U.S. patent application number 17/113633 was filed with the patent office on 2021-10-28 for methods for treating gaucher disease.
The applicant listed for this patent is Genzyme Corporation. Invention is credited to Jun CHEN, Sebastiaan J.M. GAEMERS, Vanaja KANAMALURU, Jing LI, M. Judith PETERSCHMITT, Dan RUDIN.
Application Number | 20210330633 17/113633 |
Document ID | / |
Family ID | 1000005697398 |
Filed Date | 2021-10-28 |
United States Patent
Application |
20210330633 |
Kind Code |
A1 |
LI; Jing ; et al. |
October 28, 2021 |
METHODS FOR TREATING GAUCHER DISEASE
Abstract
Methods for treating Gaucher disease in patients with renal or
hepatic impairment.
Inventors: |
LI; Jing; (Bridgewater,
NJ) ; PETERSCHMITT; M. Judith; (Watertown, MA)
; KANAMALURU; Vanaja; (Bridgewater, NJ) ; CHEN;
Jun; (Bridgewater, NJ) ; GAEMERS; Sebastiaan
J.M.; (Naarden, NL) ; RUDIN; Dan; (Cambridge,
MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Genzyme Corporation |
Cambridge |
MA |
US |
|
|
Family ID: |
1000005697398 |
Appl. No.: |
17/113633 |
Filed: |
December 7, 2020 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
16219064 |
Dec 13, 2018 |
10888544 |
|
|
17113633 |
|
|
|
|
62599467 |
Dec 15, 2017 |
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/343 20130101;
A61K 31/138 20130101; A61K 31/15 20130101; A61P 1/16 20180101; A61K
31/4422 20130101; A61P 13/12 20180101; A61K 31/496 20130101; A61K
31/4025 20130101; A61K 45/06 20130101; A61K 31/427 20130101; A61K
31/381 20130101; A61P 3/00 20180101 |
International
Class: |
A61K 31/343 20060101
A61K031/343; A61K 31/496 20060101 A61K031/496; A61K 31/15 20060101
A61K031/15; A61K 45/06 20060101 A61K045/06; A61K 31/138 20060101
A61K031/138; A61K 31/427 20060101 A61K031/427; A61P 3/00 20060101
A61P003/00; A61K 31/4422 20060101 A61K031/4422; A61K 31/381
20060101 A61K031/381; A61K 31/4025 20060101 A61K031/4025; A61P 1/16
20060101 A61P001/16; A61P 13/12 20060101 A61P013/12 |
Claims
1. A method of treating Gaucher disease comprising administering to
a patient in need thereof an effective amount of eliglustat, or a
pharmaceutically acceptable salt thereof, wherein said patient is
an extensive CYP2D6 metabolizer with mild hepatic impairment.
2. The method according to claim 1, wherein the effective amount is
a twice daily dose of 84 mg of eliglustat, or a pharmaceutically
acceptable salt thereof, measured in base form.
3. The method according to claim 2 wherein the eliglustat or
pharmaceutically acceptable salt thereof is eliglustat
hemitartrate.
4. A method of treating Gaucher disease comprising administering to
a patient in need thereof an adjusted effective amount of
eliglustat, or a pharmaceutically acceptable salt thereof, wherein
said patient is an extensive CYP2D6 metabolizer with mild hepatic
impairment and wherein said patient is concurrently taking a drug
that is a weak CYP2D6 inhibitor.
5. The method according to claim 4 wherein the adjusted effective
amount is a once daily dose of 84 mg of eliglustat or a
pharmaceutically acceptable salt thereof, measured in base
form.
6. The method according to claim 5, wherein the eliglustat or
pharmaceutically acceptable salt thereof is eliglustat
hemitartrate.
7. A method of treating Gaucher disease comprising administering to
a patient in need thereof an adjusted effective amount of
eliglustat, or a pharmaceutically acceptable salt thereof, wherein
said patient is an extensive CYP2D6 metabolizer with mild hepatic
impairment and wherein said patient is concurrently taking a drug
that is a weak CYP3A inhibitor.
8. The method according to claim 7, wherein the adjusted effective
amount is a once daily dose of 84 mg of eliglustat or a
pharmaceutically acceptable salt thereof, measured in base
form.
9. The method according to claim 8, wherein the eliglustat or
pharmaceutically acceptable salt thereof is eliglustat
hemitartrate.
10.-12. (canceled)
13. A method of providing eliglustat, or a pharmaceutically
acceptable salt thereof, wherein the eliglustat, or
pharmaceutically acceptable salt thereof, is provided along with
information indicating that it is useful for treating patients with
Gaucher disease, and in cases wherein said patient is an extensive
CYP2D6 metabolizer with mild hepatic impairment, no dose adjustment
is required.
14. An article of manufacture comprising a) a packaging material;
b) eliglustat, or a pharmaceutically acceptable salt thereof; and
c) a label or package insert contained within the packaging
material indicating that eliglustat, or a pharmaceutically
acceptable salt thereof, is contraindicated in CYP2D6 intermediate
metabolizers (IMs) or poor metabolizers (PMs) with any degree of
hepatic impairment and in CYP2D6 extensive metabolizers (EMs) with
moderate or severe hepatic impairment.
15. A package comprising eliglustat, or a pharmaceutically
acceptable salt thereof, and a label, said label comprising a
printed statement which informs a prospective user that eliglustat,
or pharmaceutically acceptable salt thereof, is i) indicated for
the treatment of Gaucher disease type 1 and ii) is contraindicated
in CYP2D6 intermediate metabolizers (IMs) or poor metabolizers
(PMs) with any degree of hepatic impairment and in CYP2D6 extensive
metabolizers (EMs) with moderate or severe hepatic impairment.
16. A method for treating Gaucher disease, comprising administering
an adjusted effective amount of eliglustat, or a pharmaceutically
acceptable salt thereof, to a patient in need thereof in
combination with a weak CYP2D6 inhibitor, wherein said patient is a
CYP2D6 extensive metabolizer and wherein said patient has mild
hepatic impairment.
17. The method according to claim 16 wherein the adjusted effect
amount of eliglustat, or pharmaceutically acceptable salt thereof,
is a dose of 84 mg of eliglustat, measured in base form, once
daily.
18. The method according to claim 17, wherein the eliglustat or
pharmaceutically acceptable salt thereof is eliglustat
hemitartrate.
19. A method for treating Gaucher disease, comprising administering
an adjusted effective dose of eliglustat, or a pharmaceutically
acceptable salt thereof, to a patient in need thereof in
combination with a weak CYP3A inhibitor, wherein said patient is a
CYP2D6 extensive metabolizer and wherein said patient has mild
hepatic impairment.
20. The method according to claim 19, wherein the adjusted effect
amount of eliglustat, or pharmaceutically acceptable salt thereof,
is a dose of 84 mg of eliglustat, measured in base form, once
daily.
21. The method according to claim 20, wherein the eliglustat or
pharmaceutically acceptable salt thereof is eliglustat
hemitartrate.
Description
FIELD OF THE INVENTION
[0001] Provided herein are methods for treating Gaucher disease in
patients with renal or hepatic impairment.
BACKGROUND OF THE INVENTION
[0002] Glycosphingolipids (GSLs) are a class of naturally-occurring
compounds which have a multitude of biological functions, including
the ability to promote cell growth, cell differentiation, adhesion
between cells or between cells and matrix proteins, binding of
microorganisms and viruses to cells, and metastasis of tumor cells.
GSLs are derived from glucosylceramide (GlcCer), which is produced
from ceramide and UDP-glucose by the enzyme UDP-glucose:
N-acylsphingosine glucosyltransferase (GlcCer synthase). The
structure of ceramide is shown below:
##STR00001##
[0003] The accumulation of GSL has been linked to a number of
diseases, including Tay-Sachs, Gaucher, and Fabry diseases (see,
for example, U.S. Pat. No. 6,051,598). Compounds which inhibit
glucosylceramide (GlcCer) synthase can lower GSL concentrations and
have been reported to be useful for treating a patient with one of
the aforementioned diseases.
[0004] Eliglustat is a glucosylceramide synthase inhibitor
currently approved in the United States as a first-line oral
therapy for adults with Gaucher disease type 1 (GD1), who are
CYP2D6 extensive metabolizers (EMs), intermediate metabolizers
(IMs), or poor metabolizers (PMs).
[0005] Eliglustat (chemical name:
N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidi-
n-1-yl)propan-2-yl)octanamide) has the structure of Formula
(I):
##STR00002##
[0006] U.S. Pat. No. 7,196,205, for example, describes the
preparation and physical and biological properties of the compound
of Formula (I).
[0007] Eliglustat is sold in the United States under the brand name
Cerdelga.RTM. as a hemitartrate salt of formula (Ia):
##STR00003##
[0008] which is also referred to herein as eliglustat tartrate.
[0009] The preparation of eliglustat tartrate is described in, for
example, WO2011/066352.
[0010] The use of eliglustat or a pharmaceutically acceptable salt
thereof for treating patients who are CYP2D6 extensive metabolizers
(EMs), intermediate metabolizers (IMs), or poor metabolizers (PMs)
is described in WO2011/066352.
[0011] Eliglustat had not previously been recommended by the FDA
and EMA in GD1 patients with hepatic impairment or moderate to
severe renal impairment due to lack of data to make dosage
recommendations. It has now been surprisingly found that eliglustat
can be safely used to treat GD1 in certain patients with hepatic or
renal impairment.
SUMMARY OF THE INVENTION
[0012] Accordingly, provided herein is a method of treating Gaucher
disease comprising administering to a patient in need thereof an
effective amount of eliglustat, or a pharmaceutically acceptable
salt thereof, wherein said patient is an extensive CYP2D6
metabolizer with mild hepatic impairment (Child-Pugh class A
cirrhosis). In one aspect, the effective amount is a twice daily
dose of 84 mg of eliglustat, or a pharmaceutically acceptable salt
thereof, measured in base form. In one aspect, the Gaucher disease
is Gaucher disease type 1.
[0013] In another embodiment, provided herein is a method of
treating Gaucher disease comprising administering to a patient in
need thereof an adjusted effective amount of eliglustat, or a
pharmaceutically acceptable salt thereof, wherein said patient is
an extensive CYP2D6 metabolizer with mild hepatic impairment and
wherein said patient is concurrently taking a drug that is a weak
CYP2D6 inhibitor. In one aspect of this embodiment, the adjusted
effective amount is a once daily dose of 84 mg of eliglustat or a
pharmaceutically acceptable salt thereof, measured in base form. In
one aspect, the Gaucher disease is Gaucher disease type 1.
[0014] In another embodiment, provided herein is a method of
treating Gaucher disease comprising administering to a patient in
need thereof an adjusted effective amount of eliglustat, or a
pharmaceutically acceptable salt thereof, wherein said patient is
an extensive CYP2D6 metabolizer with mild hepatic impairment and
wherein said patient is concurrently taking a drug that is strong,
moderate, or weak CYP3A inhibitor. In one aspect of this
embodiment, the adjusted effective amount is a once daily dose of
84 mg of eliglustat or a pharmaceutically acceptable salt thereof,
measured in base form. In one aspect, the Gaucher disease is
Gaucher disease type 1.
[0015] In another embodiment, provided herein is a method of
treating Gaucher disease comprising administering to a patient in
need thereof an effective amount of eliglustat, or a
pharmaceutically acceptable salt thereof, wherein said patient is
an extensive CYP2D6 metabolizer with mild, moderate, or severe
renal impairment. In one aspect of this embodiment, the effective
amount is a twice daily dose of 84 mg of eliglustat or a
pharmaceutically acceptable salt thereof, measured in base form. In
one aspect, the Gaucher disease is Gaucher disease type 1.
BRIEF DESCRIPTION OF THE DRAWINGS
[0016] FIG. 1 shows individual C.sub.max values after a single dose
of 84 mg eliglustat according to the study performed in Example
1.
[0017] FIG. 2 shows individual AUC values after a single dose of 84
mg eliglustat according to the study performed in Example 1.
[0018] FIG. 3 shows eliglustat concentration-time profiles
(mean.+-.SD) by impairment group following a single 84 mg dose of
eliglustat according to the study performed in Example 1
(linear-linear scale).
[0019] FIG. 4 shows eliglustat concentration-time profiles
(mean.+-.SD) by impairment group following a single 84 mg dose of
eliglustat according to the study performed in Example 1
(log-linear scale).
[0020] FIG. 5 shows individual C.sub.max values after a single dose
of 84 mg eliglustat according to the study performed in Example
3.
[0021] FIG. 6 shows individual AUC values after a single dose of 84
mg eliglustat according to the study performed in Example 3.
DETAILED DESCRIPTION OF THE INVENTION
[0022] As used above, and throughout the description of the
invention, the following terms, unless otherwise indicated, shall
be understood to have the following meanings:
[0023] As used herein, "coadministered," "coadministering," "in
combination," and "concurrently taking" means being administered or
administering at the same time, in the same day or within a period
of 24 hours, particularly within a period of 12 hours.
[0024] As used herein, "effective amount" means an amount of
eliglustat that would be recommended for a patient to take or a
doctor would prescribe the patient to take if the patient does not
have hepatic impairment or renal impairment. In one aspect, the
effective amount of eliglustat is the amount approved by U.S. Food
and Drug Administration, which is 84 mg twice daily to patients who
are CYP2D6 EMs or IMs, and which is 84 mg once daily to patients
who are PMs. The dose of eliglustat is calculated based on its free
base form. It should be understood that eliglustat can be
administered as a pharmaceutically acceptable salt, particularly as
a hemitartrate, and the amount of salt administered should be
adjusted accordingly.
[0025] As used herein, "patient" means a human.
[0026] "Pharmaceutically acceptable salt" as used herein means that
the salts of the compound of the present invention can be used in
medicinal preparations.
[0027] As used herein, the wording "a compound for use . . . ", for
example, shall be understood as being equivalent to the wording
"use of a compound for . . . " or "use of a compound for the
preparation of a medicament for use in . . . ".
[0028] In certain embodiments, a patient's liver function is
assessed by the Child-Pugh classification system, which defines
three classes of liver cirrhosis. In this classification system,
points are assigned to measurements in one of five categories:
levels of total bilirubin, serum albumin levels, prothrombin time,
ascites, and hepatic encephalopathy. Each measure is given a
ranking of 1, 2, or 3, and the sum of the five rankings is the
Child-Pugh Score. The Child-Pugh Score is used to classify hepatic
impairment by placing patients in a Child-Pugh class: Child-Pugh
class A (mild hepatic impairment), Child-Pugh class B (moderate
hepatic impairment), and Child-Pugh class C (severe hepatic
impairment).
[0029] In certain embodiments, a patient's renal function is
determined by creatinine clearance calculated by the
Cockcroft-Gault formula, wherein a subject or patient with a
creatinine clearance of >80 mL/min has normal renal function,
and wherein a subject or patient with a creatinine clearance of
50-80 mL/min has mild renal impairment, and wherein a subject or
patient with a creatinine clearance of 30-50 mL/min has moderate
renal impairment, and wherein a subject or patient with a
creatinine clearance of <30 mL/min has severe renal
impairment.
[0030] Eliglustat is metabolized by the liver, primarily by
cytochrome P450 enzymes. Cytochrome P450s ("CYPs") are the
principal hepatic xenobiotic metabolizing enzymes. There are eleven
xenobiotic-metabolizing cytochrome P450s expressed in a typical
human liver (i.e., CYP1A2, CYP2A6, CYP2B6, CYP2C8/9/18/19, CYP2D6,
CYP2E1 and CYP3A4/5). Mainly CYP2D6 and to a lesser extent CYP3A4
are the primary cytochrome P450 isoforms that are responsible for
metabolizing eliglustat and its pharmaceutically active salts, such
as eliglustat tartrate. The level of activity of some P450 enzymes
such as CYP2D6 differs according to the individual CYP2D6
phenotype. For example, individuals can be classified as poor,
intermediate, extensive, and ultra rapid CYP2D6 metabolizers.
[0031] A patient is typically assessed as being a poor,
intermediate, extensive, or ultra rapid CYP2D6 metabolizer through
genotyping, although rarely the genotype cannot be determined
(indeterminate metabolizer).
[0032] For example, a patient can be a poor P450 metabolizer as a
result of low expression of a P450 enzyme. In such instances, the
low expression can be assessed by determining P450 enzyme
expression in the patient, i.e., genotyping the patient for the
P450 enzyme. For example, expression of CYP2D6 is commonly assessed
by PCR (McElroy et. al. "CYP2D6 Genotyping as an Alternative to
Phenotyping for Determination of Metabolic Status in a Clinical
Trial Setting", AAPS Pharmsi (2000) 2(4) article 33) or by
microarray based pharmacogenomic testing. As such, the patient can
be conveniently genotyped for P450 expression (e.g., CYP2D6) prior
to the initiation of treatment and administered an adjusted
effective amount, if necessary.
[0033] For the CYP2D6 gene, there are four predicted phenotypes:
[0034] As used herein, a "poor CYP2D6 metabolizer" carries two
mutant alleles, which result in complete loss of enzyme activity.
[0035] As used herein, an "intermediate CYP2D6 metabolizer"
possesses one reduced activity allele and one null allele. [0036]
As used herein, an "extensive CYP2D6 metabolizer" possesses at
least one and no more than two normal functional alleles. [0037] As
used herein, an "ultra rapid CYP2D6 metabolizer" carries multiple
copies (3-13) of functional alleles and produce excess enzymatic
activity.
[0038] Because eliglustat is metabolized mainly by CYP2D6 and to a
lesser extent by CYP3A, eliglustat concentration may be increased
in patients when co-administered with certain drugs that are CYP2D6
enzyme inhibitors. Examples of weak CYP2D6 inhibitors include, but
are not limited to, escitalopram, abiraterone, diphenhydramine, am
iodarone, deramciclane, desvenlafaxine, fosdevirine,
daclatasvir/asunaprevir/beclabuvir, oral contraceptives,
osilodrostat, propafenone, ritonavir, cimetidine, clobazam,
cobicistat, lorcaserin, celecoxib, felodipine, fluvoxamine,
gefitinib, hydroxychloroquine, sertraline, vemurafenib, echinacea,
escitalopram, hydralazine, panobinostat, ranitidine, verapamil,
alogliptin, diltiazem, dulaglutide, lopinavir/ritonavir,
sarpogrelate, artesunate/pyronaridine, imatinib, and febuxostat.
Examples of moderate CYP2D6 inhibitors include, but are not limited
to, duloxetine, terbinafine, moclobemide, mirabegron, cinacalcet,
dronedarone, rolapitant, cimetidine, and tipranavir/ritonavir.
Examples of strong CYP2D6 inhibitors include, but are not limited
to, paroxetine, fluoxetine, quinidine, bupropion, and
dacomitinib.
[0039] Patients who are poor CYP2D6 metabolizers have little or no
CYP2D6 function, so eliglustat metabolism would primarily be via
the CYP3A pathway in these patients.
[0040] Eliglustat metabolism in these patients may be further
impaired as a result of being treated with certain drugs that are
CYP3A enzyme inhibitors. For example, examples of weak CYP3A
inhibitors include, but are not limited to, amlodipine, cilostazol,
fluvoxamine, goldenseal, isoniazid, ranitidine, and ranolazine.
Examples of moderate CYP3A inhibitors include, but are not limited
to, erythromycin, ciprofloxacin, fluconazole, diltiazem, verapamil,
aprepitant, atazanavir, darunavir, fosamprenavir, imatinib,
cimetidine, amprenavir, casopitant, crizotinib, faldaprevir,
ledipasvir, netupitant, nilotinib, tofisopam, dronedarone,
cimetidine, and cyclosporine. Examples of strong CYP3A inhibitors
include, but are not limited to, ketoconazole, clarithromycin,
itraconazole, cobicistat, indinavir, lopinavir, ritonavir,
saquinavir, telaprevir, tipranavir, posaconazole, voriconazole,
telithromycin, conivaptan, boceprevir, idelalisib, mibefradil,
nefazodone, nelfinavir, elvitegravir/ritonavir,
danopravir/ritonavir, and troleandomycin.
[0041] Another embodiment provided herein is a method of providing
eliglustat, or a pharmaceutically acceptable salt thereof, wherein
the eliglustat, or pharmaceutically acceptable salt thereof, is
provided along with information indicating that it is useful for
treating patients with Gaucher disease, particularly adult patients
with Gaucher disease type 1, and in cases wherein said patient is
an extensive CYP2D6 metabolizer with mild hepatic impairment, no
dose adjustment is required. In one aspect of this embodiment, the
recommended or effective amount is 84 mg of eliglustat, measured as
a base, twice daily.
[0042] Another embodiment provided herein is a method of providing
eliglustat, or a pharmaceutically acceptable salt thereof, wherein
the eliglustat, or pharmaceutically acceptable salt thereof, is
provided along with information indicating that it is useful for
treating patients with Gaucher disease, particularly adult patients
with Gaucher disease type 1, and in cases wherein said patient is
an extensive CYP2D6 metabolizer with mild hepatic impairment and
wherein a weak CYP2D6 inhibitor or a strong, moderate or weak CYP3A
inhibitor is coadministered, the effective amount should be reduced
to an adjusted effective amount. In one aspect of this embodiment,
the adjusted effective amount is 84 mg of eliglustat, measured as a
base, once daily.
[0043] Another embodiment provided herein is a method of providing
eliglustat, or a pharmaceutically acceptable salt thereof, wherein
the eliglustat, or pharmaceutically acceptable salt thereof, is
provided along with information indicating that eliglustat, or
pharmaceutically acceptable salt thereof, is contraindicated in
CYP2D6 IMs or PMs with any degree of hepatic impairment and in
CYP2D6 EMs with moderate or severe hepatic impairment.
[0044] Another embodiment provided herein is a method of providing
eliglustat, or a pharmaceutically acceptable salt thereof, wherein
the eliglustat, or pharmaceutically acceptable salt thereof, is
provided along with information indicating that it is useful for
treating patients with Gaucher disease, particularly adult patients
with Gaucher disease type 1, and in cases wherein said patient is
an extensive CYP2D6 metabolizer with mild, moderate, or severe
renal impairment, no dose adjustment is required. In one aspect of
this embodiment, the recommended or effective amount is 84 mg of
eliglustat, measured as a base, twice daily.
[0045] Another embodiment provided herein is a method of providing
eliglustat, or a pharmaceutically acceptable salt thereof, wherein
the eliglustat, or pharmaceutically acceptable salt thereof, is
provided along with information indicating that eliglustat, or
pharmaceutically acceptable salt thereof, is not recommended or
should be avoided in CYP2D6 EMs with end-stage renal disease and
CYP2D6 IMs or PMs with mild, moderate, or severe renal impairment
or end-stage renal disease.
[0046] Another embodiment provided herein is an article of
manufacture comprising [0047] a) a packaging material; [0048] b)
eliglustat, or a pharmaceutically acceptable salt thereof; and
[0049] c) a label or package insert contained within the packaging
material indicating that eliglustat, or a pharmaceutically
acceptable salt thereof, is contraindicated in CYP2D6 intermediate
metabolizers (IMs) or poor metabolizers (PMs) with any degree of
hepatic impairment and in CYP2D6 extensive metabolizers (EMs) with
moderate or severe hepatic impairment.
[0050] Another embodiment provided herein is an article of
manufacture comprising [0051] a) a packaging material; [0052] b)
eliglustat, or a pharmaceutically acceptable salt thereof; and
[0053] c) a label or package insert contained within the packaging
material indicating that no dose adjustment of eliglustat, or a
pharmaceutically acceptable salt thereof, is required in CYP2D6
extensive metabolizers (EMs) with mild hepatic impairment.
[0054] Another embodiment provided herein is an article of
manufacture comprising [0055] a) a packaging material; [0056] b)
eliglustat, or a pharmaceutically acceptable salt thereof; and
[0057] c) a label or package insert contained within the packaging
material indicating that eliglustat, or a pharmaceutically
acceptable salt thereof, is contraindicated in extensive
metabolizers (EMs) with mild hepatic impairment taking a strong or
moderate CYP2D6 inhibitor; and in CYP2D6 extensive metabolizers
(EMs) with mild hepatic impairment taking a weak CYP2D6 inhibitor
or a strong, moderate or weak CYP3A inhibitor, a dose of 84 mg
eliglustat once daily should be considered.
[0058] Another embodiment provided herein is an article of
manufacture comprising [0059] a) a packaging material; [0060] b)
eliglustat, or a pharmaceutically acceptable salt thereof; and
[0061] c) a label or package insert contained within the packaging
material indicating that no dose adjustment of eliglustat, or a
pharmaceutically acceptable salt thereof, is required in CYP2D6
extensive metabolizers with mild, moderate, or severe renal
impairment.
[0062] Another embodiment provided herein is an article of
manufacture comprising [0063] a) a packaging material; [0064] b)
eliglustat, or a pharmaceutically acceptable salt thereof; and
[0065] c) a label or package insert contained within the packaging
material indicating that eliglustat, or a pharmaceutically
acceptable salt thereof, is not recommended or should be avoided in
CYP2D6 extensive metabolizers (EMs) with end-stage renal
disease.
[0066] Another embodiment provided herein is an article of
manufacture comprising [0067] a) a packaging material; [0068] b)
eliglustat, or a pharmaceutically acceptable salt thereof; and
[0069] c) a label or package insert contained within the packaging
material indicating that eliglustat, or a pharmaceutically
acceptable salt thereof, is should be avoided in intermediate
metabolizers (IMs) or poor metabolizers (PMs) with mild, moderate
or severe renal impairment or end-stage renal disease.
[0070] Another embodiment provided herein is a package comprising
eliglustat, or a pharmaceutically acceptable salt thereof, and a
label, said label comprising a printed statement which informs a
prospective user that eliglustat, or pharmaceutically acceptable
salt thereof, is i) indicated for the treatment of Gaucher disease
type 1 and ii) is contraindicated in CYP2D6 intermediate
metabolizers (IMs) or poor metabolizers (PMs) with any degree of
hepatic impairment and in CYP2D6 extensive metabolizers (EMs) with
moderate or severe hepatic impairment.
[0071] Another embodiment provided herein is a package comprising
eliglustat, or a pharmaceutically acceptable salt thereof, and a
label, said label comprising a printed statement which informs a
prospective user that eliglustat, or pharmaceutically acceptable
salt thereof, is i) indicated for the treatment of Gaucher disease
type 1 and ii) contraindicated in extensive metabolizers (EMs) with
mild hepatic impairment taking a strong or moderate CYP2D6
inhibitor. In CYP2D6 extensive metabolizers (EMs) with mild hepatic
impairment taking a weak CYP2D6 inhibitor or a strong, moderate or
weak CYP3A inhibitor, a dose of 84 mg eliglustat once daily should
be considered.
[0072] Another embodiment provided herein is a package comprising
eliglustat, or a pharmaceutically acceptable salt thereof, and a
label, said label comprising a printed statement which informs a
prospective user that eliglustat, or pharmaceutically acceptable
salt thereof, is i) indicated for the treatment of Gaucher disease
type 1 and ii) not recommended or should be avoided in CYP2D6
extensive metabolizers (EMs) with end-stage renal disease
(ESRD).
[0073] Another embodiment provided herein is a package comprising
eliglustat, or a pharmaceutically acceptable salt thereof, and a
label, said label comprising a printed statement which informs a
prospective user that eliglustat, or pharmaceutically acceptable
salt thereof, is i) indicated for the treatment of Gaucher disease
type 1 and ii) not recommended in intermediate metabolizers (IMs)
or poor metabolizers (PMs) with mild, moderate or severe renal
impairment or end-stage renal disease, and eliglustat is not
recommended or should be avoided in CYP2D6 extensive metabolizers
(EMs) with end-stage renal disease.
[0074] Another embodiment provided herein is a method for treating
Gaucher disease, comprising administering an adjusted effective
amount of eliglustat, or a pharmaceutically acceptable salt
thereof, to a patient in need thereof in combination with a weak
CYP2D6 inhibitor, wherein said patient is a CYP2D6 extensive
metabolizer and wherein said patient has mild hepatic impairment.
In one aspect of this embodiment, the adjusted effect amount of
eliglustat, or pharmaceutically acceptable salt thereof, is a dose
of 84 mg of eliglustat, measured in base form, once daily. In
another aspect, the weak CYP2D6 inhibitor is escitalopram,
abiraterone, diphenhydramine, amiodarone, deramciclane,
desvenlafaxine, fosdevirine, daclatasvir/asunaprevir/beclabuvir,
oral contraceptives, osilodrostat, propafenone, ritonavir,
cimetidine, clobazam, cobicistat, lorcaserin, celecoxib,
felodipine, fluvoxamine, gefitinib, hydroxychloroquine, sertraline,
vemurafenib, echinacea, escitalopram, hydralazine, panobinostat,
ranitidine, verapamil, alogliptin, diltiazem, dulaglutide,
lopinavir/ritonavir, sarpogrelate, artesunate/pyronaridine,
imatinib, or febuxostat. In another aspect, the Gaucher disease is
Gaucher disease type 1.
[0075] Another embodiment provided herein is a method for treating
Gaucher disease, comprising administering an adjusted effective
dose of eliglustat, or a pharmaceutically acceptable salt thereof,
to a patient in need thereof in combination with a strong, moderate
or weak CYP3A inhibitor, wherein said patient is a CYP2D6 extensive
metabolizer and wherein said patient has mild hepatic impairment.
In one aspect of this embodiment, the adjusted effect amount of
eliglustat, or pharmaceutically acceptable salt thereof, is a dose
of 84 mg of eliglustat, measured in base form, once daily. Examples
of weak CYP3A inhibitors include amlodipine, cilostazol,
fluvoxamine, goldenseal, isoniazid, ranitidine, and ranolazine. In
one aspect, the moderate CYP3A inhibitor is selected from the group
consisting of erythromycin, ciprofloxacin, fluconazole, diltiazem,
verapamil, aprepitant, atazanavir, darunavir, fosamprenavir,
imatinib, cimetidine, amprenavir, casopitant, crizotinib,
faldaprevir, ledipasvir, netupitant, nilotinib, tofisopam,
dronedarone, cimetidine, and cyclosporine. In one aspect the strong
CYP3A inhibitor is selected from the group consisting of
ketoconazole, clarithromycin, itraconazole, cobicistat, indinavir,
lopinavir, ritonavir, saquinavir, telaprevir, tipranavir,
posaconazole, voriconazole, telithromycin, conivaptan, boceprevir,
idelalisib, mibefradil, nefazodone, nelfinavir,
elvitegravir/ritonavir, danopravir/ritonavir, and troleandomycin.
In another aspect, the Gaucher disease is Gaucher disease type
1.
[0076] In another embodiment, provided herein is eliglustat or a
pharmaceutically acceptable salt thereof for use in treating
Gaucher disease in a patient, wherein the patient is an extensive
CYP2D6 metabolizer with mild hepatic impairment. In one aspect,
eliglustat, or a pharmaceutically acceptable salt thereof, is
administered in an effective amount wherein the effective amount is
a twice daily dose of 84 mg, measured in base form. In another
aspect, the Gaucher disease is Gaucher disease type 1.
[0077] In another embodiment, provided herein is eliglustat, or a
pharmaceutically acceptable salt thereof, for use in treating
Gaucher disease in patient, wherein the patient is an extensive
CYP2D6 metabolizer with mild hepatic impairment and wherein said
patient is concurrently taking a drug that is a weak CYP2D6
inhibitor. In one aspect, the eliglustat, or a pharmaceutically
acceptable salt thereof, is administered in an adjusted effective
amount, wherein the adjusted effective amount is a once daily dose
of 84 mg of eliglustat, or a pharmaceutically acceptable salt
thereof, measured in base form. In another aspect, the weak CYP2D6
inhibitor is selected from escitalopram, abiraterone,
diphenhydramine, amiodarone, deramciclane, desvenlafaxine,
fosdevirin, daclatasvir/asunaprevir/beclabuvir, oral
contraceptives, osilodrostat, propafenone, ritonavir, cimetidine,
clobazam, cobicistat, lorcaserin, celecoxib, felodipine,
fluvoxamine, gefitinib, hydroxychloroquine, sertraline,
vemurafenib, echinacea, escitalopram, hydralazine, panobinostat,
ranitidine, verapamil, alogliptin, diltiazem, dulaglutide,
lopinavir/ritonavir, sarpogrelate, artesunate/pyronaridine,
imatinib, and febuxostat. In another aspect, the Gaucher disease is
Gaucher disease type 1.
[0078] In another embodiment, provided herein is eliglustat, or a
pharmaceutically acceptable salt thereof, for use in treating
Gaucher disease in a patient, wherein the patient is an extensive
CYP2D6 metabolizer with mild hepatic impairment and wherein said
patient is concurrently taking a drug that is strong, moderate, or
weak CYP3A inhibitor. In one aspect of this embodiment, the
eliglustat, or a pharmaceutically acceptable salt thereof, is
administered in an adjusted effective amount, wherein the adjusted
effective amount is a once daily dose of 84 mg of eliglustat or a
pharmaceutically acceptable salt thereof, measured in base form. In
one aspect, the weak CYP3A inhibitor is, for example, selected from
amlodipine, cilostazol, fluvoxamine, goldenseal, isoniazid,
ranitidine, and ranolazine. In one aspect, the moderate CYP3A
inhibitor is, for example, selected from the group consisting of
erythromycin, ciprofloxacin, fluconazole, diltiazem, verapamil,
aprepitant, atazanavir, darunavir, fosamprenavir, imatinib, and
cimetidine. In one aspect the strong CYP3A inhibitor is, for
example, selected from the group consisting of ketoconazole,
clarithromycin, itraconazole, cobicistat, indinavir, lopinavir,
ritonavir, saquinavir, telaprevir, tipranavir, posaconazole,
voriconazole, telithromycin, conivaptan, and boceprevir. In another
aspect, the Gaucher disease is Gaucher disease type 1.
[0079] In another embodiment, provided herein is eliglustat or a
pharmaceutically acceptable salt thereof for use in treating
Gaucher disease in a patient, wherein the patient is an extensive
CYP2D6 metabolizer with mild, moderate, or severe renal impairment.
In one aspect of this embodiment, the eliglustat, or a
pharmaceutically acceptable salt thereof, is administered in an
effective amount, wherein the effective amount is a twice daily
dose of 84 mg of eliglustat or a pharmaceutically acceptable salt
thereof, measured in base form. In another aspect, the Gaucher
disease is Gaucher disease type 1.
[0080] For their therapeutic use, eliglustat and pharmaceutically
acceptable salts thereof are generally introduced into
pharmaceutical compositions.
[0081] These pharmaceutical compositions comprise eliglustat or a
pharmaceutically acceptable salt thereof and one or more
pharmaceutically acceptable excipients.
[0082] Said excipients are chosen according to the pharmaceutical
form and the method of administration desired, from the usual
excipients which are known to those skilled in the art.
[0083] By way of example, a dose of eliglustat or a
pharmaceutically acceptable salt thereof, in capsule form, may
correspond to the following example: A capsule for oral use
comprising 84 mg of eliglustat (equivalent to 100 mg of the
hemitartrate salt), microcrystalline cellulose, lactose
monohydrate, hypromellose and glyceryl behenate.
[0084] The present invention may be better understood by reference
to the following non-limiting examples, which is exemplary of the
invention. It should in no way be construed, however, as limiting
the breath of the scope of the invention.
Example 1
[0085] A multi-center, open-label, single oral dose study of
eliglustat tartrate administered to mild or moderate HI and normal
hepatic function (healthy) matched (by body weight and cytochrome
P450 [CYP] 2D6 phenotype) subjects was carried out to study the
effect of mild and moderate hepatic impairment (HI) on the
pharmacokinetics (PK) of eliglustat.
[0086] Approximately 8 subjects were planned to be enrolled into
each HI group (mild or moderate HI) and 8 subjects with normal
hepatic function matched to impaired subjects by weight and CYP2D6
phenotype. At least 6 CYP2D6 extensive metabolizers (EMs) were to
be enrolled into each impairment group, with the remaining 2
subjects enrolled according to the following preference: at least
20 subjects were to be screened for each impairment group and if
identified, up to 2 CYP2D6 poor metabolizers (PMs) were enrolled.
If less than 2 PMs were identified, up to 2 CYP2D6 intermediate
metabolizers (IMs) were to be enrolled for a total of 8 subjects
per group. If less than 2 PMs or IMs were identified, up to 2
additional EMs were to be enrolled for a total of 8 subjects per
group. If 2 PMs were identified prior to screening 20 subjects,
screening may have been discontinued. If an eligible PM subject was
identified after satisfying the above requirements and enrolling 8
subjects for an impairment group, this subject may still have been
enrolled for that impairment group.
[0087] CYP2D6 EMs and IMs were to receive a single 100-mg dose of
eliglustat tartrate, while CYP2D6 PMs were to receive a single
50-mg dose of eliglustat tartrate.
[0088] Diagnosis and Criteria for Inclusion:
[0089] For HI subjects: Male (body weight between 50.0 and 125.0
kg, inclusive) or female subjects (body weight between 40.0 and
110.0 kg, inclusive) between 18 and 79 years, inclusive, with a
body mass index between 18.0 and 37 kg/m.sup.2, inclusive; having
stable chronic liver disease assessed by medical history, physical
examination, and laboratory values; with moderate HI (defined as
Child-Pugh score of 7 to 9, inclusive) or mild HI (defined as
Child-Pugh score of 5 to 6, inclusive). For healthy subjects: Male
or female subjects, between 18 and 79 years, inclusive; body weight
within 15% of the body weight of matched subjects with HI, and body
mass index between 18.0 and 37 kg/m.sup.2, inclusive; healthy
subjects were also matched to HI groups by CYP2D6 phenotype
predicted from genotype.
[0090] Dose Regimen:
[0091] A single 100-mg capsule of eliglustat tartrate (equivalent
to 84 mg of eliglustat) was administered to CYP2D6 EM or IM
subjects with mild or moderate HI and matching healthy
subjects.
[0092] A single 50-mg capsule of eliglustat tartrate (equivalent to
42 mg of eliglustat) was to be administered to CYP2D6 PM with mild
or moderate HI and matching healthy subjects.
[0093] Criteria for Evaluation:
[0094] Pharmacokinetics: The following PK parameters were
calculated for eliglustat plasma concentrations using
noncompartmental methods: Maximum plasma concentration observed
(C.sub.max), area under the plasma concentration versus time curve
calculated using the trapezoidal method from time zero to the time
corresponding to the last quantifiable concentration t.sub.last
(AUC.sub.last), time to reach C.sub.max (t.sub.max), area under the
plasma concentration versus time curve extrapolated to infinity
(AUC), terminal half-life associated with the terminal slope
.lamda.z (t.sub.1/2z), time corresponding to the last concentration
above the limit of quantification (t.sub.last), apparent total body
clearance of a drug from the plasma (CL/F), and apparent volume of
distribution during the terminal (.lamda.z) phase (Vz/F).
[0095] Pharmacokinetic Sampling Times and Bioanalytical
Methods:
[0096] Blood samples were collected at the following timepoints to
assess plasma concentrations of eliglustat: predose and 0.5, 1,
1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 24, 36, and 48 hours postdose.
[0097] Eliglustat concentrations in plasma were determined using a
validated liquid chromatography-tandem mass spectrometry method
with a lower limit of quantification of 0.2 ng/mL.
[0098] Statistical Methods:
[0099] Pharmacokinetics
[0100] Eliglustat PK parameters were summarized using descriptive
statistics for each population group and for each CYP2D6 phenotype.
For log-transformed C.sub.max, AUC.sub.last, AUC, t.sub.1/2z, CL/F
and Vz/F, the effect of hepatic impairment on a single dose of
eliglustat tartrate on eliglustat PK parameters were analyzed using
a linear fixed effects model for CYP2D6 EM subjects. Estimate and
90% confidence interval (CI) for geometric mean of each population
group and also for the geometric mean ratio of each hepatic
impaired group versus the normal control group were provided for
each parameter.
[0101] Safety
[0102] The safety evaluation was based upon the review of the
individual values (clinically significant abnormalities) and
descriptive statistics (summary tables). All safety analyses were
performed using the safety population and were based on the
on-treatment phase (defined as the time from investigational
medicinal product [IMP] administration up to Day 3 visit,
inclusive). For laboratory, vital signs, and ECG data, potentially
clinically significant abnormalities (PCSAs) were analyzed using
the 24 May 2014 version of the PCSA list. Electrocardiogram
parameters were obtained from automatic reading of 12-lead ECGs and
were analyzed as raw parameter values and change from baseline. For
vital signs, raw data and changes from baseline were summarized
using descriptive statistics by population group and time point.
All individual data for biochemistry, hematology, and qualitative
urinary tests were listed.
[0103] Adverse events were coded according to the Medical
Dictionary for Regulatory Activities (MedDRA v.19.1) and classified
into predefined standard categories according to chronological
criteria: [0104] Pretreatment adverse events (AEs), defined as AEs
that occurred, worsened (according to Investigator opinion), or
became serious during the pretreatment phase (defined as the time
between the signature of the informed consent and IMP
administration [excluded]); [0105] Treatment-emergent AEs (TEAEs),
defined as AEs that occurred, worsened, or became serious during
the on-treatment phase; [0106] Posttreatment AEs, defined as AEs
that occurred, worsened, or became serious during the posttreatment
phase (defined as the time after Day 3 visit through completion of
EOS).
[0107] All AEs reported in the study were listed and sorted by
subject, onset date and time. The number and percentage of subjects
with TEAEs were listed by population group, primary system-organ
class (SOC), preferred term (PT), and AE diagnosis.
[0108] Population Characteristics:
[0109] Eight subjects were enrolled into each group. Seven CYP2D6
EMs and 1 CYP2D6 IM, each, were enrolled into the moderate
impairment group and the healthy matched group, and 6 CYP2D6 EMs
and 2 CYP2D6 IMs were enrolled into the mild impairment group.
[0110] Pharmacokinetic Results:
[0111] Mean.+-.SD (Geometric Mean) [CV %] PK parameters of
eliglustat in CYP2D6 EM subjects after a single dose of 100 mg
eliglustat tartrate
TABLE-US-00001 Plasma Eliglustat CYP2D6 EM Subjects CYP2D6 IM
Subjects Parameter Healthy Mild HI Moderate HI Healthy Mild HI
Moderate HI N 7 6 7 1 2 1 C.sub.max 10.4 .+-. 7.40 22.4 .+-. 30.2
39.5 .+-. 43.4 75.9 35.9 35.6 (ng/mL) (8.81) (10.7) (24.8) (26.7,
45.1) [70.9] [135.1] [110.0] t.sub.max.sup.a 2.50 1.75 4.00 2.50
2.00 1.52 (h) (1.00-3.00) (1.00-6.00) (1.00-6.00) (2.00, 2.00)
AUC.sub.last 63.9 .+-. 47.1 166 .+-. 285 536 .+-. 642 568 334 197
(ng h/mL) (54.7) (64.3) (293) (187, 481) [73.7] [171.3] [119.6] AUC
69.0 .+-. 49.1 172 .+-. 293 575 .+-. 696 578 346 208 (ng h/mL)
(59.5) (68.5) (307) (190, 501) [71.2] [170.5] [121.0] t.sub.1/2z
7.08 .+-. 0.881 7.25 .+-. 1.46 10.5 .+-. 2.25 8.48 9.34 5.87 (h)
(7.03) (7.13) (10.3) (8.27, 10.4) [12.5] [20.1] [21.4] CL/F 1570
.+-. 628 1980 .+-. 1440 416 .+-. 295 146 306 406 (L/h) (1420)
(1230) (275) (168, 444) [40.1] [72.8] [70.9] Vz/F 16030 .+-. 6020
20000 .+-.15600 5840 .+-. 4130 1790 3910 3430 (L) (14400) (12700)
(4090) (2520, 5300) [37.5] [78.2] [70.7] t.sub.last.sup.a 24.00
30.00 48.00 48.00 48.00 24.00 (h) (24.00-24.05) (24.00-48.00)
(36.00-48.00) (48.00, 48.00) .sup.aMedian (Min-Max) b Mean (Min,
Max) for N = 2
TABLE-US-00002 Point estimates of geometric mean ratio with 90% CI
in CYP2D6 EM subjects Parameter Comparison Estimate 90% CI
C.sub.max Mild HI vs Healthy 1.22 (0.46 to 3.23) Moderate HI vs
Healthy 2.81 (1.10 to 7.17) AUC.sub.last Mild HI vs Healthy 1.18
(0.42 to 3.28) Moderate HI vs Healthy 5.35 (2.00 to 14.35) AUC Mild
HI vs Healthy 1.15 (0.41 to 3.19) Moderate HI vs Healthy 5.16 (1.93
to 13.74) t.sub.1/2z Mild HI vs Healthy 1.01 (0.85 to 1.21)
Moderate HI vs Healthy 1.47 (1.24 to 1.74) CL/F Mild HI vs Healthy
0.87 (0.31 to 2.41) Moderate HI vs Healthy 0.19 (0.07 to 0.52) Vz/F
Mild HI vs Healthy 0.88 (0.34 to 2.29) Moderate HI vs Healthy 0.28
(0.11 to 0.71)
[0112] Compared to healthy CYP2D6 EMs, eliglustat mean C.sub.max
and AUC was slightly higher in CYP2D6 EMs with mild HI (1.22 and
1.15 fold, respectively) and appreciably higher in subjects with
moderate HI (2.81 and 5.16 fold, respectively) following a single
100-mg dose of eliglustat tartrate. Mean t.sub.1/2z values were
similar in mild HI subjects and healthy subjects, but were
prolonged in moderate HI subjects (10.5 hours versus 7.08
hours).
[0113] Safety Results:
[0114] A total of 6 mild TEAEs were observed in 5 subjects. Four
TEAEs in 3 subjects were considered related to study drug by the
investigator: dysgeusia in 2 subjects with moderate HI and nausea
and headache in 1 healthy subject. No serious adverse events were
reported, and there were no deaths or other significant AEs. There
were no treatment emergent PCSA that were clinically relevant for
the laboratory values or for vital signs and ECGs.
Example 2
[0115] A physiologically-based pharmacokinetic (PBPK) model
developed using eliglustat preclinical and clinical study results
was verified using the observed single-dose data in both healthy
and hepatic impaired patients from the study described in Example
1. This PBPK model was used to predict eliglustat exposures after
repeated dosing of eliglustat in CYP2D6 EM subjects with mild and
moderate HI as well as in CYP2D6 EM healthy subjects (without HI)
for comparison. Simulation of eliglustat PK was conducted with 10
virtual trials of 10 subjects/category after repeated dosing of 84
mg twice daily (BID) or once daily (QD) eliglustat oral dose alone
for 8 days, and the simulation results are presented in Table
1.
TABLE-US-00003 TABLE 1 Simulated Mean (Range of the 10 Means of the
10 Trials) Steady-State Exposure after Oral Administration of
Eliglustat in CYP2D6 EMs (Healthy, Mild HI and Moderate HI) 84 mg
BID.sup.a Ratio.sup.b 84 mg QD.sup.a C.sub.max AUC.sub.0-tau
(HI/Healthy) C.sub.max AUC.sub.0-tau CYP2D6 EM (ng/mL) (ng h/mL)
C.sub.max AUC.sub.0-tau (ng/mL) (ng h/mL) Healthy 27 199 -- -- 17.9
146 (17.0, 37.2) (114, 291) (12.7, 22.2) (94.5, 203) Mild HI 64.2
568 2.38 2.85 32.9 351 (39.1, 97.0) (322, 893) (22.2, 49.5) (215,
606) Moderate HI 173 1760 6.41 8.86 83.5 1270 (127, 235) (1270,
2470) (59.2, 115) (852, 1890) AUC.sub.0-tau = area under the plasma
concentration versus time curve from time zero to the end of the
dosing interval of 12 hours for BID and 24 hours for QD (AUCo-tau
represents AUC.sub.0-12 for BID regimen and AUC.sub.0-24 for QD
regimen); BID = twice daily; C.sub.max = maximum observed plasma
concentration; EM = extensive metabolizer; QD = once daily; HI =
hepatic impairment .sup.aValues are reported to 3 significant
figures .sup.bRatio of the mean exposures
[0116] To ensure that eliglustat exposure will remain within the
range of eliglustat exposures that has been demonstrated to be safe
and efficacious in the clinical development program, 84 mg QD of
eliglustat when coadministered with CYP2D6 inhibitors or CYP3A
inhibitors was evaluated using PBMK modeling for CYP2D6 EM subjects
with mild HI. Various scenarios of coadministration of eliglustat
84 mg QD with CYP2D6 inhibitors or CYP3A inhibitors were simulated
using Simcyp build-in model of inhibitors with minor modifications
as needed. Paroxetine, terbinafine, and ritonavir were used as
strong, moderate, and weak CYP2D6 inhibitors, respectively, while
ketoconazole, fluconazole, and fluvoxamine were used as strong,
moderate, and weak CYP3A inhibitors, respectively. Simulation of
eliglustat PK was conducted with 10 virtual trials of 10 CYP2D6 EM
subjects with mild HI after repeated dosing of 84 mg QD eliglustat
alone for 8 days (from Day 1 to Day 8) and with CYP2D6 or CYP3A
inhibitors for an additional 7 or 10 days (Day 9 to Day 15 or Day 9
to Day 18). The PBPK-predicted eliglustat mean (range of the means
of the 10 virtual trials) exposures in CYP2D6 EMs with mild HI upon
coadministration of eliglustat with CYP2D6 or CYP3A inhibitors are
presented in Table 2. Simulated exposures in healthy EMs and EMs
with mild HI following eliglustat alone at 84 mg BID were also
included for comparison.
TABLE-US-00004 TABLE 2 Simulated Mean (Range of the 10 Means of the
10 Trials) Steady-State Exposure in CYP2D6 EMs (Heathy and Mild HI)
after Oral Administration of Eliglustat with and without CYP2D6 or
CYP3A Inhibitors Eliglustat + CYP CYP Inhibitor Inhibitor CYP
Inhibitor C.sub.max.sup.a AUC.sub.0-tau.sup.a Eliglustat Population
Type (dose) (ng/mL) (ng h/mL) 84 mg BID Healthy None -- 27 199
(17.0, 37.2) (114, 291) 84 mg BID Mild HI None -- 64.2 568 (39.1,
97.0) (322, 893) 84 mg QD Mild HI Strong Paroxetine 155 2630 CYP2D6
(30 mg QD) (119, 192) (1840, 3450) inhibitor 84 mg QD Mild HI
Strong Ketoconazole 71.7 1060 CYP3A (400 mg QD) (32.8, 138) (377,
2380) inhibitor 84 mg QD Mild HI Moderate Terbinafine 96.9 1350
CYP2D6 (250 mg QD) (82.1, 110) (1080, 1580) inhibitor 84 mg QD Mild
HI Moderate Fluconazole 53.5 700 CYP3A (400 mg (31.6, 83.7) (342,
1240) inhibitor loading dose + 200 mg QD) 84 mg QD Mild HI Weak
Ritonavir 45.5 529 CYP2D6 (100 mg BID) (31.0, 64.9) (361, 797)
inhibitor 84 mg QD Mild HI Weak Fluvoxamine 42.4 482 CYP3A (300 mg
QD) (26.4, 65.9) (281, 850) inhibitor AUC.sub.0-tau = area under
the plasma concentration versus time curve from time zero to the
end of the dosing interval of 12 hours for BID and 24 hours for QD
(AUC.sub.0-tau represents AUC.sub.0-12 for BID regimen and
AUC.sub.0-24 for QD regimen); BID = twice daily; C.sub.max =
maximum observed plasma concentration; QD = once daily.
.sup.aValues were reported to 3 significant figures
Example 3
[0117] A phase 1, open-label, 2-stage, pharmacokinetic and
tolerability study of single dose eliglustat tartrate in subjects
with renal impairment (RI) (mild, moderate, and severe) and
subjects with normal renal function, matched to RI subjects by age,
weight, and cytochrome P450 [CYP] 2D6 phenotype was carried out to
study the effect of mild, moderate, and severe RI on the
pharmacokinetics (PK) of eliglustat.
[0118] Methodology: A phase 1, open-label, 2-stage, pharmacokinetic
and tolerability study of single dose eliglustat tartrate in
subjects with renal impairment (RI) (mild, moderate, and severe)
and subjects with normal renal function, matched to RI subjects by
age, weight, and cytochrome P450 [CYP] 2D6 phenotype.
[0119] Approximately 32 subjects were planned to be enrolled in 2
stages: Stage 1 comprised of 8 subjects with severe RI and 8
subjects with normal renal function, matched by CYP2D6 phenotype,
weight, and age. Subjects with mild and moderate RI would have been
enrolled in Stage 2 if the results in subjects with severe RI
showed a substantial effect of reduced renal function on eliglustat
PK compared to the matched normal function subjects. Stage 2 was to
include 8 subjects with mild and 8 subjects with moderate RI. Each
cohort was to enroll at least 6 CYP2D6 extensive metabolizers
(EMs). The remaining 2 subjects were to be poor metabolizers (PMs),
intermediate metabolizers (IMs) or EMs, enrolled according to the
following preference: at least 20 subjects were to be screened for
each cohort and if identified, up to 2 PMs were to be enrolled. If
less than 2 PMs were identified, up to 2 IMs were to be enrolled
for a total of 8 subjects. If less than 2 PMs and IMs were
identified, up to 2 additional EMs were to be enrolled for a total
of 8 subjects. Allowed concomitant medications included no more
than one weak CYP3A inhibitor and one weak CYP2D6 inhibitor, alone
or in combination.
[0120] CYP2D6 EMs and IMs were to receive a single 100 mg dose of
eliglustat tartrate while CYP2D6 PMs were to receive a single 50 mg
dose of eliglustat tartrate.
[0121] Diagnosis and Criteria for Inclusion:
[0122] For RI subjects: Male (body weight between 50.0 and 125.0
kg, inclusive) and female (body weight between 40.0 and 110.0 kg,
inclusive) subjects between 18 and 79 years, with a body mass index
(BMI) between 18.0 and 37.0 kg/m2, inclusive, having mild, moderate
or severe RI determined by a creatinine clearance (CrCl),
calculated by Cockcroft-Gault formula, of 50-80 mL/min, 30-50
mL/min or <30 mL/min, respectively.
[0123] Normal renal function subjects: Male or female subjects,
between 18 and 79 years, inclusive, body weight within 15% of the
body weight of matched subject with RI, BMI between 18.0 and 37.0
kg/m.sup.2 and a CrCl of >80 mL/min. Healthy subjects were also
matched by age and CYP2D6 predicted phenotype based on
genotype.
[0124] Dose Regimen:
[0125] A single 100 mg capsule of eliglustat tartrate (equivalent
to 84 mg of eliglustat) was to be administered to CYP2D6 EM or IM
subjects with RI and matching healthy subjects.
[0126] A single 50 mg capsule of eliglustat tartrate (equivalent to
42 mg of eliglustat) was to be administered to CYP2D6 PM subjects
with RI and matching healthy subjects.
[0127] Criteria for Evaluation:
[0128] Pharmacokinetics: Plasma eliglustat concentrations were used
to determine the following PK parameters using noncompartmental
methods: Maximum plasma concentration observed (C.sub.max), first
time to reach C.sub.max(t.sub.max), area under the plasma
concentration versus time curve calculated using the trapezoidal
method from time zero to the time corresponding to the last
concentration above the limit of quantification, t.sub.last
(AUC.sub.last), area under the plasma concentration time curve
extrapolated to infinity (AUC), terminal half-life associated with
the terminal slope .lamda.z (t.sub.1/2z), apparent total body
clearance of a drug from plasma (CL/F), and apparent volume of
distribution during the terminal phase (VZ/F).
[0129] Pharmacokinetic/Pharmacodynamics Sampling Times and
Bioanalytical Methods:
[0130] Blood samples were collected at the following time points to
assess plasma concentrations of eliglustat: predose, and 0.5, 1,
1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 24, and 36 hours postdose.
[0131] Eliglustat concentrations in plasma were determined using a
validated liquid chromatography tandem mass spectrometry method
with a lower limit of quantification (LLOQ) of 0.2 ng/mL.
[0132] Statistical Methods:
[0133] Pharmacokinetics:
[0134] Eliglustat PK parameters were summarized using descriptive
statistics for each population group and for each CYP2D6 phenotype.
For log-transformed C.sub.max, AUC.sub.last, AUC, t.sub.1/2z, CL/F,
and Vz/F, the effect of severe RI on eliglustat PK parameters after
a single dose of eliglustat tartrate was analyzed using a linear
fixed effects model on CYP2D6 EM subjects. Inclusion of population,
CYP3A weak inhibitor, age, and weight as covariate was selected
manually, choosing the model with the lowest AIC value. After
testing, the final model chosen were those with only population as
fixed term. Estimate and 90% confidence interval (CI) for the
geometric mean of each population group and for the geometric mean
ratio of severe RI group versus the normal control group were
provided from this model for each parameter.
[0135] Safety:
[0136] The safety evaluation was based on the review of the
individual values (clinically significant abnormalities) and
descriptive statistics (summary tables). All safety analyses were
performed using the safety population and based on the on-treatment
phase (defined as the start time of investigational medicinal
product [IMP] administration up to Day 3 visit). For laboratory,
vital sign, and ECG data, the Potentially Clinically Significant
Abnormalities (PCSAs) were analyzed using PCSA list (Version 3.0,
24 May 2014). Electrocardiogram parameters were obtained from
automatic reading of the 12-lead ECGs and were analyzed as raw
parameter value and change from baseline. For vital signs, raw data
and changes from baseline were summarized using descriptive
statistics by population group and time of measurement. All
individual data for biochemistry, hematology, and qualitative
urinary tests were listed.
[0137] Vital signs and ECG readings were analyzed as raw parameter
value and change from baseline.
[0138] Adverse events were coded according to the Medical
Dictionary for Regulatory Activities (MedDRA, version 19.1). They
were classified into pre-defined standard categories according to
chronological criteria: [0139] Pretreatment adverse events: AEs
that occurred, worsened (according to the Investigator's opinion)
or became serious during the pretreatment phase (defined as the
time between the signature of the informed consent and IMP
administration [excluded]); [0140] Treatment-emergent adverse
events (TEAEs): AEs that occurred, worsened or became serious
during the on-treatment phase; [0141] Posttreatment adverse events:
AEs that occurred, worsened or became serious during the
posttreatment phase (defined as starting after the Day 3 visit and
ending with EOS).
[0142] The number and percentage of subjects with TEAEs were listed
by population group, primary system-organ class (SOC), preferred
term (PT), and AE diagnosis.
[0143] Population Characteristics:
[0144] A total of 16 subjects were enrolled: 8 subjects were
enrolled into the severe RI cohort and 8 into the healthy matched
cohort. For each cohort, 7 subjects were CYP2D6 EMs and 1 subject
was CYP2D6 IM. Since Stage 1 did not show a substantial effect of
severe RI on eliglustat PK compared to the matched normal renal
function in EMs, Stage 2 of the study was not undertaken. Five EMs
subjects in the severe RI cohort were concomitantly taking a weak
CYP3A inhibitor (amlodipine) and 1 IM subject in the severe renal
impairment cohort was taking both a weak CYP2D6 inhibitor
(escitalopram) and a weak CYP3A inhibitor (amlodipine). None of the
healthy matched subjects were taking CYP2D6 or CYP3A
inhibitors.
TABLE-US-00005 Pharmacokinetic results: Mean .+-. SD (Geometric
Mean) [CV %] plasma PK parameters of eliglustat after a single oral
dose of 100 mg eliglustat tartrate CYP2D6 EM Subjects CYP2D6 IM
Subjects Parameter Healthy Severe RI Healthy Severe RI N 7 7 1 1
C.sub.max 17.6 .+-. 13.2 12.7 .+-. 4.85 54.7 220 (ng/mL) (13.4)
[75.2] (11.8) [38.1] t.sub.max.sup.a 1.50 4.00 3 4 (h) (0.50-6.00)
(1.00-6.00) AUC.sub.last 112 .+-. 68.7 102 .+-. 41.7 520 3590 (ng
h/mL) (96.0) [61.1] (95.5) [40.7] AUC 118 .+-. 71.1 107 .+-. 42.1
559 NR.sup.b (ng h/mL) (101) [60.3] (99.8) [39.5] t.sub.1/2z 8.50
.+-. 1.51 6.56 .+-. 0.876 9.59 NR.sup.b (h) (8.39) [17.8] (6.51)
[13.3] CL/F 963 .+-. 532 903 .+-. 354 151 NR.sup.b (L/h) (834)
[55.2] (845) [39.2] Vz/F 11700 .+-. 6710 8480 .+-. 3190 2090
NR.sup.b (L) (10100) [57.5] (7940) [37.7] t.sub.last.sup.a 36.00
36.00 36.00 36.00 (h) (24.00-36.00) (24.00-36.00) .sup.aMedian
(Min-Max) .sup.bNR: not reported. AUC, CL/F, t.sub.1/2 and
V.sub.z/F values were not reported due to % AUC extrapolation
greater than 20% of total AUC
TABLE-US-00006 Point estimates of geometric mean ratio with 90% CI
in CYP2D6 EM subjects Comparison Parameter Estimate 90% CI Severe
RI vs C.sub.max 0.878 (0.462 to 1.669) Healthy AUC.sub.last 0.994
(0.608 to 1.627) AUC 0.986 (0.609 to 1.597) t.sub.1/2z 0.776 (0.671
to 0.898) CL/F 1.014 (0.626 to 1.643) Vz/F 0.787 (0.485 to 1.275)
Note: The analysis model is log(PK parameter) = Population and
conducted for EM subjects (7 severe RI and 7 Healthy).
[0145] Eliglustat geometric mean C.sub.max and AUC values were
similar in subjects with severe RI and healthy matched subjects
with CYP2D6 EM phenotype (0.878 and 0.986 fold, respectively).
Coadministration of a single weak CYP3A inhibitor (amlodipine) in
CYP2D6 EM subjects with severe RI (N=5, geometric mean [CV %] for
C.sub.max and AUC: 10.6 ng/mL [46.6] and 98.3 ngh/mL [45.9],
respectively) did not appear to result in an increase in eliglustat
exposures compared to severe RI EM subjects receiving eliglustat
tartrate alone (N=2, geometric mean [CV %] for C.sub.max and AUC:
15.2 ng/mL [12.9] and 104 ngh/mL [30.3], respectively). Mean
t.sub.1/2z values were shorter in severe RI subjects than in
healthy subjects (6.56 versus 8.50 hours) and t.sub.max values were
longer (4.0 versus 1.5 hours).
[0146] No definitive conclusion can be drawn for the effect of RI
in CYP2D6 IMs as only one CYP2D6 IM with severe RI taking
concomitant medications was included. The substantially higher
AUC.sub.last values in this subject compared to CYP2D6 IM healthy
subject (6.90-fold) or to either healthy CYP2D6 EMs (32.1-fold) or
CYP2D6 EM with severe RI (35.2-fold) is attributed, at least in
part, to the combined effect of 2 coadministered CYP inhibitors, a
CYP2D6 inhibitor (escitalopram) and a CYP3A inhibitor
(amlodipine).
[0147] Safety Results:
[0148] A total of one mild TEAE was observed in 1 subject, and was
considered related to study drug by the investigator: fatigue in a
healthy subject. No serious adverse events were reported, and there
were no deaths or withdrawals due to AEs. There were no treatment
emergent PCSA that were clinically relevant for the laboratory
values or for vital signs and ECGs.
[0149] Overall Conclusion:
[0150] The effects of mild and moderate hepatic impairment in a
subject were evaluated in a single dose phase 1 study described in
Example 1. After a single 84 mg dose, eliglustat C.sub.max and AUC
were 1.22- and 1.15-fold higher in CYP2D6 EMs with mild hepatic
impairment, and 2.81- and 5.16-fold higher in CYP2D6 EMs with
moderate hepatic impairment compared to healthy CYP2D6 EMs.
[0151] Steady state exposures were predicted in CYP2D6 EMs with
mild and moderate hepatic impairment using the PBPK model. Doses of
eliglustat that would result in the mean steady state exposures
within the efficacious and safe exposure ranges were proposed for
CYP2D6 EMs with hepatic impairment when eliglustat is administered
alone or with CYP inhibitors. Therefore, in extensive CYP2D6
metabolizers with mild hepatic impairment, no dosage adjustment
(i.e., 84 mg BID) is recommended when eliglustat is administered
alone, and eliglustat dosage is reduced to 84 mg QD when eliglustat
is taken with a weak CYP2D6 inhibitor, or a strong, moderate, or
weak CYP3A inhibitor. Eliglustat is contraindicated in extensive
CYP2D6 metabolizers with moderate hepatic impairment and in
extensive CYP2D6 metabolizers with mild hepatic impairment when
coadministered with a strong or moderate CYP2D6 inhibitor since the
mean steady state exposures were predicted much higher than the
upper end of efficacious and safe exposure ranges. Eliglustat is
contraindicated in patients with severe hepatic impairment due to a
potential of substantially elevated plasma concentrations of
eliglustat. A contraindication for eliglustat use in CYP2D6 IMs or
PMs with mild and moderate hepatic impairment is proposed since the
steady state exposures are unknown.
[0152] The effect of severe renal impairment was evaluated in a
single dose phase 1 study described in Example 2. After a single 84
mg dose, eliglustat C.sub.max and AUC were similar in CYP2D6 EMs
with severe renal impairment and healthy CYP2D6 EMs.
[0153] Considering the lack of effect of severe renal impairment
after single doses, repeated administration of eliglustat in CYP2D6
EMs is not expected to have an impact on eliglustat exposure, since
the time dependent effect due to mechanism-based inhibition of
CYP2D6 is not expected to be affected by renal impairment.
Therefore, no dose adjustment is proposed for CYP2D6 EMs with mild,
moderate and severe RI.
[0154] Limited or no data are available in CYP2D6 EMs, IMs or PMs
with end-stage renal disease and in CYP2D6 IMs or PMs with mild,
moderate, or severe renal impairment; use of eliglustat in these
patients should be avoided or not recommended.
* * * * *