U.S. patent application number 16/626748 was filed with the patent office on 2020-04-16 for medicament.
This patent application is currently assigned to KOWA COMPANY, LTD.. The applicant listed for this patent is KOWA COMPANY, LTD.. Invention is credited to Masatoshi ITO, Chisato NAGAI, Ryu OSHIMA.
Application Number | 20200113873 16/626748 |
Document ID | / |
Family ID | 64741618 |
Filed Date | 2020-04-16 |
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United States Patent
Application |
20200113873 |
Kind Code |
A1 |
OSHIMA; Ryu ; et
al. |
April 16, 2020 |
MEDICAMENT
Abstract
To provide a medicament for safely treating a patient in need of
treatment with pemafibrate, a salt thereof, or a solvate of any of
these (hereinafter also referred to as pemafibrate therapy). A
medicament for treating a patient in need of pemafibrate therapy,
the medicament comprising the step of avoiding or suspending
concomitant use of pemafibrate, a salt thereof, or a solvate of any
of these as an active ingredient in order to suppress an increase
in plasma concentration of pemafibrate when the treatment is
combined with a medicament containing an OATP1B inhibitor, or the
step of reducing the dose of pemafibrate, a salt thereof, or a
solvate of any of these.
Inventors: |
OSHIMA; Ryu; (Chuo-ku,
JP) ; ITO; Masatoshi; (Chuo-ku, JP) ; NAGAI;
Chisato; (Chuo-ku, CN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
KOWA COMPANY, LTD. |
Nagoya-shi |
|
JP |
|
|
Assignee: |
KOWA COMPANY, LTD.
Nagoya-shi
JP
|
Family ID: |
64741618 |
Appl. No.: |
16/626748 |
Filed: |
June 29, 2018 |
PCT Filed: |
June 29, 2018 |
PCT NO: |
PCT/JP2018/024954 |
371 Date: |
December 26, 2019 |
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/4709 20130101;
A61P 1/16 20180101; A61K 31/4433 20130101; A61K 31/4365 20130101;
A61K 45/06 20130101; A61K 31/7048 20130101; A61P 9/00 20180101;
A61K 38/12 20130101; A61K 31/427 20130101; A61P 3/06 20180101; A61K
31/4402 20130101; A61K 31/4353 20130101; A61K 38/13 20130101; A61P
3/10 20180101; A61K 31/513 20130101; A61K 31/7034 20130101; A61K
31/4152 20130101; A61P 29/00 20180101; A61K 31/423 20130101; A61P
43/00 20180101; A61K 31/496 20130101; A61K 31/34 20130101; A61P
9/10 20180101 |
International
Class: |
A61K 31/423 20060101
A61K031/423; A61K 31/7034 20060101 A61K031/7034; A61K 31/496
20060101 A61K031/496; A61K 31/513 20060101 A61K031/513; A61K 31/427
20060101 A61K031/427; A61K 31/4402 20060101 A61K031/4402; A61K
31/34 20060101 A61K031/34; A61K 31/4353 20060101 A61K031/4353; A61K
31/4152 20060101 A61K031/4152; A61K 31/4709 20060101 A61K031/4709;
A61K 31/4433 20060101 A61K031/4433; A61K 38/13 20060101
A61K038/13 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 30, 2017 |
JP |
2017-128188 |
Claims
1-9: (canceled)
10: A pharmaceutical kit comprising: (A) pemafibrate, a salt
thereof, or a solvate thereof (pemafibrate); and (B) an instruction
to administer the pemafibrate concomitantly with an OATP1B
inhibitor or a CYP inhibitor to a patient, wherein if the patient's
plasma concentration of pemafibrate during the concomitant
administration increases relative to the plasma concentration of
pemafibrate in the patient when pemafibrate is administered without
the OATP1B inhibitor and without the CYP inhibitor, then either (i)
or (ii): (i) stop concomitant administration of pemafibrate and the
OATP1B inhibitor or the CYP inhibitor; or (ii) continue concomitant
administration of pemafibrate and the OATP1B inhibitor or the CYP
inhibitor, with a dose of pemafibrate sufficiently reduced to
suppress the increase in plasma concentration of pemafibrate in the
patient.
11: The pharmaceutical kit according to claim 10, wherein the
pemafibrate, a salt thereof, or a solvate thereof is
pemafibrate.
12: The pharmaceutical kit according to claim 10, wherein the
OATP1B inhibitor is one or more drugs selected from the group
consisting of clarithromycin, rifampicin, cyclosporine, a
combination agent of lopinavir and ritonavir, a combination agent
of atazanavir and ritonavir, a combination agent of dalnavir and
ritonavir, clopidogrel, eltronbopag, a combination agent of
saquinavir and ritonavir, a combination agent of tipranavir and
ritonavir, and gemfibrozil.
13: (canceled)
14: The pharmaceutical kit according to claim 10, instructing to
reduce the dose of pemafibrate, compared with the dose when the
pemafibrate is administered alone, to 1/2 or less.
15: The pharmaceutical kit according to claim 10, instructing to
reduce the dose of pemafibrate to 0.1 to 0.2 mg per day.
16: The pharmaceutical kit according to claim 10, instructing to
administer pemafibrate twice per day.
17: The pharmaceutical kit according to claim 10, wherein the
instruction is a package insert, a package label, or a user
manual.
18-34: (canceled)
35: The pharmaceutical kit according to claim 10, wherein the CYP
inhibitor is a drug that inhibits CYP3A.
36: The pharmaceutical kit according to claim 35, wherein the drug
that inhibits CYP3A is one or more drugs selected from the group
consisting of clarithromycin, cyclosporine, cobicistat, indinavir,
itraconazole, ritonavir, telaprevir, voriconazole, nelfinavir,
saquinavir, boceprevir, conivaptan, ketoconazole, a combination
agent of lopinavir and ritonavir, mibefradil, nefazodone,
posaconazole, telithromycin, fluconazole, amprenavir, aprepitant,
atazanavir, ciprofloxacin, crizotinib, a combination agent of
darnavir and ritonavir, diltiazem, erythromycin, fosamprenavir,
imatinib, istradefylline, miconazole, tofisopam, casopitant,
dronedarone, and verapamil.
37: The pharmaceutical kit according to claim 10, wherein the CYP
inhibitor is a drug that inhibits CYP2C8.
38: The pharmaceutical kit according to claim 37, wherein the drug
that inhibits CYP2C8 is one or more drugs selected from the group
consisting of gemfibrozil, clopidogrel, cyclosporine, deferasirox,
and teriflunomide.
39: The pharmaceutical kit according to claim 10, wherein the CYP
inhibitor is a drug that inhibits CYP2C9.
40: The pharmaceutical kit according to claim 39, wherein the drug
that inhibits CYP2C9 is one or more drugs selected from the group
consisting of a fluorouracil derivative, carmofur, sulfaphenazole,
amiodarone, bucolome, cyclosporine, fluconazole, miconazole, and
oxandrolone.
41-50: (canceled)
51: A method of treating a patient in need of with pemafibrate
therapy with the concomitant administration of an OATP1B inhibitor
where the pemafibrate plasma concentration becomes excessive,
comprising: administering pemafibrate, a salt thereof, or a solvate
thereof (pemafibrate) concomitantly with an OATP1B inhibitor to the
patient, and if the patient's plasma concentration of pemafibrate
during the concomitant administration increases relative to the
plasma concentration of pemafibrate in the patient when pemafibrate
is administered without the OATP1B inhibitor, then either (i) or
(ii): (i) stopping concomitant administration of pemafibrate and
the OATP1B inhibitor; or (ii) continuing concomitant administration
of pemafibrate and the OATP1B inhibitor, with a dose of pemafibrate
sufficiently reduced to suppress the increase in plasma
concentration of pemafibrate in the patient.
52-54: (canceled)
55: A method of treating a patient with pemafibrate therapy with
the concomitant administration of a CYP inhibitor where the
pemafibrate plasma concentration becomes excessive, comprising:
administering pemafibrate, a salt thereof, or a solvate thereof
(pemafibrate) concomitantly with a CYP inhibitor to the patient,
and if the patient's plasma concentration of pemafibrate during the
concomitant administration increases relative to the plasma
concentration of pemafibrate in the patient when pemafibrate is
administered without the CYP inhibitor, then either (i) or (ii):
(i) stopping concomitant administration of pemafibrate and the CYP
inhibitor, or (ii) continuing concomitant administration of
pemafibrate and the CYP inhibitor, with a dose of pemafibrate
sufficiently reduced to suppress the increase in plasma
concentration of pemafibrate in the patient.
56-58: (canceled)
59: The method of claim 51, wherein the dose of pemafibrate
sufficiently reduced to suppress the increase in plasma
concentration of pemafibrate in the patient is a dose that is 1/2
or less the dose when the pemafibrate is administered alone.
60: The method of claim 51, wherein the dose of pemafibrate
sufficiently reduced to suppress the increase in plasma
concentration of pemafibrate in the patient is a dose that is 0.1
to 0.2 mg per day.
61: The method of claim 55, wherein the dose of pemafibrate
sufficiently reduced to suppress the increase in plasma
concentration of pemafibrate in the patient is a dose that is 1/2
or less the dose when the pemafibrate is administered alone.
62: The method of claim 55, wherein the dose of pemafibrate
sufficiently reduced to suppress the increase in plasma
concentration of pemafibrate in the patient is a dose that is 0.1
to 0.2 mg per day.
Description
TECHNICAL FIELD
[0001] The present invention relates to a new medicament for
efficient and safe use of pemafibrate, a salt thereof, or a solvate
of any of these.
BACKGROUND ART
[0002] Pemafibrate (Chemical name:
(2R)-2-[3-({1,3-benzoxazol-2-yl[3-(4-methoxyphenoxy)propyl]amino}m
ethyl)phenoxy]butanoic acid), a salt thereof, or a solvate of any
of these are compounds having PPAR.alpha. activity and are known to
be useful for the prevention and/or treatment of diseases such as
dyslipidemia (Patent Literature 1).
[0003] Rifampicin (2S, 12Z, 14E, 16S, 17S, 18R, 19R, 20R, 21S, 22R,
23S, 24E)
5,6,9,17,19-pentahydroxy-23-methoxy-2,4,12,20,22-heptamethyl-8-(4-me-
thylpiperazin-1-yliminomethyl) 1,11-dioxo-1,2-dihydro-7-(epox
ypentadeca [1,11,13] trienimino) [2,1-b] furan-21yl acetate is an
organic compound represented by the following formula (1)
##STR00001##
which is an antibiotic listed in the WHO-Essential Drug Model List
(WHO Model List of Essential Medicines, 19th List).
[0004] Clarithromycin is a compound represented by the following
formula (2)
##STR00002##
[0005] which is an antibiotic listed in the WHO-Essential Drug
Model List (WHO
Model List of Essential Medicines, 19th List).
[0006] Cyclosporine is an immunosuppressive agent used to suppress
rejection in the organ transplantation of kidneys, liver, heart or
bone-marrow and to treat graft-versus-host diseases, which is
listed in the WHO-Essential Drug Model List (WHO Model List of
Essential Medicines, 19th List).
[0007] Clopidogrel (Chemical Name:
methyl(2S)-2-(2-chlorophenyl)-2-[6,7-dihydrothieno[3,2-c]pyridin-5
(4H)-y l]acetate), a salt thereof, or a solvate of any of these are
compounds known to have platelet aggregation inhibitory and
antithrombotic activities (Patent Literature 2).
[0008] Multiple drugs are often prescribed for therapeutic purposes
in the clinical practice, and attention should be paid to
interactions between the drugs used concomitantly. Because drug
interactions may cause serious side effects and/or diminish
therapeutic effects, the property and extent of potential drug
interactions should be adequately assessed and addressed in the
development of new drugs so that they do not pose a disadvantage to
the patients.
PRIOR ART DOCUMENTS
Patent Literature
[0009] [Patent Literature 1] WO 2005/023777 pamphlet
[0010] [Patent Literature 2] JP--B-Hei 6-45622
SUMMARY OF THE INVENTION
Problems to be Solved by the Invention
[0011] The pharmacokinetics of pemafibrate, a salt thereof, or a
solvate of any of these and their interactions with other drugs are
not described in the above Prior art Documents.
[0012] The present invention addresses to provide a medicament for
safe treatment of a patient in need of treatment with pemafibrate,
a salt thereof, or a solvate of any of these (hereinafter also
referred to as pemafibrate therapy).
Means for Solving the Problem
[0013] In order to solve the above problems, the present inventors
conducted extensive researches, and as a result, the present
inventors have found that caution should be exercised when
pemafibrate is used concomitantly with rifampicin because of the
rise in the plasma concentration of pemafibrate. We also found that
the interaction caused by the concomitant use of pemafibrate with
rifampicin was due to the fact that rifampicin is an inhibitor of
organic anion-transporting polypeptides (OATP1B), which is a
hepatic uptake transporter. The present inventors have found that a
patient in need of treatment with pemafibrate, a salt thereof, or a
solvate of any of these can be safely treated by avoiding or
suspending the concomitant use of pemafibrate with an OATP1B
inhibitor such as rifampicin, or by reducing the dose of
pemafibrate, a salt thereof, or a solvate of any of these, and the
present invention has been completed.
[0014] In addition, it was found that concomitant use of
pemafibrate with clarithromycin, cyclosporine, or clopidogrel also
increased the plasma concentration of pemafibrate, requiring
caution when concomitantly used.
[0015] The present invention also found that the combined
interaction of pemafibrate with clarithromycin, cyclosporine, or
clopidogrel was due to clarithromycin, cyclosporine, or clopidogrel
being a drug that inhibits OATP1B and further inhibits the action
of certain cytochrome P450 (CYPs). The present inventors have found
that a patient in need of treatment with pemafibrate a salt
thereof, or a solvate of any of these can be safely treated by
avoiding or suspending the concomitant use of pemafibrate with an
OATP1B inhibitor and/or a CYP inhibitor, or by reducing the dose of
pemafibrate, a salt thereof, or a solvate of any of these, and the
present invention has been completed.
[0016] The present invention provides the following [1] to
[58].
[1] A medicament comprising pemafibrate, a salt thereof, or a
solvate of any of these as an active ingredient, for use in the
treatment of a patient in need of pemafibrate therapy, in order to
suppress an increase in plasma concentration of pemafibrate when
the treatment is concomitant use of pemafibrate with a medicament
comprising an OATP1B inhibitor, the medicament comprising a step of
avoiding or suspending the concomitant use or a step of reducing
the dose of pemafibrate, a salt thereof, or a solvate of any of
these. [2] The medicament according to [1], wherein the
pemafibrate, a salt thereof, or a solvate of any of these is
pemafibrate. [3] The medicament according to [1] or [2], wherein
the OATP1B inhibitor is one or more drugs selected from the group
consisting of clarithromycin, rifampicin, cyclosporine, a
combination agent of lopinavir and ritonavir, a combination agent
of atazanavir and ritonavir, a combination agent of dalnavir and
ritonavir, clopidogrel, eltronbopag, a combination agent of
saquinavir and ritonavir, a combination agent of tipranavir and
ritonavir, and gemfibrozil. [4] The medicament according to any one
of [1] to [3], wherein the patient in need of pemafibrate therapy
is a patient with one or more diseases selected from the group
consisting of hyperlipidemia, dyslipidemia, arteriosclerosis,
diabetes mellitus, diabetic complications, inflammation,
non-alcoholic steatohepatitis, primary biliary cirrhosis, and heart
disease. [5] The medicament according to any one of [1] to [4],
wherein the patient is a patient further in need of pemafibrate
therapy during treatment with an OATP1B inhibitor. [6] The
medicament according to any one of [1] to [4], wherein the patient
is a patient further in need of treatment with an OATP1B inhibitor
during pemafibrate therapy. [7] The medicament according to any one
of [1] to [6], wherein the step of reducing the dose of
pemafibrate, a salt thereof, or a solvate of any of these is to
reduce the dose of pemafibrate, a salt thereof, or a solvate of any
of these, compared with the dose when the drug is administered
alone, to 1/2 or less. [8] The medicament according to any one of
[1] to [7], wherein the step of reducing the dose of pemafibrate, a
salt thereof, or a solvate of any of these is to set the dose of
pemafibrate, a salt thereof, or a solvate of any of these as 0.1 to
0.2 mg/day. [9] The medicament according to any one of [1] to [8],
wherein the pemafibrate, a salt thereof, or a solvate of any of
these is administered twice per day. [10] A pharmaceutical kit
comprising (A) a medicament comprising pemafibrate, a salt thereof,
or a solvate of any of these as an active ingredient; and (B) an
instruction to avoid or suspend concomitant use of the (A) with a
medicament comprising an OATP1B inhibitor, or to reduce the dose of
pemafibrate, a salt thereof, or a solvate of any of these at the
time of the concomitant use. [11] The pharmaceutical kit according
to [10], wherein the pemafibrate, a salt thereof, or a solvate of
any of these is pemafibrate. [12] The pharmaceutical kit according
to [10] or [11], wherein the OATP1B inhibitor is one or more drugs
selected from the group consisting of clarithromycin, rifampicin,
cyclosporine, a combination agent of lopinavir and ritonavir, a
combination agent of atazanavir and ritonavir, a combination agent
of dalnavir and ritonavir, clopidogrel, ertronbopag, a combination
agent of saquinavir and ritonavir, a combination agent of
tipranavir and ritonavir, and gemfibrozil. [13] The pharmaceutical
kit according to any one of [10] to [12], wherein the medicament of
(A) is a drug for the prevention and/or treatment for one or more
diseases selected from the group consisting of hyperlipidemia,
dyslipidemia, arteriosclerosis, diabetes mellitus, diabetic
complications, inflammation, non-alcoholic steatohepatitis, primary
biliary cirrhosis, and heart disease. [14] The pharmaceutical kit
according to any one of [10] to [13], instructing to reduce the
dose of pemafibrate, a salt thereof, or a solvate of any of these,
compared with the dose when the drug is administered alone, to 1/2
or less. [15] The pharmaceutical kit according to any one of [10]
to [14], instructing to set the dose of pemafibrate, a salt
thereof, or a solvate of any of these as 0.1 to 0.2 mg per day.
[16] The pharmaceutical kit according to any one of [10] to [15],
instructing to administer pemafibrate, a salt thereof, or a solvate
of any of these twice per day. [17] The pharmaceutical kit
according to any one of [10] to [16], wherein the instruction is a
package insert, a package label, or a user manual. [18] A
medicament comprising pemafibrate, a salt thereof, or a solvate of
any of these as an active ingredient, for use in the treatment of a
patient in need of pemafibrate therapy, in order to suppress an
increase in plasma concentration of pemafibrate when the treatment
is concomitant use of pemafibrate with a medicament comprising a
CYP inhibitor, the medicament comprising a step of avoiding or
suspending the concomitant use or a step of reducing the dose of
pemafibrate, a salt thereof, or a solvate of any of these. [19] The
medicament according to [18], wherein the pemafibrate, a salt
thereof, or a solvate of any of these is pemafibrate. [20] The
medicament according to [18] or [19], wherein the CYP inhibitor is
a drug that inhibits CYP3A. [21] The medicament according to [20],
wherein the drug that inhibits CYP3A is one or more drugs selected
from the group consisting of clarithromycin, cyclosporine,
cobicistat, indinavir, itraconazole, ritonavir, telaprevir,
voriconazole, nelfinavir, saquinavir, boceprevir, conivaptan,
ketoconazole, a combination agent of lopinavir and ritonavir,
mibefradil, nefazodone, posaconazole, telithromycin, fluconazole,
amprenavir, aprepitant, atazanavir, ciprofloxacin, crizotinib, a
combination agent of darnavir and ritonavir, diltiazem,
erythromycin, fosamprenavir, imatinib, istradefylline, miconazole,
tofisopam, casopitant, dronedarone, and verapamil. [22] The
medicament according to [18] or [19], wherein the CYP inhibitor is
a drug that inhibits CYP2C8. [23] The medicament according to [22],
wherein the drug that inhibits CYP2C8 is one or more drugs selected
from the group consisting of gemfibrozil, clopidogrel,
cyclosporine, deferasirox, and teriflunomide. [24] The medicament
according to [18] or [19], wherein the CYP inhibitor is a drug that
inhibits CYP2C9. [25] The medicament according to [24], wherein the
drug that inhibits CYP2C9 is one or more drugs selected from the
group consisting of a fluorouracil derivative, carmofur,
sulfaphenazole, amiodarone, bucolome, cyclosporine, fluconazole,
miconazole, and oxandrolone. [26] The medicament according to any
one of [19] to [25], wherein the patient in need of pemafibrate
therapy is a patient with one or more diseases selected from the
group consisting of hyperlipemia, dyslipidemia, arteriosclerosis,
diabetes mellitus, diabetic complications, inflammation,
non-alcoholic steatohepatitis, primary biliary cirrhosis, and heart
disease. [27] The medicament according to any one of [19] to [26],
wherein the patient is a patient further in need of pemafibrate
therapy during treatment with a CYP inhibitor. [28] The medicament
according to any of [19] to [26], wherein the patient is a patient
further in need of treatment with a CYP inhibitor during
pemafibrate therapy. [29] The medicament according to any one of
[19] to [28], wherein the step of reducing the dose of pemafibrate,
a salt thereof, or a solvate of any of these is to reduce the dose
of pemafibrate, a salt thereof, or a solvate of any of these,
compared with the dose when the drug is administered alone, to 1/2
or less. [30] The medicament according to any one of [19] to [29],
wherein the step of reducing the dose of pemafibrate, a salt
thereof, or a solvate of any of these is to set the dose of
pemafibrate, a salt thereof, or a solvate of any of these as 0.1 to
0.2 mg/day. [31] The medicament according to any one of [19] to
[30], wherein the pemafibrate, a salt thereof, or a solvate of any
of these is administered twice per day. [32] The medicament
according to any one of [19] to [31], wherein the CYP inhibitor is
a drug that further inhibits OATP1B. [33] A pharmaceutical kit
comprising (A) a medicament comprising pemafibrate, a salt thereof,
or a solvate of any of these as an active ingredient; and (B) an
instruction to avoid or suspend concomitant use of the (A) with a
medicament comprising a CYP inhibitor, or to reduce the dose of
pemafibrate, a salt thereof, or a solvate of any of these at the
time of the concomitant use. [34] The pharmaceutical kit according
to [33], wherein the pemafibrate, a salt thereof, or a solvate of
any of these is pemafibrate. [35] The pharmaceutical kit according
to [33] or [34], wherein the CYP inhibitor is a drug that inhibits
CYP3A. [36] The pharmaceutical kit according to [35], wherein the
drug that inhibits CYP3A is one or more drugs selected from the
group consisting of clarithromycin, cyclosporine, cobicistat,
indinavir, itraconazole, ritonavir, telaprevir, voriconazole,
nelfinavir, saquinavir, boceprevir, conivaptan, ketoconazole, a
combination agent of lopinavir and ritonavir, mibefradil,
nefazodone, posaconazole, telithromycin, fluconazole, amprenavir,
aprepitant, atazanavir, ciprofloxacin, crizotinib, a combination
agent of darnavir and ritonavir, diltiazem, erythromycin,
fosanprenavir, imatinib, istradefylline, miconazole, tofisopam,
casopitant, dronedarone, and verapamil. [37] The pharmaceutical kit
according to [33] or [34], wherein the CYP inhibitor is a drug that
inhibits CYP2C8. [38] The pharmaceutical kit according to [37],
wherein the drug that inhibits CYP2C8 is one or more drugs selected
from the group consisting of gemfibrozil, clopidogrel,
cyclosporine, deferasirox, and teriflunomide. [39] The
pharmaceutical kit according to [33] or [34], wherein the CYP
inhibitor is a drug that inhibits CYP2C9. [40] The pharmaceutical
kit according to [39], wherein the drug that inhibits CYP2C9 is one
or more drugs selected from the group consisting of a fluorouracil
derivative, carmofur, sulfaphenazole, amiodarone, bucolome,
cyclosporine, fluconazole, miconazole, and oxandrolone. [41] The
pharmaceutical kit according to any one of [33] to [40], wherein
the medicament of (A) is a drug for the prevention and/or treatment
for one or more diseases selected from the group consisting of
hyperlipidemia, dyslipidemia, arteriosclerosis, diabetes mellitus,
diabetic complications, inflammation, non-alcoholic
steatohepatitis, primary biliary cirrhosis, and heart disease. [42]
The pharmaceutical kit according to any one of [33] to [41],
instructing to reduce the dose of pemafibrate, a salt thereof, or a
solvate of any of these, compared with the dose when the drug is
administered alone, to 1/2 or less. [43] The pharmaceutical kit
according to any one of [33] to [42], instructing to set the dose
of pemafibrate, a salt thereof, or a solvate of any of these as 0.1
to 0.2 mg per day. [44] The pharmaceutical kit according to any one
of [33] to [43], instructing to administer pemafibrate, a salt
thereof, or a solvate of any of these twice per day. [45] The
pharmaceutical kit according to any one of [33] to [44], wherein
the instruction is a package insert, a package label, or a user
manual. [46] The pharmaceutical kit according to any one of [33] to
[45], wherein the CYP inhibitor is a drug that further inhibits
OATP1B. [47] A medicament comprising pemafibrate, a salt thereof,
or a solvate of any of these as an active ingredient, for use in
the treatment of a patient in need of pemafibrate therapy, in order
to suppress an increase in plasma concentration of pemafibrate when
the treatment is concomitant use of pemafibrate with a medicament
comprising an OATP1B inhibitor, comprising an optional step of
avoiding or suspending the concomitant use or reducing the dose of
pemafibrate, a salt thereof, or a solvate of any of these. [48] A
pharmaceutical kit comprising (A) a medicament comprising
pemafibrate, a salt thereof, or a solvate of any of these as an
active ingredient; and (B) an instruction optionally to avoid or
suspend concomitant use of the (A) with a medicament comprising an
OATP1B inhibitor, or to reduce the dose of pemafibrate, a salt
thereof, or a solvate of any of these at the time of the
concomitant use. [49] A medicament comprising pemafibrate, a salt
thereof, or a solvate of any of these as an active ingredient, for
use in the treatment of a patient in need of pemafibrate therapy,
in order to suppress an increase in plasma concentration of
pemafibrate when the treatment is concomitant use of pemafibrate
with a medicament comprising a CYP inhibitor, comprising an
optional step of avoiding or suspending the concomitant use or
reducing the dose of pemafibrate, a salt thereof, or a solvate of
any of these. [50] A pharmaceutical kit comprising (A) a medicament
comprising pemafibrate, a salt thereof, or a solvate of any of
these as an active ingredient; and (B) an instruction optionally to
avoid or suspend concomitant use of the (A) with a CYP inhibitor,
or to reduce the dose of pemafibrate, a salt thereof, or a solvate
of any of these at the time of the concomitant use. [51] A method
of treating a patient in need of pemafibrate therapy, comprising a
step of avoiding or suspending concomitant use of pemafibrate, a
salt thereof, or a solvate of any of these with an OATP1B inhibitor
or reducing the dose of pemafibrate, a salt thereof, or a solvate
of any of these, in order to suppress an increase in plasma
concentration of pemafibrate in the concomitant use. [52] A method
of treating a patient in need of pemafibrate therapy, comprising an
optional step of avoiding or suspending concomitant use of
pemafibrate, a salt thereof, or a solvate of any of these with an
OATP1B inhibitor or reducing the dose of pemafibrate, a salt
thereof, or a solvate of any of these, in order to suppress an
increase in plasma concentration of pemafibrate in the concomitant
use. [53] Use of pemafibrate, a salt thereof, or a solvate of any
of these for treating a patient in need of pemafibrate therapy,
comprising a step of avoiding or suspending concomitant use of
pemafibrate, a salt thereof, or a solvate of any of these with an
OATP1B inhibitor or reducing the dose of pemafibrate, a salt
thereof, or a solvate of any of these, in order to suppress an
increase in plasma concentration of pemafibrate in the concomitant
use. [54] Use of pemafibrate, a salt thereof, or a solvate of any
of these for treating a patient in need of pemafibrate therapy,
comprising an optional step of avoiding or suspending concomitant
use of pemafibrate, a salt thereof, or a solvate of any of these
with an OATP1B inhibitor or reducing the dose of pemafibrate, a
salt thereof, or a solvate of any of these, in order to suppress an
increase in plasma concentration of pemafibrate in the concomitant
use. [55] A method of treating a patient in need of pemafibrate
therapy, comprising a step of avoiding or suspending concomitant
use of pemafibrate, a salt thereof, or a solvate of any of these
with a CYP inhibitor or reducing the dose of pemafibrate, a salt
thereof, or a solvate of any of these, in order to suppress an
increase in plasma concentration of pemafibrate in the concomitant
use. [56] A method of treating a patient in need of pemafibrate
therapy, comprising an optional step of avoiding or suspending
concomitant use of pemafibrate, a salt thereof, or a solvate of any
of these with a CYP inhibitor or reducing the dose of pemafibrate,
a salt thereof, or a solvate of any of these, in order to suppress
an increase in plasma concentration of pemafibrate in the
concomitant use. [57] Use of pemafibrate, a salt thereof, or a
solvate of any of these for treating a patient in need of
pemafibrate therapy, comprising a step of avoiding or suspending
concomitant use of pemafibrate, a salt thereof, or a solvate of any
of these with a CYP inhibitor or reducing the dose of pemafibrate,
a salt thereof, or a solvate of any of these, in order to suppress
an increase in plasma concentration of pemafibrate in the
concomitant use. [58] Use of pemafibrate, a salt thereof, or a
solvate of any of these for treating a patient in need of
pemafibrate therapy, comprising an optional step of avoiding or
suspending concomitant use of pemafibrate, a salt thereof, or a
solvate of any of these with a CYP inhibitor or reducing the dose
of pemafibrate, a salt thereof, or a solvate of any of these, in
order to suppress an increase in plasma concentration of
pemafibrate in the concomitant use.
Effect of the Invention
[0017] According to the present invention, since an increase in
plasma concentration of pemafibrate, a salt thereof, or a solvate
of any of these is suppressed, a medicament for effective and safe
use can be provided.
DETAILED DESCRIPTION OF THE INVENTION
[0018] In the present specification, pemafibrate is a compound
represented by the following formula (3)
##STR00003##
[0019] In the present invention, "pemafibrate, a salt thereof, or a
solvate of any of these" includes, in addition to pemafibrate
itself, a pharmaceutically acceptable salt of pemafibrate, and a
solvate of pemafibrate or a pharmaceutically acceptable salt of
pemafibrate with water and the like. In one embodiment of the
present invention, the pemafibrate, a salt thereof, or a solvate of
any of these is pemafibrate.
[0020] Pemafibrate, a salt thereof, or a solvate of any of these
can be produced according to the method described in, for example,
WO 2005/023777. The compounds may also be formulated according to
the methods described in literatures in order to provide them as a
medicament.
[0021] The medicament containing pemafibrate, a salt thereof, or a
solvate of any of these are preferably those for oral
administration, and include a tablet, a capsule, a granule and the
like.
[0022] In the present invention, an "OATP1B inhibitor" is a drug
that inhibits the action of organic anion-transporting polypeptides
(OATP) 1B1 and/or OATP1B3 in the body, examples of which include
clarithromycin, rifampicin, cyclosporine, a combination agent of
lopinavir and ritonavir, a combination agent of atazanavir and
ritonavir, a combination agent of dalnavir and ritonavir,
clopidogrel, eltrombopag, a combination agent of saquinavir and
ritonavir, a combination agent of tipranavir and ritonavir, and
gemfibrozil. It may also be an OATP1B inhibitor as described in the
"Drug Interaction Guidelines for Drug Development and Proper
Information" (Final Draft), Evaluation and Licensing Division,
Pharmaceutical and Food Safety Bureau, MHLW, Jul. 8, 2014, the
Guidelines (Guidance for Industry Drug Interaction Studies-Study
Design, Data Analysis, Implications for Dosing, and Labeling
Recommendations Draft Guidance (February 2012)) of the U.S. Food
and Drug Administration, or the Guidelines (Guideline on the
investigation of drug interactions (21 Jun. 2012)) of the European
Medicines Agency. In one embodiment of the present invention, the
OATP1B inhibitor is clarithromycin. In another embodiment of the
present invention, the OATP1B inhibitor is rifampicin. In another
embodiment of the present invention, the OATP1B inhibitor is
cyclosporine. In another embodiment of the present invention, the
OATP1B inhibitor is clopidogrel.
[0023] Also included in the OATP1B inhibitor are "a drug that
inhibits OATP1B1", "a drug that inhibits OATP1B3", and "a drug that
inhibits OATP1B1 and OATP1B3." Examples of "a drug that inhibits
OATP1B1" include cyclosporine, rifampicin, clarithromycin, a
combination agent of lopinavir and ritonavir, combination of
atazanavir and ritonavir, a combination agent of dalnavir and
ritonavir, a combination agent of saquinavir and ritonavir,
gemfibrozil, eltrombopag, a combination agent of tipranavir and
ritonavir, and clopidogrel. Examples of "a drug that inhibits
OATP1B3" include cyclosporine, rifampicin, clarithromycin, a
combination agent of lopinavir and ritonavir, a combination agent
of atazanavir and ritonavir, a combination agent of darnavir and
ritonavir, a combination agent of saquinavir and ritonavir, and
gemfibrozil. Examples of "a drug that inhibit OATP1B1 and OATP1B3"
include cyclosporine, rifampicin, clarithromycin, a combination
agent of lopinavir and ritonavir, a combination agent of atazanavir
and ritonavir, a combination agent of darnavir and ritonavir, a
combination agent of saquinavir and ritonavir, and gemfibrozil.
[0024] For a medicament containing an OATP1B inhibitor, those for
oral administration are preferable, and examples of which include a
tablet, a capsule and a granule.
[0025] In the present invention, cytochrome P450 or "CYP" are
enzymes involved in metabolizing drugs in the liver, and "a CYP
inhibitor" refers to a drug that inhibits the action of CYP in the
body by ingestion. Examples of "a CYP inhibitor" include, but are
not limited to, "a CYP3A inhibitor", "a CYP2C8 inhibitor", and "a
CYP2C9 inhibitor." Examples of a drug that inhibits CYP3A include
clarithromycin, cyclosporine, cobicystat, indinavir, itraconazole,
ritonavir, telaprevir, voriconazole, nelfinavir, saquinavir,
boceprevir, conibaptan, ketoconazole, a combination agent of
lopinavir and ritonavir, mibefradil, nefazodone, posaconazole,
telithromycin, fluconazole, amprenavir, aprepitant, atazanavir,
ciprofloxacin, crizotinib, a combination agent of darunavir and
ritonavir, diltiazem, erythromycin, fosamprenavir, imatinib,
istradefillyne, miconazole, tofisopam, casopitant, dronedarone, and
verapamil. Examples of "a drug that inhibits CYP2C8" include
gemfibrozil, clopidogrel, cyclosporine, deferasirox, and
teriflunomide. Examples of "a drug that inhibits CYP2C9" include
fluorouracil derivatives, carmofur, sulfaphenazole, amiodarone,
bucolome, cyclosporine, fluconazole, miconazole, and
oxandrolone.
[0026] The "CYP inhibitor" may be a "drug that inhibits CYP3A", "a
drug that inhibits CYP2C8", or "a drug that inhibits CYP2C9" as
described in the "Drug Interaction Guideline for Drug Development
and Proper Information (Final Draft) (Evaluation and Licensing
Division, Pharmaceutical and Food Safety Bureau, MHLW, Jul. 8,
2014), the guideline (Guidance for Industry Drug Interaction
Studies-Study Design, Data Analysis, Implications for Dosing, and
Labeling Recommendations Draft Guidance (February 2012)) of the
U.S. Food and Drug Administration, or the guideline (Guideline on
the investigation of drug interactions (21 Jun. 2012)) of the
European Medicines Agency.
[0027] With respect to CYP enzymes, the U.S. Food and Drug
Administration generally defines a "potent inhibitor" as an
inhibitor that, in clinical evaluation, caused a >5-fold
increase in plasma AUC values or a >80% decrease in clearance of
CYP substrates (not limited to sensitive CYP substrates). The U.S.
Food and Drug Administration generally defines a "moderate
inhibitor" as an inhibitor that, in clinical evaluation, caused a
>2-fold increase in AUC values, but a <5-fold increase in
clearance of sensitive CYP substrates or a 50% to 80% decrease in
clearance of sensitive CYP substrates when the inhibitor was given
at the highest approved dose and at the shortest dosing interval.
Among the CYP3A inhibitors listed in the above U.S. Food and Drug
Administration guidelines, potent CYP3A inhibitors include
boceprevir, clarithromycin, conivaptan, indinavir, itraconazole,
ketoconazole, a combination agent of lopinavir and ritonavir,
mibefradil, nefazodone, nelfinavir, posaconazole, ritonavir,
saquinavir, telaprevir, voriconazole; moderate CYP3A inhibitors
include amprenavir, aprepitant, atazanavir, ciprofloxacin,
crizotinib, a combination agent of darnavir and ritonavir,
diltiazem, erythromycin, fluconazole, fosamprenavir, imatinib and
verapamil. In the above U.S. Food and Drug Administration
guidelines, among the "drug that inhibits CYP2C8", gemfibrozil is
listed as a potent CYP2C8 inhibitor. In the above U.S. Food and
Drug Administration guidelines, among the "drug that inhibits
CYP2C9," amiodarone, fluconazole, miconazole, and oxandrolone are
listed as moderate CYP2C9 inhibitors.
[0028] In the present invention, "rifampicin" includes, not only
rifampicin itself, but also a pharmaceutically acceptable salt
thereof, and a solvate of rifampicin or its pharmaceutically
acceptable salt with water and the like. In one embodiment of the
present invention, rifampicin is rifampicin as listed in the
Japanese Pharmacopoeia, Seventeenth Edition.
[0029] In the present specification, "clarithromycin" includes not
only clarithromycin itself, but also a pharmaceutically acceptable
salt thereof, a solvate of clarithromycin or its pharmaceutically
acceptable salt with water and the like. In one embodiment of the
present invention, clarithromycin is clarithromycin as listed in
the Japanese Pharmacopoeia, Seventeenth Edition.
[0030] In the present specification, "cyclosporine" includes not
only cyclosporine A represented by the following formula (4); but
also cyclosporine B, cyclosporine C, cyclosporine D, cyclosporine
E, cyclosporine F, cyclosporine G, and cyclosporine H, which are
analogs of cyclosporine A; a pharmaceutically acceptable salt of
cyclosporine; and a solvate of cyclosporine or its pharmaceutically
acceptable salt with water and the like.
##STR00004##
[0031] In one embodiment of the present invention, cyclosporine is
cyclosporine A, preferably cyclosporine listed in the Japanese
Pharmacopeia, Seventeenth Edition (cyclosporine A).
[0032] In the present invention, "clopidogrel" includes, not only
clopidogrel itself, but also a pharmaceutically acceptable salt
thereof, and a solvate of clopidogrel or its pharmaceutically
acceptable salt with water and the like. Examples of salt of
clopidogrel include, but are not limited to, a hydrochloride, a
sulfate, a bisulfate, a hydrobromide, and a taurocholate. In one
embodiment of the present invention, clopidogrel is clopidogrel
sulfate, preferably clopidogrel sulfate as listed in the Japanese
Pharmacopoeia, Seventeenth Edition.
[0033] In the present invention, "a patient in need of pemafibrate
therapy" or "a patient in need of treatment with pemafibrate, a
salt thereof, or a solvate of any of these" includes, but not
limited to, a patient expressing one or more diseases selected from
the group consisting of, for example, hyperlipidemia, dyslipidemia,
arteriosclerosis, diabetes mellitus, diabetic complications,
inflammation, non-alcoholic steatohepatitis, primary biliary
cirrhosis, and heart disease.
[0034] In the present invention, "treatment with an OATP1B
inhibitor" refers to administration of an OATP1B inhibitor for the
treatment of a disease, and the OATP1B inhibitor used can differ
depending on the disease to be treated. For example, rifampicin is
used in the treatment of pulmonary tuberculosis and other
tuberculosis, non-tuberculous mycobacteriosis, including
Mycobacterium avium complex (MAC) disease, and leprosy.
Clarithromycin is used for the treatment of general infectious
diseases (superficial skin infections, deep skin infections,
lymphangitis, lymphadenitis, chronic pyoderma, secondary infections
caused by trauma, burns and surgical wounds, perianal abscess,
pharyngeal/laryngitis, tonsillitis, acute bronchitis, pneumonia,
lung abscess, secondary infection of chronic respiratory lesions,
urethritis, cervicitis, infectious enteritis, otitis media,
sinusitis, periodontitis, pericoronitis, or jaw inflammation by one
or more bacteria selected from the group consisting of
Staphylococcus, Streptococcus, Streptococcus pneumoniae, Moraxella
(Branhamera) catarrhalis, Haemophilus influenzae, Legionella,
Campylobacter, Peptostreptococcus, Chlamydia, and Mycoplasma),
nontuberculous mycobacterial disease including Mycobacterium avium
complex (MAC) disease and Helicobacter pylori infection.
Cyclosporine reduces rejection in organ transplantation (kidney,
liver, heart, lung, pancreas, small intestine), rejection in bone
marrow transplantation and graft-versus-host disease, Behcet's
disease (if ocular symptoms are present) and other noninfectious
uveitis (limited to active intermediate or posterior noninfectious
uveitis that may be ineffective with existing therapy), psoriasis
(psoriasis vulgaris (if skin rash is more than 30% of the whole
body or refractory), pustular psoriasis, erythrodermic psoriasis,
arthritic psoriasis), anemia (aplastic anemia (severe), pure red
cell aplasia), nephrotic syndrome (frequent relapsing, or with
resistance in steroid), myasthenia gravis (in the treatment after
thymectomy, when the effect of steroids is insufficient or when it
is difficult to administer steroids due to adverse reactions). It
is also used for the treatment of atopic dermatitis (patients who
are unable to achieve a satisfactory effect with existing
treatments). Clopidogrel is used to suppress recurrence after
ischemic cerebrovascular disorder (excluding cardiogenic
cerebrovascular embolism), to treat ischemic heart disease to which
percutaneous coronary intervention (PCI) is applied (acute coronary
syndrome (unstable angina pectoris, non-ST-elevation myocardial
infarction, ST-elevation myocardial infarction), stable angina
pectoris, old myocardial infarction), and to suppress thrombus and
embolus formation in peripheral arterial disease. However,
treatment with an OATP1B inhibitor is not limited to the treatment
of these diseases.
[0035] In one embodiment of the present invention, the patient in
need of pemafibrate therapy is a patient in need of further
treatment with an OATP1B inhibitor. Such patients include, a
patient in need of additional pemafibrate therapy during treatment
with an OATP1B inhibitor, a patient in need of additional therapy
with an OATP1B inhibitor during pemafibrate therapy, and a patient
in need of simultaneous start of pemafibrate therapy and treatment
with an OATP1B inhibitor.
[0036] In the present invention, "treatment with a CYP inhibitor"
refers to administration of a CYP inhibitor for the treatment of a
disease, and the CYP inhibitor to be used depends on the disease to
be treated. For example, clarithromycin is used for the treatment
of general infectious diseases (superficial skin infections, deep
skin infections, lymphangitis, lymphadenitis, chronic pyoderma,
secondary infections caused by trauma, burns and surgical wounds,
perianal abscess, pharyngeal/laryngitis, tonsillitis, acute
bronchitis, pneumonia, lung abscess, secondary infection of chronic
respiratory lesions, urethritis, cervicitis, infectious enteritis,
otitis media, sinusitis, periodontitis, pericoronitis, or jaw
inflammation by one or more bacteria selected from the group
consisting of Staphylococcus, Streptococcus, Streptococcus
pneumoniae, Moraxella (Branhamera) catarrhalis, Haemophilus
influenzae, Legionella, Campylobacter, Peptostreptococcus,
Chlamydia, and Mycoplasma), nontuberculous mycobacterial disease
including Mycobacterium avium complex (MAC) disease and
Helicobacter pylori infection. Cyclosporine reduces rejection in
organ transplantation (kidney, liver, heart, lung, pancreas, small
intestine), rejection in bone marrow transplantation and
graft-versus-host disease, Behcet's disease (if ocular symptoms are
present) and other noninfectious uveitis (limited to active
intermediate or posterior noninfectious uveitis that may be
ineffective with existing therapy), psoriasis (psoriasis vulgaris
(if skin rash is more than 30% of the whole body or refractory),
pustular psoriasis, erythrodermic psoriasis, arthritic psoriasis),
anemia (if erythroderma, arthritic psoriasis), (aplastic anemia
(severe), pure red cell aplasia), nephrotic syndrome (frequent
relapsing, or with resistance in steroid), myasthenia gravis (in
the treatment after thymectomy, when the effect of steroids is
insufficient or when it is difficult to administer steroids due to
adverse reactions). It is also used for the treatment of atopic
dermatitis (patients who are unable to achieve a satisfactory
effect with existing treatments). Clopidogrel is used to suppress
recurrence after ischemic cerebrovascular disorder (excluding
cardiogenic cerebrovascular embolism), to treat ischemic heart
disease to which percutaneous coronary angioplasty (PCI) is applied
(acute coronary syndrome (unstable angina pectoris,
non-ST-elevation myocardial infarction, ST-elevation myocardial
infarction), stable angina pectoris, old myocardial infarction),
and to suppress thrombus and embolus formation in peripheral
arterial diseases. However, treatment with a CYP inhibitor is not
limited to the treatment of these diseases.
[0037] In one embodiment of the present invention, the patient in
need of pemafibrate therapy is a patient in need of further
treatment with a CYP inhibitor. Such patients include, for example,
a patient in need of further pemafibrate therapy during treatment
with a CYP inhibitor, a patient in need of additional treatment
with a CYP inhibitor during pemafibrate therapy, and a patient in
need of simultaneous start of pemafibrate therapy and treatment
with a CYP inhibitor.
[0038] In the present invention, a "concomitant use" refers to a
patient's taking two or more medicaments or to let a patient take
two or more medicaments. In one embodiment of the present
invention, when the patient takes two medicaments, for example, the
patient may take two medications simultaneously or one by one at an
interval.
[0039] Investigations by the present inventors revealed that the
plasma concentration of pemafibrate were increased when
pemafibrate, a salt thereof, or a solvate of any of these was used
concomitant with rifampicin, as compared with administration of
pemafibrate, a salt thereof, or a solvate of any of these alone
(see Examples below). Such an increase in plasma concentration of
pemafibrate may cause unexpected side effects. Therefore, in the
present invention, in order to suppress such an increase in plasma
concentration of pemafibrate, the concomitant use is avoided or
suspended, or the dose of pemafibrate, a salt thereof, or a solvate
of any of these is reduced.
[0040] Rifampicin is a drug known to act as an inhibitor of OATP1B1
and OATP1B3 by a single administration, and it is conceivable that
its inhibitory effect is involved in increasing plasma
concentration of pemafibrate. That is, concomitant use of an OATP1B
inhibitor with pemafibrate, a salt thereof, or a solvate of any of
these may increase plasma concentration of pemafibrate. Therefore,
in order to suppress the increase in the plasma concentration of
pemafibrate, the concomitant use was avoided or suspended, or the
dose of pemafibrate, a salt thereof, or a solvate of any of these
was reduced.
[0041] Clarithromycin is known to inhibit CYP3A, OATP1B1, and
OATP1B3, thereby causing drug interactions, and may be involved in
increasing plasma concentration of pemafibrate. That is, if the
drug inhibits CYP3A, OATP1B1, and OATP1B3, the plasma concentration
of pemafibrate may be increased by concomitant use of pemafibrate,
a salt thereof, or a solvate of any of these. Therefore, in order
to suppress the increase in the plasma concentration of
pemafibrate, the concomitant use was avoided or suspended, or the
dose of pemafibrate, a salt thereof, or a solvate of any of these
was reduced.
[0042] In the present invention, examples of "a drug that inhibits
CYP3A, OATP1B1, and OATP1B3" include clarithromycin, cyclosporine,
and HIV-protease inhibitors. Examples of HIV protease inhibitors
include atazanavir, a salt thereof, or a solvate of any of these
(atazanavir sulfate etc.), indinavir, a salt thereof, or a solvate
of any of these (indinavir sulfate ethanol adduct etc.),
saquinavir, a salt thereof, or a solvate of any of these
(saquinavir mesylate etc.), darnavir, a salt thereof, or a solvate
of any of these (darnavir ethanol adduct etc.), nelfinavir, a salt
thereof, or a solvate of any of these (nelfinavir mesylate etc.),
phosamprenavir, a salt thereof, or a solvate of any of these
(phosamprenavir calcium hydrate etc.), ritonavir, a salt thereof,
or a solvate of any of these or a solvate, and lopinavir, a salt
thereof, or a solvate of any of these, and in particular ritonavir,
a salt thereof, or a solvate of any of these, are known to inhibit
CYP3A, OATP1B1 and OATP1B3.
[0043] In one embodiment of the present invention, "a medicament
comprising a drug that inhibits CYP3A, OATP1B1, and OATP1B3"
includes a concomitant drug that exhibits other pharmacological
action than a medicament that includes either clarithromycin,
cyclosporine, or an HIV-protease inhibitor as the sole
pharmacological action compound. The above combination agents
include a combination agent of ritonavir and lopinavir (e.g.,
Kaletra), a combination agent of ritonavir and ombitavir hydrate
and palitaprevir hydrate (VIEKIRAX), a combination agent of
ritonavir and darnavir ethanol adduct, and a combination agent of
darnavir ethanol adduct and cobicistat (Prezcobix).
[0044] Concomitant use of "a drug that inhibits CYP3A" and "a drug
that inhibits OATP1B1 and OATP1B3" may inhibit CYP3A, OATP1B1, and
OATP1B3, and may increase plasma concentration of pemafibrate by
administering pemafibrate, a salt thereof, or a solvate of any of
these to the same patients. Therefore, caution should be exercised
when pemafibrate, a salt thereof, or a solvate of any of these is
used concomitant with "a drug that inhibits CYP3A" or "a drug that
inhibits OATP1B1 and OATP1B3," and avoiding or suspending the
concomitant use, or reducing the dose of pemafibrate, a salt
thereof, or a solvate of any of these can suppress the increase in
plasma concentration of pemafibrate.
[0045] Cyclosporine is also known to inhibit CYP3A, CYP2C8, CYP2C9,
OATP1B1, and OATP1B3, and to cause drug interactions, and it is
considered that cyclosporine is involved in increasing plasma
concentration of pemafibrate. That is, if a drug inhibits CYP3A,
CYP2C8, CYP2C9, OATP1B1, and OATP1B3, plasma concentration of
pemafibrate may be increased by concomitant use of pemafibrate, a
salt thereof, or a solvate of any of these with such a drug.
Therefore, in order to suppress the increase in the plasma
concentration of pemafibrate, the present inventors determined to
avoid or suspend the concomitant use, or reduce the dose of
pemafibrate, a salt thereof, or a solvate of any of these.
[0046] In addition, concomitant use of "a drug that inhibits
CYP3A", "a drug that inhibits CYP2C8", "a drug that inhibits
CYP2C9", and "a drug that inhibits OATP1B1 and OATP1B3" may inhibit
CYP3A, CYP2C8, CYP2C9, OATP1B1 and OATP1B3, and may increase the
plasma concentration of pemafibrate by administering pemafibrate, a
salt thereof, or a solvate of any of these to the same subject.
Therefore, care must be taken when pemafibrate, a salt thereof, or
a solvate of any of these is concomitantly used with one or more
drugs selected from the group consisting of "a drug that inhibits
CYP3A", "a drug that inhibits CYP2C8", "a drug that inhibits
CYP2C9" and "a drug that inhibits OATP1B1 and OATP1B3". Increase in
the plasma concentration of pemafibrate can be suppressed by
avoiding or suspending the concomitant use or by reducing the dose
of pemafibrate, a salt thereof, or a solvate of any of these.
[0047] Clopidogrel is also known to inhibit CYP2C8 and OATP1B1 and
cause drug interactions, and may be involved in increasing plasma
concentration of pemafibrate. That is, if the drug inhibits CYP2C8
and OATP1B1, the plasma concentration of pemafibrate may be
increased by concomitant use with pemafibrate, a salt thereof, or a
solvate of any of these or solvates thereof. Therefore, in order to
suppress an increase in the plasma concentration of pemafibrate,
the present inventors determined to avoid or suspend the
concomitant use, or to reduce the dose of pemafibrate, a salt
thereof, or a solvate of any of these.
[0048] In addition, concomitant use of "a drug that inhibits
CYP2C8" with "a drug that inhibits OATP1B1" may inhibit CYP2C8 and
OATP1B1, and if pemafibrate, a salt thereof, or a solvate of any of
these is further administered to the same patients, the plasma
concentration of pemafibrate may be increased. Therefore, caution
should be exercised when using pemafibrate, a salt thereof, or a
solvate of any of these concomitant with "a drug that inhibits
CYP2C8" or "a drug that inhibits OATP1B1", and avoidance or
suspension of such concomitant use or reduction of pemafibrate, a
salt thereof, or a solvate of any of these can suppress an increase
in plasma concentration of pemafibrate.
[0049] In the present specification, the "step of avoiding or
suspending the concomitant use with the pharmaceutical containing
the OATP1B inhibitor" is not particularly limited, and includes,
for example, any one of the following steps (i) to (vii).
[0050] (i) Recommending a patient to contraindicate the use of
pemafibrate, a salt thereof, or a solvate of any of these
concomitant with a drug containing an OATP1B inhibitor because of
increased plasma concentration of pemafibrate.
[0051] (ii) Recommending a patient to avoid or discontinue
concomitant use of pemafibrate, a salt thereof, or a solvate of any
of these with a medicament containing an OATP1B inhibitor because
of increased plasma concentration of pemafibrate.
[0052] (iii) Recommending the subject that the use of a medicament
containing an OATP1B inhibitor should be suspended prior to the use
of a medicament containing pemafibrate, a salt thereof, or a
solvate of any of these.
[0053] (iv) Recommending a patient to contraindicate concomitant
use of pemafibrate, a salt thereof, or a solvate of any of these
with a medicament containing an OATP1B inhibitor because of
increased plasma concentration of pemafibrate.
[0054] (v) Recommending a patient to avoid or discontinue
concomitant use of pemafibrate, a salt thereof, or a solvate of any
of these with a medicament containing an OATP1B inhibitor because
of increased plasma concentration of pemafibrate in principle.
[0055] (vi) Recommending a patient to administer a medication
containing pemafibrate, a salt thereof, or a solvate of any of
these with caution against the onset of adverse reactions, because
the plasma concentration of pemafibrate are increased by
concomitantly administering it with a medication containing an
OATP1B inhibitor. Recommending patients to administer a medication
containing pemafibrate, a salt thereof, or a solvate of any of
these with caution against the onset of adverse reactions.
[0056] (vii) Any one of the steps selected from the group
consisting of (i) to (vi) which is carried out after explaining to
the patient that the normal metabolism of pemafibrate, a salt
thereof, or a solvate of any of these is inhibited by taking a
medicament comprising an OATP1B inhibitor.
[0057] The above (i) to (vii) can replace the "OATP1B inhibitor"
with any drug, and can be read as a step for an arbitrary drug. The
arbitrary drug is one or more drugs selected from the group
consisting of, for example, but not limited to, a CYP inhibitor, a
drug that inhibits CYP3A, a drug that inhibits CYP2C8, a drug that
inhibits CYP2C9, a drug that inhibits OATP1B1 and OATP1B3, and a
drug that inhibits OATP1B1.
[0058] In the present invention, "dose" means an amount of active
ingredient used per day and is expressed in units of g/day or
mg/day. In one embodiment of the present invention, the dose of
pemafibrate, a salt thereof, or a solvate of any of these to a
patient in need of pemafibrate therapy is preferably 0.1 to 0.4
mg/day. If the patient further requires treatment with an OATP1B
inhibitor, less than 0.4 mg/day is preferable, and 0.1 to 0.2
mg/day is more preferable. In one embodiment of the present
invention, when pemafibrate is used concomitantly with
clarithromycin or clopidogrel, it is preferable that the daily dose
of pemafibrate be 0.1 mg and the maximal dose be up to 0.2 mg per
day, but the dose is not limited thereto. It is also preferable
that pemafibrate, a salt thereof, or a solvate of any of these be
administered in a manner that the above daily dose is divided into
twice.
[0059] In the present invention, "a step of reducing the dose of
pemafibrate, a salt thereof, or a solvate of any of these" means
changing the dose of pemafibrate, a salt thereof, or a solvate of
any of these selected from the group consisting of from 0.4 mg/day
to 0.35 mg/day, from 0.4 mg/day to 0.3 mg/day, from 0.4 mg/day to
0.25 mg/day, from 0.4 mg/day to 0.2 mg/day, from 0.4 mg/day to 0.15
mg/day, from 0.4 mg/day to 0.1 mg/day, from 0.4 mg/day to 0.05
mg/day, from 0.35 mg/day to 0.3 mg/day, from 0.35 mg/day to 0.25
mg/day, and from 0.35 mg/day to 0.2 mg/day, and from 0.35 mg/day to
0.15 mg/day, from 0.35 mg/day to 0.1 mg/day, from 0.35 mg/day to
0.05 mg/day, from 0.3 mg/day to 0.25 mg/day, from 0.3 mg/day to 0.2
mg/day, from 0.3 mg/day to 0.15 mg/day, from 0.3 mg/day to 0.05
mg/day, from 0.25 mg/day to 0.2 mg/day, from 0.25 mg/day to 0.15
mg/day, 0.25 mg/day to 0.1 mg/day, from 0.25 mg/day to 0.05 mg/day,
from 0.2 mg/day to 0.15 mg/day, from 0.2 mg/day to 0.1 mg/day, from
0.2 mg/day to 0.05 mg/day, from 0.15 mg/day to 0.1 mg/day, from
0.15 mg/day to 0.05 mg/day, and from 0.1 mg/day to 0.05 mg/day.
Among these, it is preferable to reduce the dose of pemafibrate, a
salt thereof, or a solvate of any of these, compared with the dose
when pemafibrate is administered alone, to 1/2 or less.
[0060] In the present invention, "reducing the dose of pemafibrate,
a salt thereof, or a solvate of any of these" can be expressed, for
example, as "reducing the amount of pemafibrate, a salt thereof, or
a solvate of any of these to be administered", "reducing the amount
of pemafibrate, a salt thereof, or a solvate of any of these" or
"lowering the dose of pemafibrate, a salt thereof, or a solvate of
any of these."
[0061] In another embodiment of the present invention, the "step of
avoiding or suspending concomitant use" and the "step of reducing
the dose of pemafibrate, a salt thereof, or a solvate of any of
these" for suppressing an increase in plasma concentration of
pemafibrate can be performed as required, and embodiments thereof
include, for example, the medicaments recited in [47] and [49], the
pharmaceutical kits recited in [48] and [50], the methods for
treatment recited in [52] and [56], and the use for treatment
recited in [54] and [58], and the like.
[0062] In one embodiment of the present invention, the dose of
clarithromycin to a patient in need of treatment with
clarithromycin is preferably from 200 to 1,600 mg/day, preferably
200 to 800 mg/day for the treatment of general infectious diseases,
400 to 1,600 mg/day for the treatment of non-tuberculous
mycobacteriosis, and 200 to 800 mg/day for the treatment of
Helicobacter pylori infections.
[0063] In one embodiment of the present invention, the dose of
clopidogrel, a salt thereof, or a solvate of any of these to a
patient in need of treatment with clopidogrel, a salt thereof, or a
solvate of any of these is 75 to 400 mg/day, preferably 75 to 300
mg/day as clopidogrel, more preferably 391.5 mg/day of clopidogrel
sulfate (equivalent to 300 mg/day of clopidogrel) on day 1 and
97.875 mg/day of clopidogrel sulfate (equivalent to 75 mg/day of
clopidogrel) on and after day 2 of administration.
[0064] One embodiment of the present invention includes a
pharmaceutical kit comprising (A) a medicament comprising
pemafibrate, a salt thereof, or a solvate of any of these or
solvate thereof as an active ingredient; and (B) an instruction to
avoid or suspend concomitant use of the (A) and a medicament
comprising an OATP1B inhibitor or to reduce the dose of
pemafibrate, a salt thereof, or a solvate of any of these.
[0065] In this specification, "an instruction to avoid or suspend
concomitant use" is an instruction describing a situation in which
concomitant use of two specific medicaments should be avoided or
suspended. In one embodiment of the present invention, the
"instruction to avoid or suspend concomitant use of Medicament A
and Medicament B" is not particularly limited, but includes, for
example, an instruction for instructing (a) to (h) below.
[0066] (a) Do not administer Medicament B to a patient receiving
Medicament A.
[0067] (b) Do not concomitantly use Medicament A and Medicament
B
[0068] (c) In principle, Medicament A should not be administered to
a patient receiving Medicament B, but should be administered with
care when particularly necessary.
[0069] (d) In principle, Medicament A and Medicament B should not
be used concomitantly, but concomitant use should be made with
caution only when it is judged that the concomitant use is
unavoidable for treatment.
[0070] (e) Caution should be exercised when administering
Medicament A to a patient receiving Medicament B.
[0071] (f) Caution should be exercised when Medicament A and
Medicament B are used concomitantly.
[0072] (g) If the patient is taking Medicament B, suspend taking
medicament B before using Medicament A.
[0073] (h) If the patient is taking Medicament B, explain the
current compliance status to the physician or pharmacist before
using Medicament A.
[0074] In the present invention, "instruction" include a package
insert, a package label, or a user manual, and include, but are not
limited to, a package insert, an interview form, a prescribing
information, a patient information leaflet, for example.
[0075] The following examples and test example are given to explain
the present invention in more detail, but the present invention is
not limited thereto.
EXAMPLES
Example 1: Drug Interaction Study of Pemafibrate with
Rifampicin
[0076] A study was conducted to investigate the effect of
rifampicin on the pharmacokinetics of pemafibrate in healthy adult
subjects.
[Subject]
[0077] 20 healthy adults
[Dose and Administration]
[0078] Subjects were orally administered on the following schedule.
The administration of 0.4 mg of pemafibrate on Days 1 and 4 was
carried out under fasting for at least 8 hours, and the fasting was
maintained for 4 hours after the administration.
[0079] Day 1: Pemafibrate 0.4 mg alone
[0080] Day 4: A single dose of 0.4 mg of pemafibrate plus 600 mg of
rifampicin
[0081] Days 5-6: Rifampicin 600 mg alone
[Measurement]
[0082] Plasma concentration of pemafibrate was measured on blood
samples from patients taken prior to and at 0.25, 0.5, 1, 1.5, 2,
3, 4, 6, 8, 10, 12, 14, 16, 24, 36, 48, 72 hours after
administration of the drug on Days 1 and 4.
[0083] For estimates of the C.sub.max of pemafibrate and the area
under the concentration-time curves (AUC.sub.0-inf) up to infinity
hours, the geometric mean values and the ratios of the geometric
mean values for concomitant administration to those for the single
administration are shown in Table 1. As can be seen from Table 1,
concomitant administration of pemafibrate and rifampicin resulted
in an increase in the plasma concentration of pemafibrate compared
with administration of pemafibrate alone.
TABLE-US-00001 TABLE 1 Ratio (concomitant use/ Single Concomitant
single use) Parameter administration administration 90% confidence
interval Cmax 5.672 53.512 9.4336 (ng/mL) 8.3626-10.6419
AUC.sub.0-inf 20.069 218.774 10.9009 (ng h/mL) 9.9154-11.9844
Example 2: Drug Interaction Study of Pemafibrate with
Clarithromycin
[0084] A study was conducted to investigate the effect of
clarithromycin on the pharmacokinetics of pemafibrate in healthy
adult subjects.
[ Subject]
[0085] 20 healthy adult subjects
[Dose and Administration]
[0086] Subjects were orally administered on the following schedule.
The administration of 0.4 mg of pemafibrate on Days 1 and 9 was
carried out under fasting for at least 8 hours, and the fasting was
maintained for 4 hours after the administration.
[0087] Day 1: Pemafibrate 0.4 mg alone
[0088] Day 4 to 8: Clarithromycin 500 mg twice per day (1000
mg/day)
[0089] Day 9: Pemafibrate 0.4 mg single dose and Clarithromycin 500
mg twice per day (1000 mg/day)
[0090] Day 10 to 11: Clarithromycin 500 mg twice per day (1000
mg/day)
Measurement
[0091] Plasma concentration of pemafibrate was measured on blood
samples from patients collected prior to and at 0.25, 0.5, 1, 1.5,
2, 3, 4, 6, 8, 10, 12, 14, 16, 24, 36, 48, 72 hours after
administration of 0.4 mg of pemafibrate on Days 1 and 9.
[0092] For estimates of the C.sub.max of pemafibrate and the area
under the concentration-time curves (AUC.sub.0-inf) up to infinity
hours, the geometric mean values and the ratios of the geometric
mean values for concomitant administration to those for the single
administration are shown in Table 2. As can be seen from Table 2,
concomitant administration of pemafibrate and clarithromycin
resulted in an increase in the plasma concentration of pemafibrate
compared with administration of pemafibrate alone.
TABLE-US-00002 TABLE 2 Ratio (concomitant use/ Single Concomitant
single use) Parameter administration administration 90% confidence
interval Cmax 4.673 11.331 2.4246 (ng/mL) 2.1632-2.7174
AUC.sub.0-inf 17.006 35.670 2.0975 (ng h/mL) 1.9158-2.2964
Example 3: Drug Interaction Study of Pemafibrate with
Cyclosporine
[0093] A study was conducted to investigate the effect of
cyclosporine on the pharmacokinetics of pemafibrate in healthy
adult subjects.
[Subject]
[0094] 20 healthy adults
[Dose and Administration]
[0095] Subjects were orally administered on the following schedule.
Drug administration was carried out under fasting for at least 8
hours, and fasting was maintained for 4 hours after
administration.
[0096] Day 1: Pemafibrate 0.4 mg alone
[0097] Day 4: Combined single dose of 0.4 mg of pemafibrate and 600
mg of cyclosporine (Neoral.RTM. or its equivalent)
[Measurement]
[0098] Plasma concentration of pemafibrate was measured on blood
samples from patients taken prior to and at 0.25, 0.5, 1, 1.5, 2,
3, 4, 6, 8, 10, 12, 14, 16, 24, 36, 48, 72 hours after
administration of the drug on Days 1 and 4.
[0099] For estimates of the C.sub.max of pemafibrate and the area
under the concentration-time curves (AUC.sub.0-inf) up to infinity
hours, the geometric mean values and the ratios of the geometric
mean values for concomitant administration to those for the single
administration are shown in Table 3. As can be seen from Table 3,
concomitant administration of pemafibrate and cyclosporine resulted
in an increase in the plasma concentration of pemafibrate compared
with administration of pemafibrate alone.
TABLE-US-00003 TABLE 3 Ratio (concomitant use/ Single Concomitant
single use) Parameter administration administration 90% confidence
interval Cmax 4.593 41.175 8.9644 (ng/mL) 7.5151-10.6931
AUC.sub.0-inf 13.388 187.363 13.9947 (ng h/mL) 12.6175-15.5223
Example 4: Drug Interaction Study of Pemafibrate with
Clopidogrel
[0100] A study was conducted to investigate the effect of
clopidogrel on the pharmacokinetics of pemafibrate in healthy adult
subjects.
[Subject]
[0101] 20 healthy adults
[Dose and Administration]
[0102] Subjects were orally administered on the following schedule.
Pemafibrate administration on Days 1, 4, and 7 was carried out
under fasting for at least 8 hours and maintained fasting for 4
hours after administration.
[0103] Day 1: Pemafibrate 0.4 mg alone
[0104] Day 4: A single dose of 0.4 mg of pemafibrate plus 391.5 mg
of clopidogrel sulfate (equivalent to 300 mg of clopidogrel)
[0105] Day 5 to 6: Clopidogrel Sulfate 91.875 mg (equivalent to
Clopidogrel 75 mg) alone
[0106] Day 7: A single dose of 0.4 mg of pemafibrate and 91.875 mg
of clopidogrel sulfate (equivalent to 75 mg of clopidogrel)
[0107] Day 8 to 9: Clopidogrel Sulfate 91.875 mg (equivalent to
Clopidogrel 75 mg) alone
Measurement
[0108] Plasma concentration of pemafibrate was measured on blood
samples from patients taken prior to and at 0.25, 0.5, 1, 1.5, 2,
3, 4, 6, 8, 10, 12, 14, 16, 24, 36, 48, 72 hours after
administration of the drug on Days 1, 4, and 7.
[0109] For estimates of the C.sub.max of pemafibrate and the area
under the concentration-time curves (AUC.sub.0-inf) up to infinity
hours, the geometric mean values and the ratios of the geometric
mean values of the single-dose concomitant administration (Day 4)
to those for the single administration (Day 1) are shown in Table
4. As can be seen from Table 4, concomitant administration of
pemafibrate and clopidogrel resulted in an increase in the plasma
concentration of pemafibrate compared with administration of
pemafibrate alone.
TABLE-US-00004 TABLE 4 Ratio (concomitant use/ Single Concomitant
single use) Parameter administration administration 90% confidence
interval Cmax 4.7661 7.0799 1.4855 (ng/mL) 1.3915-1.5858
AUC.sub.0-inf 16.0763 38.1452 2.3728 (ng h/mL) 2.2473-2.5052
[0110] For the C.sub.max and AUC.sub.0-inf of pemafibrate, the
geometric mean values and the ratios of the geometric mean values
for concomitant administration after repeated administration of
clopidogrel (day 7) to those for the single administration (day 1)
are shown in Table 5. As can be seen from Table 5, concomitant
administration of pemafibrate and clopidogrel resulted in an
increase in the plasma concentration of pemafibrate compared with
administration of pemafibrate alone.
TABLE-US-00005 TABLE 5 Ratio (concomitant use/ Single Concomitant
single use) Parameter administration administration 90% confidence
interval Cmax 4.7661 6.3935 1.3415 (ng/mL) 1.2583-1.4302
AUC.sub.0-inf 16.0763 33.5611 2.0876 (ng h/mL) 1.9811-2.1998
INDUSTRIAL APPLICABILITY
[0111] The present invention can avoid an increase in plasma
concentration of pemafibrate, a salt thereof, or a solvate of any
of these. Thus, a medicament can be provided for the effective and
safe use of pemafibrate, a salt thereof, or a solvate of any of
these.
* * * * *