wetting, emulsifying or suspending, stabilizing and/or
dispersing agents. Alternatively, the active ingredient may be in
powder form, obtained by aseptic isolation of sterile solid or by
lyophilisation from solution for constitution before use with a
suitable vehicle, e.g., sterile, pyrogen-free water.
[0058] The compounds of the present invention may be formulated for
administration as suppositories. A low melting wax, such as a
mixture of fatty acid glycerides or cocoa butter is first melted
and the active component is dispersed homogeneously, for example,
by stirring. The molten homogeneous mixture is then poured into
convenient sized molds, allowed to cool, and to solidify.
[0059] The compounds of the present invention may be formulated for
vaginal administration. Pessaries, tampons, creams, gels, pastes,
foams or sprays containing in addition to the active ingredient
such carriers as are known in the art to be appropriate.
[0060] When desired, formulations can be prepared with enteric
coatings adapted for sustained or controlled release administration
of the active ingredient. For example, the compounds of the present
invention can be formulated in transdermal or subcutaneous drug
delivery devices. These delivery systems are advantageous when
sustained release of the compound is necessary and when patient
compliance with a treatment regimen is crucial. Compounds in
transdermal delivery systems are frequently attached to an
skin-adhesive solid support. The compound of interest can also be
combined with a penetration enhancer, e.g., Azone
(1-dodecylaza-cycloheptan-2-one). Sustained release delivery
systems are inserted subcutaneously into to the subdermal layer by
surgery or injection. The subdermal implants encapsulate the
compound in a lipid soluble membrane, e.g., silicone rubber, or a
biodegradable polymer, e.g., polyactic acid.
[0061] Suitable formulations along with pharmaceutical carriers,
diluents and expcipients are described in Remington: The Science
and Practice of Pharmacy 1995, edited by E. W. Martin, Mack
Publishing Company, 19th edition, Easton, Pa. A skilled formulation
scientist may modify the formulations within the teachings of the
specification to provide numerous formulations for a particular
route of administration without rendering the compositions of the
present invention unstable or compromising their therapeutic
activity.
[0062] The modification of the present compounds to render them
more soluble in water or other vehicle, for example, may be easily
accomplished by minor modifications (salt formulation,
esterification, etc.), which are well within the ordinary skill in
the art. It is also well within the ordinary skill of the art to
modify the route of administration and dosage regimen of a
particular compound in order to manage the pharmacokinetics of the
present compounds for maximum beneficial effect in patients.
[0063] The methods described herein comprise administration of
combinations of a Hepatitis C virus NS3/4A protease inhibitor and a
cytochrome P450 monooxygenase inhibitor. Such administration is
referred to herein as co-administration. Co-administration includes
administering each inhibitor in the same dosage form or in
different dosage forms. When administered in different dosage
forms, the inhibitors may be administered at the same or at
different times and in any order. Accordingly, this invention
provides methods wherein the CYP inhibitor is administered together
with the Hepatitis C virus NS3/4A protease inhibitor in the same
dosage form or in separate dosage forms.
[0064] If the CYP inhibitor and protease inhibitor are administered
in separate dosage forms, each inhibitor may be administered about
simultaneously. Alternatively, the CYP inhibitor may be
administered in any time period around administration of the
protease inhibitor. That is, the CYP inhibitor may be administered
prior to, together with, or following the NS3/4A protease
inhibitor. The time period of administration should be such that
the CYP inhibitor affects the metabolism of the protease inhibitor.
For example, if the protease inhibitor is administered first, the
CYP inhibitor should be administered before the protease inhibitor
is metabolized and/or excreted
[0065] The term "therapeutically effective amount" as used herein
means an amount required to reduce symptoms of the disease in an
individual. The level therapeutic of effectiveness in HCV therapy
is generally determined by measuring the levels of viral RNA. The
dose will be adjusted to the individual requirements in each
particular case. That dosage can vary within wide limits depending
upon numerous factors such as the severity of the disease to be
treated, the age and general health condition of the patient, other
medicaments with which the patient is being treated, the route and
form of administration and the preferences and experience of the
medical practitioner involved.
[0066] Dosage levels of between about 100 and about 800 mg per day,
preferably between about 200 and about 600 mg per day of the NS3
protease inhibitor are useful for the prevention and treatment of
HCV mediated disease. For the CYP inhibitor, the dosage levels of
between about 50 to about 400 mg per day, would be typical. More
typical would be dosage levels of between about 100 to about 200 mg
per day. Typically, the pharmaceutical compositions of, and
according to, this invention will be administered from about 1 to
about 2 times per day. The amount of active ingredient that may be
combined with the carrier materials to produce a single dosage form
will vary depending upon the host treated and the particular mode
of administration. Generally, treatment is initiated with smaller
dosages which are less than the optimum dose of the compound.
Thereafter, the dosage is increased by small increments until the
optimum effect for the individual patient is reached. One of
ordinary skill in treating diseases described herein will be able,
without undue experimentation and in reliance on personal
knowledge, experience and the disclosures of this application, to
ascertain a therapeutically effective amount of the compounds of
the present invention for a given disease and patient.
[0067] For preferred dosage forms of ritonavir have been disclosed
by L. A. Al-Razzak et al. in U.S. Pat. No. 5,484,801 published Jan.
16, 1996, U.S. Pat. No. 5,948,436 published Sep. 7, 1999, WO
95/07696 published Mar. 23, 1995 and WO 95/09614 published Apr. 13,
1995.
[0068] The methods described herein comprise administration of
combinations of a Hepatitis C virus NS3 protease inhibitor and a
cytochrome P450 monooxygenase inhibitor. Such administration is
referred to herein as co-administration. Co-administration includes
administering each inhibitor in the same dosage form or in
different dosage forms. When administered in different dosage
forms, the inhibitors may be administered at the same or at
different times and in any order. Accordingly, this invention
provides methods wherein the CYP inhibitor is administered together
with the Hepatitis C virus NS3/4A protease inhibitor in the same
dosage form or in separate dosage forms.
[0069] If the CYP inhibitor and protease inhibitor are administered
in separate dosage forms, each inhibitor may be administered about
simultaneously. Alternatively, the CYP inhibitor may be
administered in any time period around administration of the
protease inhibitor. That is, the CYP inhibitor may be administered
prior to, together with, or following the NS3/4A protease
inhibitor. The time period of administration should be such that
the CYP inhibitor affects the metabolism of the protease inhibitor.
For example, if the protease inhibitor is administered first, the
CYP inhibitor should be administered before the protease inhibitor
is metabolized and/or excreted
[0070] Combination therapy has proven to be a valuable component of
antiviral therapy and therefore treatment of HCV with R7227 and
ritonavir may comprise administration of another component
comprising an additional agent selected from an immunomodulatory
agent; an antiviral agent; another HCV protease inhibitor; an
inhibitor of HCV polymerase or another target in the HCV life cycle
or combinations thereof.
[0071] Pharmaceutical compositions may also be prescribed to the
patient in "patient packs" containing the whole course of treatment
in a single package, usually a blister pack. Patient packs have an
advantage over traditional prescriptions, where a pharmacists
divides a patient's supply of a pharmaceutical from a bulk supply,
in that the patient always has access to the package insert
contained in the patient pack, normally missing in traditional
prescriptions. The inclusion of a package insert has been shown to
improve patient compliance with the physician's instructions.
[0072] Administration of the combination of the invention by means
of a single patient pack, or patient packs of each formulation,
containing within a package insert instructing the patient to the
correct use of the invention is a desirable additional feature of
this invention which can improve patient compliance.
[0073] According to a further aspect of the invention is a pack
comprising at least a NS3 protease inhibitor and a CYP 3A4
inhibitor of the invention and an information insert containing
directions on the use of the combination of the invention. In an
alternative embodiment of this invention, the pharmaceutical pack
further comprises one or more of additional agent as described
herein. The additional agent or agents may be provided in the same
pack or in separate packs.
[0074] Another aspect of this involves a packaged kit for a patient
to use in the treatment of HCV infection or in the prevention of
HCV infection, comprising: a single or a plurality of
pharmaceutical formulation of each pharmaceutical component; a
container housing the pharmaceutical formulation(s) during storage
and prior to administration; and instructions for carrying out drug
administration in a manner effective to treat or prevent HCV
infection.
[0075] Accordingly, this invention provides kits for the
simultaneous or sequential administration of a NS3/4A protease
inhibitor and a CYP inhibitor (and optionally an additional agent)
or derivatives thereof are prepared in a conventional manner.
Typically, such a kit will comprise, e.g. a composition of each
inhibitor and optionally the additional agent(s) in a
pharmaceutically acceptable carrier (and in one or in a plurality
of pharmaceutical formulations) and written instructions for the
simultaneous or sequential administration.
[0076] In another embodiment, a packaged kit is provided that
contains one or more dosage forms for self administration; a
container means, preferably sealed, for housing the dosage forms
during storage and prior to use; and instructions for a patient to
carry out drug administration. The instructions will typically be
written instructions on a package insert, a label, and/or on other
components of the kit, and the dosage form or forms are as
described herein. Each dosage form may be individually housed, as
in a sheet of a metal foil-plastic laminate with each dosage form
isolated from the others in individual cells or bubbles, or the
dosage forms may be housed in a single container, as in a plastic
bottle. The present kits will also typically include means for
packaging the individual kit components, i.e., the dosage forms,
the container means, and the written instructions for use. Such
packaging means may take the form of a cardboard or paper box, a
plastic or foil pouch, etc.
[0077] In order that this invention be more fully understood, the
following preparative and testing examples are set forth. These
examples are for the purpose of illustration only and are not to be
construed as limiting the scope of the invention in any way.
EXAMPLE
Pharmacokinetic Enhancement of R7227 in Healthy Adults
[0078] Subjects were screened for participation in this study
within 21 days before dosing. The study enrolled 14 healthy
volunteers (n=14 per group). The dosing schedule is illustrated
below:
TABLE-US-00001 TABLE I Study Day Procedure 1 2 3 4 to 11 12 R7227
dosing.sup.1 x x x Ritonavir Dosing.sup.2 x x x PK collections 24-h
PK 48-h PK 48-h PK .sup.1R7227 100 mg single oral dose
.sup.2Ritonavir 100 mg dose orally every 12 h.
[0079] R7227 formulation--R7227 was formulated into clear size 10
oval soft gelatin capsules for oral administration at a strength of
100 mg per capsule (anhydrous free acid equivalent). The capsule
fill solution consists of R7227-001, polyethylene glycol PEG400
(Macrogol 400), and butylated hydroxytoluene (BHT). All excipients
are compendial grade (NF or EP). Gelatin Type 195 (NF, EP) is used
as the bulk gel mass for the capsule shell, with small amounts of
sorbitol liquid 85/70/00 (NF, EP) and water (USP) used as
plasticizers.
[0080] All study medications were with a meal. On the R7227
administration days (alone or with ritonavir), study medications
were administered after completion of a standard high-fat breakfast
and the breakfasts on these days were identical. R7227 was
administered orally as a single dose of a 100 mg soft gel capsule
on days 1, 3 and 12. On days 3 and 12, R7227 was administered with
the morning dose of ritonavir. Ritonavir 100 mg was administered
orally twice daily (every 12 hours) from day 3 to day 12.
[0081] Blood samples (5 mL) were collected to determine plasma
concentrations of R7227 (and metabolites when assays were
available) according to the following schedule
[0082] Day 1, PK samples (5 mL) were be collected before R7227
dosing (predose) and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12,
and 24 hours after R7227 dosing;
[0083] Days 3 and 12, PK samples (5 mL) were collected before R7227
dosing (predose) and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12,
24, 36, and 48 hours after R7227 dosing.
[0084] Primary PK parameters of R7227 that were determined are
C.sub.max and AUC.sub.0.fwdarw..infin.. Secondary PK parameters of
R7227 that were measured include T.sub.max and
AUC.sub.0.fwdarw.last, CL/F, t.sub.1/2, C.sub.12hr and
C.sub.24h.
[0085] Analysis of variance (ANOVA) was applied to the
log-transformed primary pharmacokinetic parameters. Two-sided 90%
confidence intervals for the ratios of the geometric means of the
primary parameters (AUC.sub.0.fwdarw..infin., and C.sub.max of
R7227) were derived for the following comparisons:
(R7227+Ritonavir) Day 3 versus R7227 Day 1 and (R7227+Ritonavir)
Day 12 versus 87227 Day 1
[0086] Analysis of variance (ANOVA) was used to analyze all primary
study parameters using the following model:
Yij=.mu.+.tau.i+sj+.epsilon.ij
where Yij denotes the PK parameter to be analyzed, .mu. denotes the
general mean of the transformed variable, .tau.i, the fixed effect
of treatment; sj the random effect of subject; .epsilon.ij (error).
The random deviations .epsilon.ij are assumed to be independent and
normally distributed with zero mean and common variance
.sigma..sup.2. The group comparisons .tau.
R7227+Ritonavir-.tau.R7227, the residual variance .sigma..sup.2,
and the 90% confidence limits for the group comparisons were
estimated from the ANOVA model. For log-transformed variables
(AUC.sub.0.fwdarw..infin. and C.sub.max), the ratio of true group
means and the confidence limits for the corresponding ratio of
means of the untransformed variables will be calculated by
exponentiation of the least squares means differences and the
confidence limits for the transformed values, respectively.
TABLE-US-00002 TABLE II Geometric Least Square Mean (GLSM) Day 3
Day 12 R7227 Day 1 (with Ritonavir (with Ritonavir Ratio of GLSM
(90% CI) PK (unit) N (Alone) single dose) multiple dose) Day 3 vs
Day 1 Day 12 vs Day 1 AUC.sub.0.fwdarw..infin. 12 14.4 82. 79.4
5.70 (4.07, 7.99) 5.50 (4.05, 7.48) ng*h/mL C.sub.max 12 8.40 26.4
27.3 3.14 (1.87, 5.25) 3.25 (2.12, 4.96) (ng/mL) C.sub.12 h 8.sup.a
0.02 1.00 0.53 50.6 (25.6, 100) 26.9 (17.7, 41.0) (ng/mL) C.sub.12
h 12.sup.b 0.01 0.55 0.36 65.2 (34.8, 122) 42.4 (25.7, 70.0)
(ng/mL) .sup.aNon-missing, non-BLQ (0.010 ng/mL) data from all
three treatment days. (BLQ = Below Limit of Quantitation)
.sup.bInclude extrapolated C.sub.12 h values from 4 subjects with
BLQ values on day 1
[0087] The foregoing invention has been described in some detail by
way of illustration and example, for purposes of clarity and
understanding. It will be obvious to one of skill in the art that
changes and modifications may be practiced within the scope of the
appended claims. Therefore, it is to be understood that the above
description is intended to be illustrative and not restrictive. The
scope of the invention should, therefore, be determined not with
reference to the above description, but should instead be
determined with reference to the following appended claims, along
with the full scope of equivalents to which such claims are
entitled.
[0088] All patents, patent applications and publications cited in
this application are hereby incorporated by reference in their
entirety for all purposes to the same extent as if each individual
patent, patent application or publication were so individually
denoted.
* * * * *
References