U.S. patent application number 16/598785 was filed with the patent office on 2020-02-06 for methods of administering pirfenidone therapy.
The applicant listed for this patent is INTERMUNE, INC.. Invention is credited to Williamson Z. Bradford, Javier Szwarcberg.
Application Number | 20200038387 16/598785 |
Document ID | / |
Family ID | 42941192 |
Filed Date | 2020-02-06 |
United States Patent
Application |
20200038387 |
Kind Code |
A1 |
Bradford; Williamson Z. ; et
al. |
February 6, 2020 |
METHODS OF ADMINISTERING PIRFENIDONE THERAPY
Abstract
The present invention relates to methods involving avoiding
adverse drug interactions with fluvoxamine and pirfenidone or other
moderate to strong inhibitors of CYP enzymes.
Inventors: |
Bradford; Williamson Z.;
(Wilson, WY) ; Szwarcberg; Javier; (San Francisco,
CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
INTERMUNE, INC. |
South San Francisco |
CA |
US |
|
|
Family ID: |
42941192 |
Appl. No.: |
16/598785 |
Filed: |
October 10, 2019 |
Related U.S. Patent Documents
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Application
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Filing Date |
Patent Number |
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16283270 |
Feb 22, 2019 |
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16598785 |
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16020508 |
Jun 27, 2018 |
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16283270 |
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15809511 |
Nov 10, 2017 |
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16020508 |
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15179279 |
Jun 10, 2016 |
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15809511 |
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14454980 |
Aug 8, 2014 |
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15179279 |
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13513485 |
Oct 12, 2012 |
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PCT/US2010/058943 |
Dec 3, 2010 |
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14454980 |
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12684879 |
Jan 8, 2010 |
7816383 |
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13513485 |
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61310679 |
Mar 4, 2010 |
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61266815 |
Dec 4, 2009 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 11/02 20180101;
A61P 11/06 20180101; A61P 9/10 20180101; A61P 25/06 20180101; Y02A
50/401 20180101; A61P 1/12 20180101; A61P 25/00 20180101; A61P
37/08 20180101; A61K 31/44 20130101; A61P 3/00 20180101; A61P 35/00
20180101; Y02A 50/475 20180101; A61P 21/00 20180101; A61P 37/06
20180101; A61P 19/00 20180101; A61K 31/4418 20130101; A61P 1/18
20180101; A61P 9/04 20180101; A61P 43/00 20180101; A61P 7/06
20180101; A61P 17/00 20180101; A61P 31/16 20180101; A61P 19/10
20180101; A61P 31/04 20180101; A61P 25/16 20180101; A61P 29/02
20180101; A61P 27/02 20180101; A61P 31/20 20180101; A61P 31/18
20180101; Y02A 50/409 20180101; A61P 1/02 20180101; A61P 3/10
20180101; A61K 36/752 20130101; A61P 21/04 20180101; A61P 25/28
20180101; A61P 35/04 20180101; A61P 29/00 20180101; A61K 45/06
20130101; A61P 9/00 20180101; A61P 9/06 20180101; A61P 19/02
20180101; Y02A 50/411 20180101; A61K 31/15 20130101; A61P 7/02
20180101; A61P 13/12 20180101; A61P 37/00 20180101; A61K 31/135
20130101; A61P 13/08 20180101; A61P 17/06 20180101; A61P 25/04
20180101; A61P 11/00 20180101; A61P 19/06 20180101; A61P 1/04
20180101; A61P 31/22 20180101; A61P 41/00 20180101; A61P 25/14
20180101; A61P 1/16 20180101; A61P 33/02 20180101; Y02A 50/30
20180101; A61P 7/00 20180101; A61P 31/12 20180101; A61P 27/14
20180101; A61P 31/14 20180101; A61P 33/06 20180101; A61P 35/02
20180101 |
International
Class: |
A61K 31/4418 20060101
A61K031/4418; A61K 31/135 20060101 A61K031/135; A61K 31/15 20060101
A61K031/15; A61K 31/44 20060101 A61K031/44; A61K 36/752 20060101
A61K036/752; A61K 45/06 20060101 A61K045/06 |
Foreign Application Data
Date |
Code |
Application Number |
Mar 3, 2010 |
EP |
10250379.4 |
Aug 17, 2010 |
CA |
2710358 |
Claims
1. Pirfenidone for use in treating a patient in need of pirfenidone
therapy, characterized in that the treating comprises (a) avoiding,
contraindicating, discontinuing or using with caution concomitant
use or co-administration of a cytochrome P450 1 A2 (CYP1A2)
inhibitor that is a moderate to strong inhibitor of both (i)
cytochrome P450 1A2 (CYP1A2) and (ii) another CYP enzyme selected
from the group consisting of CYP3A4, CYP2C9, CYP2C19, CYP2B6 and/or
CYP2D6, or (b) using with caution pirfenidone in patients receiving
a strong inhibitor of CYP1A2, or (c) using with caution a strong
CYP1A2 inhibitor in patients receiving pirfenidone.
2. Use of pirfenidone in preparation of a medicament for treating a
patient in need of pirfenidone therapy, characterized in that the
treating comprises (a) avoiding, contraindicating, discontinuing or
using with caution concomitant use or co-administration of a
cytochrome P450 1A2 (CYP1A2) inhibitor that is a moderate to strong
inhibitor of both (i) cytochrome P450 1A2 (CYP1A2) and (ii) another
CYP enzyme selected from the group consisting of CYP3A4, CYP2C9,
CYP2C19, CYP2B6 and/or CYP2D6, or (b) using with caution
pirfenidone in patients receiving a strong inhibitor of CYP1A2, or
(c) using with caution a strong CYP1A2 inhibitor in patients
receiving pirfenidone.
3. A method of administering pirfenidone therapy to a patient in
need thereof, comprising administering an effective amount of
pirfenidone, and (a) avoiding, contraindicating, discontinuing or
using with caution a cytochrome P450 1A2 (CYP1A2) inhibitor that is
a moderate to strong inhibitor of both (i) cytochrome P450 1A2
(CYP1A2) and (ii) another CYP enzyme selected from the group
consisting of CYP3A4, CYP2C9, CYP2C19, CYP2B6 and/or CYP2D6, or (b)
using with caution pirfenidone in patients receiving a strong
inhibitor of CYP1A2, or (c) using with caution a strong CYP1A2
inhibitor in patients receiving pirfenidone.
4. The pirfenidone, use or method of any of claims 1-3 wherein the
CYP1A2 inhibitor is a moderate to strong inhibitor of CYP1A2 and
another CYP enzyme selected from the group consisting of CYP2C9,
CYP2C19 and/or CYP2D6.
5. The pirfenidone, use or method of any of claims 1-3 wherein the
CYP1A2 inhibitor is a strong CYP1A2 inhibitor.
6. The pirfenidone, use or method of any of claims 1-4 wherein the
CYP1A2 inhibitor is discontinued prior to starting pirfenidone
therapy to avoid an adverse drug interaction with pirfenidone, or
to avoid a reduced clearance of pirfenidone.
7. The pirfenidone of any one of claims 1-6 wherein the CYP1A2
inhibitor is discontinued within 1 month prior to starting
pirfenidone therapy.
8. The pirfenidone of any one of claims 1-7 wherein the CYP1A2
inhibitor is discontinued within 2 weeks prior to starting
pirfenidone therapy.
9. The pirfenidone, use or method of any of claims 1-4 wherein the
CYP1A2 inhibitor is avoided during pirfenidone therapy.
10. The pirfenidone, use or method of any of claims 1-9 wherein the
patient is in need of therapy with a CYP1A2 inhibitor.
11. The pirfenidone, use or method of any of claims 1-5 wherein the
CYP1 A2 inhibitor is used with caution.
12. The pirfenidone of any one of claims 1-11 wherein the patient
has idiopathic pulmonary fibrosis (IPF).
13. The pirfenidone of any of claims 1-11 wherein the patient
suffers from a disease selected from idiopathic pulmonary fibrosis,
pulmonary fibrosis, idiopathic interstitial pneumonia, autoimmune
lung diseases, benign prostate hypertrophy, coronary or myocardial
infarction, atrial fibrillation, cerebral infarction, myocardiac
fibrosis, musculoskeletal fibrosis, post-surgical adhesions, liver
cirrhosis, renal fibrotic disease, fibrotic vascular disease,
scleroderma, Hermansky-Pudlak syndrome, neurofibromatosis,
Alzheimer's disease, diabetic retinopathy, or skin lesions, lymph
node fibrosis associated with HIV, chronic obstructive pulmonary
disease (COPD), inflammatory pulmonary fibrosis, rheumatoid
arthritis; rheumatoid spondylitis; osteoarthritis; gout, other
arthritic conditions; sepsis; septic shock; endotoxic shock;
gram-negative sepsis; toxic shock syndrome; myofacial pain syndrome
(MPS); Shigellosis; asthma; adult respiratory distress syndrome;
inflammatory bowel disease; Crohn's disease; psoriasis; eczema;
ulcerative colitis; glomerular nephritis; scleroderma; chronic
thyroiditis; Grave's disease; Ormond's disease; autoimmune
gastritis; myasthenia gravis; autoimmune hemolytic anemia;
autoimmune neutropenia; thrombocytopenia; pancreatic fibrosis;
chronic active hepatitis including hepatic fibrosis; acute or
chronic renal disease; renal fibrosis; diabetic nephropathy;
irritable bowel syndrome; pyresis; restenosis; cerebral malaria;
stroke or ischemic injury; neural trauma; Alzheimer's disease;
Huntington's disease; Parkinson's disease; acute or chronic pain;
allergies, including allergic rhinitis or allergic conjunctivitis;
cardiac hypertrophy, chronic heart failure; acute coronary
syndrome; cachexia; malaria; leprosy; leishmaniasis; Lyme disease;
Reiter's syndrome; acute synoviitis; muscle degeneration, bursitis;
tendonitis; tenosynoviitis; herniated, ruptured, or prolapsed
intervertebral disk syndrome; osteopetrosis; thrombosis; silicosis;
pulmonary sarcosis; bone resorption diseases, such as osteoporosis
or multiple myeloma-related bone disorders; cancer, including but
not limited to metastatic breast carcinoma, colorectal carcinoma,
malignant melanoma, gastric cancer, or non-small cell lung cancer;
graft-versus-host reaction; or auto-immune diseases, such as
multiple sclerosis, lupus or fibromyalgia; AIDS or other viral
diseases such as Herpes Zoster, Herpes Simplex I or II, influenza
virus, Severe Acute Respiratory Syndrome (SARS) or cytomegalovirus;
or diabetes mellitus, proliferative disorders (including both
benign or malignant hyperplasias), acute myelogenous leukemia,
chronic myelogenous leukemia, Kaposi's sarcoma, metastatic
melanoma, multiple myeloma, breast cancer, including metastatic
breast carcinoma; colorectal, carcinoma; malignant melanoma;
gastric cancer; non-small cell lung cancer (NSCLC); bone
metastases; pain disorders including neuromuscular pain, headache,
cancer pain, dental pain, or arthritis pain; angiogenic disorders
including solid tumor angiogenesis, ocular neovascularization, or
infantile hemangioma; conditions associated with the cyclooxygenase
or lipoxygenase signaling pathways, including conditions associated
with prostaglandin endoperoxide synthase-2 (including edema, fever,
analgesia, or pain); organ hypoxia; thrombin-induced platelet
aggregation; or protozoal diseases.
14. The pirfenidone of any one of claims 1 through 13 wherein the
pirfenidone is administered at a total daily dosage of at least
1800 mg.
15. The pirfenidone of any one of claims 1 through 13 wherein the
pirfenidone is administered at a total daily dosage of about 2400
mg or 2403 mg.
16. The pirfenidone of any one of claims 1 through 13 wherein 800
or 801 mg of pirfenidone is administered to the patient three times
per day, with food.
17. The pirfenidone of any one of claims 1 through 16 wherein the
CYP1A2 inhibitor is fluvoxamine.
18. The pirfenidone of any one of claims 1 through 17 wherein the
CYP1A2 inhibitor is ciprofloxacin, amiodarone or propafenone.
19. The pirfenidone of any one of claims 1 through 16 wherein the
CYP1A2 inhibitor is grapefruit juice.
20. A package or kit comprising (a) pirfenidone, optionally in a
container, and (b) a package insert, package label, instructions or
other labeling comprising avoiding or discontinuing or
contraindicating concomitant use of or co-administration of or
using with caution (1) a strong inhibitor of CYP1 A2, or (2) a
moderate to strong inhibitor of both (i) CYP1A2 and (ii) another
CYP enzyme selected from the group consisting of CYP3A4, CYP2C9,
CYP2C19, CYP2B6 and/or CYP2D6, optionally according to any of the
embodiments of claims 1-19.
Description
FIELD OF THE INVENTION
[0001] The invention relates to improved methods of administering
pirfenidone therapy involving avoiding adverse drug interactions
with fluvoxamine, a strong inhibitor of CYP1A2.
BACKGROUND
[0002] Pirfenidone is small molecule with a molecular weight of
185.23 daltons whose chemical name is
5-methyl-1-phenyl-2-(1H)-pyridone. Pirfenidone has anti-fibrotic
properties and has been investigated for therapeutic benefits to
patients suffering from various fibrotic conditions. It is approved
in Japan for treatment of idiopathic pulmonary fibrosis (IPF) under
the trade name Pirespa.RTM..
[0003] Pirfenidone has been shown to be metabolized by various
isoforms of the cytochrome P450 (CYP) protein [See the Report on
the Deliberation Results, Evaluation and Licensing Division,
Pharmaceutical and Food Safety Bureau, Ministry of Health Labour
and Welfare, Sep. 16, 2008]. Specifically, several cytochrome P450
(CYP) isoforms (CYP1A2, 2C9, 2C19, 2D6 and 2E1) were involved in
the earliest stages of oxidative metabolism of pirfenidone.
[0004] Fluvoxamine belongs to a class of therapeutics known as
selective serotonin reuptake inhibitors (SSRIs). The SSRIs are a
group of antidepressants with similar pharmacologic effects, but
with different chemical structures. Fluvoxamine has been approved
for treatment of social anxiety disorder (social phobia), obsessive
compulsive disorder (OCD), and has been prescribed to treat major
depression, and other anxiety disorders such as panic disorder and
post-traumatic stress disorder [McClellan et al., (Drugs October
2000). "Fluvoxamine An Updated Review of its Use in the Management
of Adults with Anxiety Disorders". Adis Drug Evaluation 60 (4):
925-954]. In addition to fluvoxamine, other clinically available
SSRIs are citalopram, fluoxetine, paroxetine and sertraline. The
elimination of these lipophilic compounds proceeds predominantly
via oxidation catalysed by CYP in the liver. SSRIs have the
potential for inhibition of CYP enzymes [Brosen, The
pharmacogenetics of the selective serotonin reuptake inhibitors.
Clin Invest 71(12):1002-1009, 1993]. Jeppesen et al. reported that
fluvoxamine is a potent inhibitor of CYP1A2 in humans in vivo
[Jeppesen et al., Dose-dependent inhibition of CYP1A2, CYP2C19 and
CYP2D6 by citalopram, fluoxetine, fluvoxamine and paroxetine. Eur J
Clin Pharmacol 51: 73-78, 1996]. Fluvoxamine has also been shown to
be a very potent inhibitor of CYP1A2 in vitro [Brosen et al.,
Fluvoxamine is a potent inhibitor of cytochrome P4501A2. Biochem
Pharmacol 45:1211-1214, 1993; Rasmussen et al., Selective serotonin
reuptake inhibitors and theophylline metabolism in human liver
microsomes: potent inhibition by fluvoxamine. Br J Clin Pharmacol
39:151-159, 1995].
SUMMARY OF THE INVENTION
[0005] The invention disclosed herein is based on the discovery of
an adverse drug interaction between pirfenidone and
fluvoxamine.
[0006] The invention generally relates to improved uses and methods
of administering pirfenidone to a patient in need of pirfenidone
therapy, and to methods of preparing or packaging pirfenidone
medicaments, containers, packages and kits. In any of the aspects
or embodiments, the patient may have idiopathic pulmonary fibrosis
(IPF) and the medicament is for treatment of IPF. In any of the
aspects or embodiments, the therapeutically effective amount of
pirfenidone being administered may be a daily dosage of 2400 mg or
2403 mg per day. In any of the aspects of the invention, the daily
dosage may be administered in divided doses three times a day, or
two times a day, or alternatively is administered in a single dose
once a day. In any of the aspects of the invention, the pirfenidone
may be administered with food. For example, the daily dosage of
2400 mg or 2403 mg pirfenidone per day may be administered as
follows: 801 mg taken three times a day, with food.
[0007] In some aspects, the invention provides a method of
administering pirfenidone therapy to a patient in need of
pirfenidone therapy (e.g., a patient with IPF), involving
administering to the patient a therapeutically effective amount of
pirfenidone, and avoiding administration of fluvoxamine despite the
patient being in need of fluvoxamine therapy.
[0008] In other aspects, the invention provides a method of
administering pirfenidone therapy to a patient in need of
pirfenidone therapy, comprising discontinuing administration of
fluvoxamine to avoid an adverse drug interaction and administering
a therapeutically effective amount of pirfenidone. In one
embodiment, the patient is in need of and thus is receiving
fluvoxamine, and fluvoxamine is discontinued concurrent with
starting administration of pirfenidone. In another embodiment,
fluvoxamine is discontinued within at least 3 days to 1 month prior
to or after starting pirfenidone therapy. This time period, for
example, permits adequate time for tapering and withdrawal without
adverse effects. In one example, in a method of administering a
therapeutically effective amount of pirfenidone to a patient with
IPF, the invention provides an improvement that comprises avoiding
or discontinuing administration of fluvoxamine and administering a
therapeutically effective amount of pirfenidone.
[0009] As used herein, an adverse drug interaction can include
reduced clearance of pirfenidone, the potential for reduced
clearance of pirfenidone, increased exposure to pirfenidone, or the
potential for increased exposure to pirfenidone.
[0010] Thus, an aspect of the invention provides pirfenidone for
use in treating a patient in need of pirfenidone therapy,
characterized in that the treating comprises avoiding,
contraindicating or discontinuing concomitant use (or
co-administration) of fluvoxamine. In some embodiments, the
concomitant use of fluvoxamine is avoided, contraindicated or
discontinued, in order to avoid reduced clearance of pirfenidone,
or the potential for reduced clearance of pirfenidone. In some
embodiments, the concomitant use of fluvoxamine is avoided,
contraindicated or discontinued, in order to avoid increased
exposure to pirfenidone, or the potential for increased exposure to
pirfenidone. Administration of pirfenidone in patients that
concomitantly use or are being administered fluvoxamine results in
about a 6-fold increase in pirfenidone exposure. It is understood
that any of the aspects or embodiments or examples described herein
with respect to methods of treatment apply to this aspect of the
invention that provides pirfenidone for use in treating a patient.
For example, the patient may be a patient with IPF, and the
therapeutically effective amount administered may be 2400 or 2403
mg per day.
[0011] Similarly, a further aspect of the invention provides the
use of pirfenidone in the manufacture of a medicament for treating
a patient in need of pirfenidone therapy, characterized in that the
treating comprises avoiding, contraindicating or discontinuing
concomitant use (or co-administration) of fluvoxamine. It is
understood that any of the aspects or embodiments or examples
described herein with respect to methods of treatment or
"pirfenidone for use" in treating a patient apply to this aspect of
the invention that provides for the use of pirfenidone in
manufacture of a medicament. For example, the patient may be a
patient with IPF, and the therapeutically effective amount
administered may be 2400 or 2403 mg per day.
[0012] As used herein, "concomitant use" is understood to be
interchangeable with concurrent administration or
co-administration. Thus, the terms are understood to encompass
administration simultaneously, or at different times, and by the
same route or by different routes, as long as the two agents are
given in a manner that allows both agents to be affecting the body
at the same time. For example, concomitant use can refer to a
medication concomitantly administered, whether prescribed by the
same or a different practitioner, or for the same or a different
indication.
[0013] In some embodiments, the patient is a patient in need of
therapy with a CYP1A2 inhibitor. In some embodiments, the patient
is a patient in need of therapy with a strong CYP1A2 inhibitor, or
a moderate to strong CYP1A2 inhibitor. In some embodiments, the
patient is a patient in need of fluvoxamine therapy. In some
embodiments, the patient is a patient who is avoiding concomitant
use of fluvoxamine, e.g. because concomitant use of pirfenidone
with fluvoxamine is contraindicated. In some embodiments, the
patient is a patient who was or is being administered a strong
CYP1A2 inhibitor, or a moderate to strong CYP1 A2 inhibitor, e.g.
fluvoxamine. In some embodiments, the patient is a patient who has
discontinued use of a strong CYP1A2 inhibitor, or a moderate to
strong CYP1A2 inhibitor prior to the initiation of pirfenidone
therapy in order to avoid reduced clearance (or increased exposure
to) pirfenidone, or the potential for reduced clearance of (or
increased exposure to) pirfenidone. In some embodiments, the
patient is a patient who has discontinued use of fluvoxamine prior
to the initiation of pirfenidone therapy in order to avoid reduced
clearance of pirfenidone, or the potential for reduced clearance of
pirfenidone. In some embodiments, the patient is a patient who has
discontinued use of fluvoxamine prior to the initiation of
pirfenidone therapy in order to avoid increased exposure to
pirfenidone, or the potential for increased exposure to
pirfenidone. In some embodiments, the patient is a patient who has
discontinued administration of the strong CYP1A2 inhibitor, or
moderate to strong CYP1A2 inhibitor, e.g., fluvoxamine, within 1
month, or within 2 weeks, prior to starting pirfenidone therapy, or
concurrent with starting pirfenidone therapy. It is understood that
any of the aspects or embodiments or examples described herein with
respect to methods of treatment apply to this aspect of the
invention that provides for characterization of the patients to be
treated with pirfenidone.
[0014] In yet other aspects, a method of administering pirfenidone
therapy to a patient in need of pirfenidone therapy and in need of
fluvoxamine therapy is provided, comprising administering a
therapeutically effective amount of pirfenidone to the patient, and
administering an alternative therapy that is not fluvoxamine. In
one aspect, the alternative therapy that is not fluvoxamine is a
drug that is not a strong or moderate to strong inhibitor of
cytochrome P450 1A2 (CYP1A2). Preferably, such drug is not a
moderate to strong inhibitor of both CYP1A2, and another CYP enzyme
selected from the group consisting of CYP3A4, CYP2C9, and/or
CYP2C19. In some examples, the alternative drug is selected from
the group consisting of Citalopram (Celexa), Escitalopram
(Lexapro), Fluoxetine (Prozac, Prozac Weekly), Paroxetine (Paxil,
Paxil CR, Pexeva), and/or Sertraline (Zoloft).
[0015] In some aspects, the invention provides a method of
administering pirfenidone therapy to a patient in need of
pirfenidone therapy (e.g., a patient with IPF), involving
administering to the patient a therapeutically effective amount of
pirfenidone, and advising the patient in any one, two, three or
more of the following ways:
[0016] (a) advising the patient that fluvoxamine should be avoided
or discontinued,
[0017] (b) advising the patient that co-administration of
pirfenidone with drugs that are moderate to strong inhibitors of
both CYP1A2 and another CYP enzyme selected from the group
consisting of CYP3A4, CYP2C9, and/or CYP2C19, can alter the
therapeutic effect or adverse reaction profile of pirfenidone,
[0018] (c) advising the patient that co-administration of
pirfenidone with fluvoxamine can alter the therapeutic effect or
adverse reaction profile of pirfenidone,
[0019] (d) advising the patient that use of pirfenidone in patients
being treated with fluvoxamine is contraindicated,
[0020] (e) advising the patient that co-administration of
pirfenidone and fluvoxamine resulted in an average 6-fold increase
in exposure to pirfenidone, and/or.
[0021] (f) advising the patient that strong CYP1A2 inhibitors
should be used with caution in patients receiving pirfenidone due
to the potential for reduced pirfenidone clearance.
[0022] In some embodiments, the method further includes advising
the patient that co-administration of pirfenidone and fluvoxamine
resulted in a 2-fold increase in average peak serum concentration
of pirfenidone (Cmax). In yet further embodiments, the method also
includes avoiding administering a strong CYP1A2 inhibitor, or
discontinuing administration of a strong CYP1A2 inhibitor.
[0023] In some embodiments, a method of reducing toxicity of
pirfenidone treatment in a patient is provided comprising
administering a therapeutically effective amount of pirfenidone to
the patient and advising the patient of any of the foregoing
advice.
[0024] In some embodiments, a method of improving safety of
pirfenidone treatment in a patient is provided comprising
administering a therapeutically effective amount of pirfenidone to
the patient and advising the patient of any of the foregoing
advice.
[0025] In some embodiments, a method of reducing adverse drug
interaction with pirfenidone treatment in a patient is provided
comprising administering a therapeutically effective amount of
pirfenidone to the patient and advising the patient of any of the
foregoing advice.
[0026] Thus, in some embodiments, the concomitant use of
fluvoxamine is avoided, contraindicated or discontinued in order
to:
[0027] (a) avoid altering the therapeutic effect profile of
pirfenidone, and/or
[0028] (b) avoid altering the adverse reaction profile of
pirfenidone, and/or
[0029] (c) avoid the increased exposure or potential for increased
exposure, and/or
[0030] (d) avoid the reduced clearance or potential for reduced
clearance, and/or
[0031] (e) avoid the average 6-fold increase in exposure to
pirfenidone upon concomitant administration with fluvoxamine,
and/or
[0032] (f) avoid the average 2-fold increase in average peak serum
concentration of pirfenidone (Cmax) upon concomitant administration
with fluvoxamine, and/or
[0033] (g) reduce toxicity of pirfenidone treatment, and/or
[0034] (h) improve safety of pirfenidone treatment, and/or
[0035] (i) reduce adverse drug interaction associated with
pirfenidone treatment.
BRIEF DESCRIPTION OF THE DRAWING
[0036] FIG. 1 depicts a symmetrical dot plot of AUC.sub.0-.infin.
estimates by study day--circles indicate smokers, triangles
indicate nonsmokers.
DETAILED DESCRIPTION OF THE INVENTION
[0037] Pirfenidone is an orally active, anti-fibrotic agent.
Results of in vivo experiments indicated that pirfenidone is
primarily metabolized by CYP1A2 (approx. 48%) with multiple other
CYPs contributing as well (each <13%) (i.e., 1A1, 2A6, 2B6, 2C8,
2C9, 2C18, 2C19, 2D6, 2E1, 2J2, 3A4, 3A5, 4A11, and 4F2). Oral
administration of pirfenidone results in the formation of four
metabolites, 5 hydroxymethyl-pirfenidone, 5 carboxy-pirfenidone,
4'-hydroxy-pirfenidone, and the 5 O-acyl glucuronide metabolite of
5 carboxy-pirfenidone. In humans, only pirfenidone and
5-carboxy-pirfenidone are present in plasma in significant
quantities; none of the other metabolites occur in sufficient
quantities to allow for PK analysis. There are no unique human
metabolites.
[0038] Fluvoxamine is a potent CYP1A2 and CYP2C19 inhibitor, and a
moderate CYP2C9, CYP2D6, and CYP3A4 inhibitor [Hemeryek et al.,
Selective Serotonin Reuptake Inhibitors and Cytochrome P-450
Mediated Drug-Drug Interactions: An Update. Current Drug Metabolism
3(1): 13-37, 2002].
[0039] The invention disclosed herein is based on the discovery of
an adverse drug interaction between pirfenidone and fluvoxamine.
Adverse drug interactions represent 3-5% of preventable in-hospital
adverse drug reactions, and are an important contributor to the
number of emergency room visits and hospital admissions [Leape L L
et al., JAMA 1995; 274(1):35-43; Raschetti R et al. Eur J Clin
Pharmacol 1999; 54(12):959-963].
[0040] Data reported herein show that co-administration of
pirfenidone with fluvoxamine resulted in an average 6-fold increase
in exposure (AUC, or area under the curve) to pirfenidone. It also
resulted in an average 2-fold increase in Cmax, the mean maximum
plasma concentration. Depending on the circumstances, FDA draft
guidance suggests that a drug-drug interaction is present when
comparisons indicate twofold or greater systemic exposure for a
drug when given in combination with the second drug, compared to
when given alone. FDA Preliminary Concept Paper, "Drug Interaction
Studies--Study Design, Data Analysis, and Implications for Dosing
and Labeling," Oct. 1, 2004.
Definitions
[0041] The terms "therapeutically effective amount," as used
herein, refer to an amount of a compound sufficient to treat,
ameliorate, or prevent the identified disease or condition, or to
exhibit a detectable therapeutic, prophylactic, or inhibitory
effect. The effect can be detected by, for example, an improvement
in clinical condition, or reduction in symptoms. The precise
effective amount for a subject will depend upon the subject's body
weight, size, and health; the nature and extent of the condition;
and the therapeutic or combination of therapeutics selected for
administration. Where a drug has been approved by the U.S. Food and
Drug Administration (FDA), a "therapeutically effective amount"
refers to the dosage approved by the FDA or its counterpart foreign
agency for treatment of the identified disease or condition.
[0042] As used herein, a patient "in need of pirfenidone therapy"
is a patient who would benefit from administration of pirfenidone.
The patient may be suffering from any disease or condition for
which pirfenidone therapy may be useful in ameliorating symptoms.
Such diseases or conditions include pulmonary fibrosis, idiopathic
pulmonary fibrosis, idiopathic interstitial pneumonia, autoimmune
lung diseases, benign prostate hypertrophy, coronary or myocardial
infarction, atrial fibrillation, cerebral infarction, myocardiac
fibrosis, musculoskeletal fibrosis, post-surgical adhesions, liver
cirrhosis, renal fibrotic disease, fibrotic vascular disease,
scleroderma, Hermansky-Pudlak syndrome, neurofibromatosis,
Alzheimer's disease, diabetic retinopathy, and/or skin lesions,
lymph node fibrosis associated with HIV, chronic obstructive
pulmonary disease (COPD), inflammatory pulmonary fibrosis,
rheumatoid arthritis; rheumatoid spondylitis; osteoarthritis; gout,
other arthritic conditions; sepsis; septic shock; endotoxic shock;
gram-negative sepsis; toxic shock syndrome; myofacial pain syndrome
(MPS); Shigellosis; asthma; adult respiratory distress syndrome;
inflammatory bowel disease; Crohn's disease; psoriasis; eczema;
ulcerative colitis; glomerular nephritis; scleroderma; chronic
thyroiditis; Grave's disease; Ormond's disease; autoimmune
gastritis; myasthenia gravis; autoimmune hemolytic anemia;
autoimmune neutropenia; thrombocytopenia; pancreatic fibrosis;
chronic active hepatitis including hepatic fibrosis; acute and
chronic renal disease; renal fibrosis; diabetic nephropathy;
irritable bowel syndrome; pyresis; restenosis; cerebral malaria;
stroke and ischemic injury; neural trauma; Alzheimer's disease;
Huntington's disease; Parkinson's disease; acute and chronic pain;
allergies, including allergic rhinitis and allergic conjunctivitis;
cardiac hypertrophy, chronic heart failure; acute coronary
syndrome; cachexia; malaria; leprosy; leishmaniasis; Lyme disease;
Reiter's syndrome; acute synovitis; muscle degeneration, bursitis;
tendonitis; tenosynovitis; herniated, ruptured, or prolapsed
intervertebral disk syndrome; osteopetrosis; thrombosis; silicosis;
pulmonary sarcosis; bone resorption diseases, such as osteoporosis
or multiple myeloma-related bone disorders; cancer, including but
not limited to metastatic breast carcinoma, colorectal carcinoma,
malignant melanoma, gastric cancer, and non-small cell lung cancer;
graft-versus-host reaction; and auto-immune diseases, such as
multiple sclerosis, lupus and fibromyalgia; AIDS and other viral
diseases such as Herpes Zoster, Herpes Simplex I or II, influenza
virus, Severe Acute Respiratory Syndrome (SARS) and
cytomegalovirus; and diabetes mellitus. In addition, the methods of
the embodiments can be used to treat proliferative disorders
(including both benign and malignant hyperplasias), including acute
myelogenous leukemia, chronic myelogenous leukemia, Kaposi's
sarcoma, metastatic melanoma, multiple myeloma, breast cancer,
including metastatic breast carcinoma; colorectal, carcinoma;
malignant melanoma; gastric cancer; non-small cell lung cancer
(NSCLC): bone metastases, and the like; pain disorders including
neuromuscular pain, headache, cancer pain, dental pain, and
arthritis pain; angiogenic disorders including solid tumor
angiogenesis, ocular neovascularization, and infantile hemangioma;
conditions associated with the cyclooxygenase and lipoxygenase
signaling pathways, including conditions associated with
prostaglandin endoperoxide synthase-2 (including edema, fever,
analgesia, and pain); organ hypoxia; thrombin-induced platelet
aggregation; protozoal diseases.
[0043] As used herein, a patient in need of "fluvoxamine therapy"
is understood to be a patient in need of "selective serotonin
reuptake inhibitor (SSRI) therapy." Such patients include patients
suffering from social anxiety disorder (social phobia), obsessive
compulsive disorder (OCD), depression, anxiety disorders, panic
disorder and post-traumatic stress disorder.
[0044] For CYP enzymes, the FDA generally defines a "strong
inhibitor" as one that caused a >5-fold increase in the plasma
AUC values or more than 80% decrease in clearance of CYP substrates
(not limited to sensitive CYP substrate) in clinical evaluations.
The FDA generally defines a "moderate inhibitor" as one that caused
a >2-but <5-fold increase in the AUC values or 50-80%
decrease in clearance of sensitive CYP substrates when the
inhibitor was given at the highest approved dose and the shortest
dosing interval in clinical evaluations.
CYP Inhibitors and Substrates
[0045] In any of the embodiments described herein, including but
not limited to providing pirfenidone for use in treating a patient,
the use of pirfenidone in the manufacture of a medicament for
treating a patient in need of pirfenidone therapy, and treatment
methods involving the advice, warnings, discontinuation or dose
titration downwards, the packages and kits, and/or the methods of
preparing or packaging pirfenidone, the pirfenidone, uses, methods,
packages, kits, advice, warnings, discontinuation or dose titration
may apply not only to fluvoxamine but also to any other drug that
is a moderate to strong inhibitor of both CYP1A2 and another CYP
enzyme selected from the group consisting of CYP3A4, CYP2C9, and/or
CYP2C19 (or a drug that is a strong inhibitor of CYP1A2 that also
has inhibitory effects on other CYP isozymes [2C9, 2C19, and or
3A4]), such as fluvoxamine. The embodiments may also apply to any
other drug that is a moderate to strong inhibitor of both CYP1A2
and another CYP enzyme selected from the group consisting of
CYP3A4, CYP2C9, CYP2C19, CYP2B6, and/or CYP2D6. The embodiments may
also apply to any other drug that is a moderate to strong inhibitor
of both CYP1A2 and another CYP enzyme that metabolizes pirfenidone,
e.g. selected from the group consisting of CYP1A1, CYP2A6, CYP2B6,
CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP2J2 CYP3A4,
CYP3A5, CYP4A11 and/or CYP4F2.
[0046] As yet other alternatives, in any of the embodiments
described herein, including but not limited to the pirfenidone for
use in treating a patient, the use of pirfenidone in the
manufacture of a medicament for treating a patient in need of
pirfenidone therapy, and treatment methods involving the advice,
warnings, discontinuation or dose titration downwards, the packages
and kits, and/or the methods of preparing or packaging pirfenidone,
the pirfenidone, uses, methods, packages, kits, advice, warnings,
discontinuation or dose titration may apply not only to fluvoxamine
but also to any other drug that is a strong inhibitor of CYP1A2 or
a substrate for CYP1A2.
[0047] CYP1A2 metabolizes many commonly used drugs including
theophylline, imipramine, propranolol, and clozapine. These drugs
are commonly referred to as "substrates" for CYP1A2. Additional
CYP1A2 substrates include but are not limited to acetominophen,
amitriptyline, caffeine, chlordiazepoxide, cinacalcet,
clomipramine, clopidogrel, cyclobenzaprine, desipramine, diazepam,
duloxetine, erlotinib, estradiol, flutamide, haloperidol,
levobupivacaine, methadone, mirtazapine, naproxen, nortriptyline,
olanzapine, ondansetron, ramelteon, riluzole, ropinirole,
ropivacaine, tacrine, tizanidine, verapamil, and warfarin.
[0048] Inhibitors of CYP1A2 include fluvoxamine, cimetidine,
amiodarone, echinacea, enoxacin, norfloxacin, oral contraceptives,
tacrine, ticlopidine, and many fluoroquinolone antibiotics.
Moderate inhibitors of CYP1A2 include ciprofloxacin, mexiletine,
propafenone and zileuton. Additional inhibitors of CYP1A2 include
atazanavir, citalopram, clarithromycin, diltiazem, erythromycin,
ethinyl estradiol, isoniazid, ketoconazole, methoxsalen, nalidixic
acid, norethindrone, omeprazole, paroxetine, tipranavir, and
troleandomycin. Other inhibitors of CYP1A2 include acyclovir,
caffeine, famotidine, flutamide, grapefruit juice, lidocaine,
lomefloxacin, moclobemide, ofloxacin, perphenazine, phenacetin,
propafenone, ropinirole, tocainide, and verapamil.
[0049] Inhibitors of CYP3A4 include amiodarone, cimetidine,
ciprofloxacin, delavirdine, fluvoxamine, miconazole, and
voriconazole (VFEND). Strong inhibitors of CYP3A4 include
atazanavir, clathromycin, indinavir, itraconazole, ketoconazole,
nefazodone, nelfinavir, ritonavir, saquinavir and telithromycin.
Moderate inhibitors of CYP3A4 include amprenavir, aprepitant,
diltiazem, erythromycin, fluconazole, fosamprenavir, grapefruit
juice and verapamil. Additional inhibitors of CYP3A4 include
acitretin, cyclosporine, danazol, diethyldithiocarbamate,
efavirenz, ethinyl estradiol, fluoxetine, gestodene, imatinib,
isoniazid, metronidazole, methylprednisolone, mifepristone,
nicardipine, nifedipine, norethindrone, norfloxacin, norfluoxetine,
oxiconazole, pomegranate, prednisone, quinine, ranolazine,
roxithromycin, sertraline, Synercid, troleandomycin, zafirlukast,
and zileuton. Other inhibitors of CYP3A4 include doxycycline,
echinacea, and enoxacin.
[0050] Inhibitors of CYP2C9 include cimetidine, delavirdine,
efavirenz, fenofibrate (Tricor), fluoxetine, fluvastatin,
fluvoxamine, isoniazid, ketoconazole, leflunomide, modafinil,
sertraline, voriconazole (VFEND), and zafirlukast (Accolate).
Moderate inhibitors of CYP2C9 include amiodarone, fluconazole and
oxandrolone. Additional CYP2C9 inhibitors include atazanavir,
chloramphenicol, clopidogrel, cotrimoxazole, cranberry, disulfiram,
fluorouracil, gemfibrozil, ginkgo, imatinib, itraconazole,
lovastatin, metronidazole, omeprazole, paroxetine, sulfonamides,
triclopidine, and tipranavir. Other inhibitors of CYP2C9 include
anastrazole, phenylbutazone, sulfamethoxazole, sulfaphenazole,
tamoxifen, teniposide, valproic acid, and 5-fluorouracil.
[0051] Inhibitors of CYP2D6 include amiodarone, bupropion,
celecoxib, chlorpheniramine, cimetidine, cinacalcet, citalopram,
clomipramine, desipramine, diphenhydramine, halofantrine,
haloperidol, methadone, moclobemide, propafenone, ritonavir,
sertraline, and thioridazine. Strong CYP2D6 inhibitors include
fluoxetine, paroxetine and quinidine, while moderate CYP2D6
inhibitors include duloxetine and terbinafine. Additional
inhibitors of CYP2D6 include chloroquine, cocaine, darifenacin,
escitalopram, fluphenazine, hydroxychloroquine, imatinib,
levomepromazine, norfluoxetine, perphenazine, pomegranate,
propoxyphene, propranolol, quinacrine, ranitidine, ranolazine, and
tipranavir. Other inhibitors of CYP2D6 include amitriptyline,
chlorpromazine, doxepin, fluvoxamine, goldenseal, hydroxyzine,
imipramine, metoclopramide, pimozide, and ticlopidine (Ticlid).
[0052] Inhibitors of CYP2C19 include delavirdine, efavirenz,
esomeprazole, felbamate, fluconazole, fluoxetine, fluvoxamine,
indomethacin, isoniazid (INH), modafinil (Provigil), oxcarbazepine,
ticlopidine, topiramate, and voriconazole (VFEND) A strong
inhibitor of CYP2C19 is omeprazole. Additional inhibitors of
CYP2C19 include citalopram, fluvastatin, ketoconazole,
lansoprazole, letrozole, paroxetine, sertraline, telmisartan, and
tipranavir. Other inhibitors of CYP2C19 include artemisinin,
chloramphenicol, and oral contraceptives.
[0053] Inhibitors of CYP2B6 include clopidogrel (Plavix),
efavirenz, fluoxetine, fluvoxamine, ketoconazole, memantine,
nelfinavir, oral contraceptives, paroxetine, ritonavir, thiotepa,
and ticlopidine (Ticlid).
Avoiding or Discontinuing Administration of a Drug to Avoid Adverse
Drug Interactions with Pirfenidone
[0054] As used herein, the term "avoid" and forms thereof are
contemplated to have as alternatives the terms abstain, desist,
forbear, and refrain, and forms thereof. In some cases, the
alternative terms will be equivalent. For example, "avoiding" means
"refraining from." Merriam-Webster Online Dictionary, 11.sup.th
ed., 24 Nov. 2009. As used herein, the term "discontinue" and forms
thereof are contemplated to have as alternatives the terms cease,
stop, suspend, and quit. In the methods described herein, the
avoiding and/or discontinuing steps can be performed in
anticipation of pirfenidone therapy. For example, impending or
imminent pirfenidone administration can be the proximate cause of
the avoiding and/or discontinuing steps. As another example,
concurrent pirfenidone administration can be the proximate cause of
discontinuing and/or further avoiding steps.
[0055] In some aspects, the invention provides a method of
administering pirfenidone therapy to a patient in need of
pirfenidone therapy (e.g., a patient with IPF), involving
administering to the patient a therapeutically effective amount of
pirfenidone, and avoiding or contraindicating administration of a
CYP1A2 inhibitor. In some embodiments, the CYP1A2 inhibitor is a
strong CYP1A2 inhibitor. In some embodiments, the CYP1A2 inhibitor
is a moderate to strong CYP1A2 inhibitor. In some embodiments, the
CYP1A2 inhibitor is a drug that is a moderate-strong inhibitor of
both CYP1 A2 and another CYP enzyme selected from the group
consisting of CYP2C9, CYP2C19 and/or CYP3A4 (or a drug that is a
strong inhibitor of CYP1A2 that also has inhibitory effects on
other CYP isozymes [2C9, 2C19, and/or 3A4]), or a drug that is a
moderate to strong inhibitor of both CYP1A2 and another CYP enzyme
selected from the group consisting of CYP3A4, CYP2C9, CYP2C19,
CYP2B6, and/or CYP2D6. In some embodiments, the drug is
fluvoxamine.
[0056] In some aspects, the invention provides a method of
administering pirfenidone therapy to a patient in need of
pirfenidone therapy (e.g., a patient with IPF), involving
administering to the patient a therapeutically effective amount of
pirfenidone, and avoiding or contraindicating administration of a
moderate-strong inhibitor of both CYP1A2 and another CYP enzyme
selected from the group consisting of CYP1A1, CYP2A6, CYP2B6,
CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP2J2 CYP3A4,
CYP3A5, CYP4A11 and/or CYP4F2.
[0057] In some aspects, the invention provides a method of
administering pirfenidone therapy to a patient in need of
pirfenidone therapy (e.g., a patient with IPF), involving
administering to the patient a therapeutically effective amount of
pirfenidone, and avoiding or contraindicating administration of a
strong CYP1A2 inhibitor.
[0058] In some aspects, the invention provides a method of
administering pirfenidone therapy to a patient in need of
pirfenidone therapy (e.g., a patient with IPF), involving
administering to the patient a therapeutically effective amount of
pirfenidone, and avoiding or contraindicating administration of a
CYP1A2 substrate.
[0059] In other aspects, the invention provides a method of
administering pirfenidone therapy to a patient in need of
pirfenidone therapy, comprising discontinuing administration of a
drug that is a moderate-strong inhibitor of both CYP1A2 and another
CYP enzyme selected from the group consisting of CYP2C9, CYP2C19
and/or CYP3A4 (or a drug that is a strong inhibitor of CYP1A2 that
also has inhibitory effects on other CYP isozymes [2C9, 2C19,
and/or 3A4]) to avoid an adverse drug interaction, and
administering a therapeutically effective amount of pirfenidone. In
some embodiments, the drug being discontinued is a drug that is a
moderate to strong inhibitor of both CYP1A2 and another CYP enzyme
selected from the group consisting of CYP3A4, CYP2C9, CYP2C19,
CYP2B6, and/or CYP2D6. In some embodiments, the drug is
fluvoxamine.
[0060] In some aspects, the invention provides a method of
administering pirfenidone therapy to a patient in need of
pirfenidone therapy, comprising discontinuing administration of a
drug that is a moderate-strong inhibitor of both CYP1A2 and another
CYP enzyme selected from the group consisting of CYP1A1, CYP2A6,
CYP2B6, CYP2C8, CYP2C9, CYP2C8, CYP2C9, CYP2D6, CYP2E1, CYP2J2
CYP3A4, CYP3A5, CYP4A11 and/or CYP4F2 to avoid an adverse drug
interaction, and administering a therapeutically effective amount
of pirfenidone.
[0061] In other aspects, the invention provides a method of
administering pirfenidone therapy to a patient in need of
pirfenidone therapy, comprising discontinuing administration of a
drug that is a strong CYP1A2 inhibitor to avoid an adverse drug
interaction, and administering a therapeutically effective amount
of pirfenidone. In other aspects, the invention provides a method
of administering pirfenidone therapy to a patient in need of
pirfenidone therapy, comprising discontinuing administration of a
drug that is a CYP1A2 inhibitor, e.g. a moderate to strong CYP1A2
inhibitor.
[0062] In one example, in a method of administering a
therapeutically effective amount of pirfenidone to a patient with
IPF, the invention provides an improvement that comprises avoiding,
contraindicating or discontinuing administration of the drug that
is a CYP inhibitor and administering a therapeutically effective
amount of pirfenidone.
[0063] In some embodiments, the drug that is a CYP inhibitor is
discontinued concurrent with starting administration of
pirfenidone. In other embodiments, the drug that is a CYP inhibitor
is discontinued within at least 3 days to 1 month prior to or after
starting pirfenidone therapy. This time period, for example,
permits adequate time for tapering and withdrawal without adverse
effects.
[0064] Thus, an aspect of the invention provides pirfenidone for
use in treating a patient in need of pirfenidone therapy,
characterized in that the treating comprises avoiding,
contraindicating or discontinuing concomitant use (or
co-administration) of a strong CYP1A2 inhibitor; or a moderate to
strong CYP1A2 inhibitor; or a drug that is a moderate-strong
inhibitor of both CYP1A2 and another CYP enzyme selected from the
group consisting of CYP2C9, CYP2C19 and/or CYP3A4; or a drug that
is a strong inhibitor of CYP1A2 that also has inhibitory effects on
other CYP isozymes [2C9, 2C19, and/or 3A4]; or a drug that is a
moderate-strong inhibitor of both CYP1A2 and another CYP enzyme
selected from the group consisting of CYP1A1, CYP2A6, CYP2B6,
CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP2J2 CYP3A4,
CYP3A5, CYP4A11 and/or CYP4F2; or fluvoxamine (collectively
referred to as "CYP1A2 inhibitors"). In some embodiments, the
concomitant use of the CYP1A2 inhibitor is avoided, contraindicated
or discontinued, in order to avoid reduced clearance of
pirfenidone, or the potential for reduced clearance of pirfenidone.
In some embodiments, the concomitant use of the CYP1A2 inhibitor is
avoided, contraindicated or discontinued, in order to avoid
increased exposure to pirfenidone, or the potential for increased
exposure to pirfenidone. Administration of pirfenidone in patients
that concomitantly use or are being administered fluvoxamine
results in about a 6-fold increase in pirfenidone exposure. It is
understood that any of the aspects or embodiments or examples
described herein with respect to methods of treatment apply to this
aspect of the invention that provides pirfenidone for use in
treating a patient. For example, the patient may be a patient with
IPF, and the therapeutically effective amount administered may be
2400 or 2403 mg per day.
[0065] Similarly, a further aspect of the invention provides the
use of pirfenidone in the manufacture of a medicament for treating
a patient in need of pirfenidone therapy, characterized in that the
treating comprises avoiding, contraindicating or discontinuing
concomitant use (or co-administration) of a CYP1A2 inhibitor. It is
understood that any of the aspects or embodiments or examples
described herein with respect to methods of treatment or
"pirfenidone for use" in treating a patient apply to this aspect of
the invention that provides for the use of pirfenidone in
manufacture of a medicament. For example, the patient may be a
patient with IPF, and the therapeutically effective amount
administered may be 2400 or 2403 mg per day.
[0066] In some embodiments, the patient is a patient in need of
therapy with a CYP1A2 inhibitor. In some embodiments, the patient
is a patient in need of therapy with a strong CYP1A2 inhibitor. In
some embodiments, the patient is a patient in need of therapy with
a moderate to strong CYP1A2 inhibitor. In some embodiments, the
patient is a patient in need of therapy with a drug that is a
moderate-strong inhibitor of both CYP1A2 and another CYP enzyme
selected from the group consisting of CYP2C9, CYP2C19 and/or
CYP3A4; or a drug that is a strong inhibitor of CYP1A2 that also
has inhibitory effects on other CYP isozymes [2C9, 2C19, and/or
3A4]. In some embodiments, the patient is a patient in need of
fluvoxamine therapy. In some embodiments, the patient is a patient
who is avoiding concomitant use of the CYP1A2 inhibitor, e.g.
because concomitant use of pirfenidone with the CYP1A2 inhibitor is
contraindicated or to be used with caution. In some embodiments,
the patient is a patient who was or is being administered the
CYP1A2 inhibitor. In some embodiments, the patient is a patient who
is discontinuing use of the CYP1A2 inhibitor prior to the
initiation of pirfenidone therapy in order to avoid reduced
clearance (or increased exposure to) pirfenidone, or the potential
for reduced clearance of (or increased exposure to) pirfenidone. In
some embodiments, the patient is a patient who is discontinuing
administration of the the CYP1A2 inhibitor, within 1 month, or
within 2 weeks, prior to starting pirfenidone therapy, or
concurrent with starting pirfenidone therapy. It is understood that
any of the aspects or embodiments or examples described herein with
respect to methods of treatment apply to this aspect of the
invention that provides for characterization of the patients to be
treated with pirfenidone.
[0067] In some embodiments, the concomitant use of the CYP1A2
inhibitor is avoided, contraindicated or discontinued in order
to:
[0068] (a) avoid altering the therapeutic effect profile of
pirfenidone, and/or
[0069] (b) avoid altering the adverse reaction profile of
pirfenidone, and/or
[0070] (c) avoid the increased exposure or potential for increased
exposure, and/or
[0071] (d) avoid the reduced clearance or potential for reduced
clearance, and/or
[0072] (e) avoid the average 6-fold increase in exposure to
pirfenidone upon concomitant administration with fluvoxamine,
and/or
[0073] (f) avoid the average 2-fold increase in average peak serum
concentration of pirfenidone (Cmax) upon concomitant administration
with fluvoxamine, and/or
[0074] (g) reduce toxicity of pirfenidone treatment, and/or
[0075] (h) improve safety of pirfenidone treatment, and/or
[0076] (i) reduce adverse drug interaction associated with
pirfenidone treatment.
[0077] In some embodiments in which fluvoxamine is discontinued to
avoid an adverse drug interaction, fluvoxamine is discontinued
within at least 3 days prior to or after starting pirfenidone
therapy. In various embodiments, fluvoxamine is discontinued within
at least 4 days, or at least 5 days, or at least 6 days, or at
least 7 days (or one week), or at least 8 days, or at least 9 days,
or at least 10 days, or at least 11 days, or at least 12 days, or
at least 13 days, or at least 14 days (or two weeks), or at least
15 days, or at least 16 days, or at least 17 days, or at least 18
days, or at least 19 days, or at least 20 days, or at least 21 days
(or three weeks), or at least 22 days, or at least 23 days, or at
least 24 days, or at least 25 days, or at least 26 days, or at
least 27 days, or at least 28 days (or four weeks), or at least 29
days, or at least 30 days, or at least one month, prior to or after
starting pirfenidone therapy. In some embodiments, the fluvoxamine
is discontinued no earlier than one month, 3 weeks, 2 weeks or 1
week before starting pirfenidone therapy. Preferably, sufficient
time is allowed for tapering and/or withdrawal of fluvoxamine
therapy.
[0078] In some embodiments in which the drug being discontinued is
a CYP inhibitor, the drug is discontinued within at least 3 days
prior to or after starting pirfenidone therapy. In various
embodiments, the drug that is a CYP inhibitor is discontinued
within at least 4 days, or at least 5 days, or at least 6 days, or
at least 7 days (or one week), or at least 8 days, or at least 9
days, or at least 0 days, or at least 11 days, or at least 12 days,
or at least 13 days, or at least 14 days (or two weeks), or at
least 15 days, or at least 16 days, or at least 17 days, or at
least 18 days, or at least 19 days, or at least 20 days, or at
least 21 days (or three weeks), or at least 22 days, or at least 23
days, or at least 24 days, or at least 25 days, or at least 26
days, or at least 27 days, or at least 28 days (or four weeks), or
at least 29 days, or at least 30 days, or at least one month, prior
to or after starting pirfenidone therapy. In some embodiments, the
drug that is a CYP inhibitor is discontinued no earlier than one
month, 3 weeks, 2 weeks or 1 week before starting pirfenidone
therapy. Preferably, sufficient time is allowed for tapering and/or
withdrawal of the drug upon discontinuation.
[0079] In some aspects, the invention provides a method of
administering pirfenidone therapy to a patient in need of
pirfenidone therapy, comprising discontinuing administration of the
CYP1A2 substrate to avoid an adverse drug interaction and
administering a therapeutically effective amount of pirfenidone. In
some embodiments, the drug that is a CYP1A2 substrate is
discontinued concurrent with starting administration of
pirfenidone. In other embodiments, the drug that is a CYP1A2
substrate is discontinued within at least 3 days to 1 month prior
to or after starting pirfenidone therapy. This time period, for
example, permits adequate time for tapering and withdrawal without
adverse effects.
[0080] In some embodiments in which a CYP1A2 substrate is
discontinued to avoid an adverse drug interaction, the CYP1A2
substrate is discontinued within at least 3 days prior to or after
starting pirfenidone therapy. In various embodiments, the CYP1A2
substrate is discontinued within at least 4 days, or at least 5
days, or at least 6 days, or at least 7 days (or one week), or at
least 8 days, or at least 9 days, or at least 10 days, or at least
11 days, or at least 12 days, or at least 13 days, or at least 14
days (or two weeks), or at least 15 days, or at least 16 days, or
at least 17 days, or at least 18 days, or at least 19 days, or at
least 20 days, or at least 21 days (or three weeks), or at least 22
days, or at least 23 days, or at least 24 days, or at least 25
days, or at least 26 days, or at least 27 days, or at least 28 days
(or four weeks), or at least 29 days, or at least 30 days, or at
least one month, prior to or after starting pirfenidone therapy. In
some embodiments, the CYP1A2 substrate is discontinued no earlier
than one month, 3 weeks, 2 weeks or 1 week before starting
pirfenidone therapy. Preferably, sufficient time is allowed for
tapering and/or withdrawal of the CYP1A2 substrate therapy.
Selecting an Alternative Drug to Administer Concurrently with
Pirfenidone Therapy
[0081] In some aspects, the invention provides a method of
administering pirfenidone therapy to a patient in need of
pirfenidone therapy and in need of therapy with a drug that is a
moderate-strong inhibitor of both CYP1A2 and another CYP enzyme
selected from the group consisting of CYP1A1, CYP2A6, CYP2B6,
CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP2J2 CYP3A4,
CYP3A5, CYP4A11 and/or CYP4F2, comprising administering a
therapeutically effective amount of pirfenidone to the patient, and
administering an alternative therapy that is not a moderate strong
inhibitor of both CYP1 A2 and another CYP enzyme selected from the
group consisting of CYP1A1, CYP2A6, CYP2B6, CYP2C8, CYP2C9,
CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP2J2 CYP3A4, CYP3A5, CYP4A11
and/or CYP4F2.
[0082] In another embodiment, the invention provides a method of
administering pirfenidone therapy to a patient in need of
pirfenidone therapy and in need of therapy with a drug that is a
moderate-strong inhibitor of both CYP1A2 and another CYP enzyme
selected from the group consisting of CYP2C9, CYP2C19, CYP3A4,
CYP2B6 and/or CYP2D6, comprising administering a therapeutically
effective amount of pirfenidone to the patient, and administering
an alternative therapy that is not a moderate-strong inhibitor of
both CYP1A2 and another CYP enzyme selected from the group
consisting of CYP2C9, CYP2C19, CYP3A4, CYP2B6 and/or CYP2D6.
[0083] In some embodiments, the invention provides a method of
administering pirfenidone therapy to a patient in need of
pirfenidone therapy and in need of therapy with a drug that is a
moderate-strong inhibitor of both CYP1A2 and another CYP enzyme
selected from the group consisting of CYP2C9, CYP2C19, and/or
CYP3A4, comprising administering a therapeutically effective amount
of pirfenidone to the patient, and administering an alternative
therapy that is not a moderate-strong inhibitor of both CYP1A2 and
another CYP enzyme selected from the group consisting of CYP2C9,
CYP2C19, and/or CYP3A4.
[0084] In other aspects, the invention provides a method of
administering pirfenidone therapy to a patient in need of
pirfenidone therapy and in need of therapy with a drug that is a
strong CYP1A2 inhibitor, comprising administering a therapeutically
effective amount of pirfenidone to the patient, and administering
an alternative therapy that is not a strong CYP1A2 inhibitor.
[0085] In yet other aspects, the invention provides a method of
administering pirfenidone therapy to a patient in need of
pirfenidone therapy and in need of therapy with a drug that is a
CYP1A2 substrate, comprising administering a therapeutically
effective amount of pirfenidone to the patient, and administering
an alternative therapy that is not a CYP1A2 substrate.
Improving Administration of Pirfenidone by Advising or Cautioning
Patient
[0086] The administration of a therapeutically effective amount of
pirfenidone to a patient in need of pirfenidone therapy can be
improved. In some embodiments, the patient is advised that
co-administration of pirfenidone with drugs that are a
moderate-strong inhibitor of both CYP1A2 and another CYP enzyme
selected from the group consisting of CYP2C9, CYP2C19 and/or CYP3A4
can alter the therapeutic effect or adverse reaction profile of
pirfenidone. In some embodiments, the patient is advised that
co-administration of pirfenidone with fluvoxamine can alter the
therapeutic effect or adverse reaction profile of pirfenidone. In
some embodiments, the patient is advised that co-administration of
pirfenidone with drugs that are a moderate-strong inhibitor of both
CYP1A2 and another CYP enzyme selected from the group consisting of
CYP1A1, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6,
CYP2E1, CYP2J2 CYP3A4, CYP3A5, CYP4A11 and/or CYP4F2, can alter the
therapeutic effect or adverse reaction profile of pirfenidone. In
some embodiments, the patient is advised that co-administration of
pirfenidone with a drug that is a strong CYP1A2 inhibitor can alter
the therapeutic effect or adverse reaction profile of pirfenidone.
In some embodiments, the patient is advised that co-administration
of pirfenidone with a drug that is a CYP1A2 substrate can alter the
therapeutic effect or adverse reaction profile of pirfenidone.
[0087] In some embodiments, the patient is advised that use of
pirfenidone in patients being treated with fluvoxamine is
contraindicated. In some embodiments, the patient is advised that
co-administration of pirfenidone and fluvoxamine resulted in a
6-fold increase in exposure to pirfenidone.
[0088] In some embodiments, the patient is advised that use of
pirfenidone in patients being treated with a drug that is a
moderate-strong inhibitor of both CYP1A2 and another CYP enzyme
selected from the group consisting of CYP2C9, CYP2C19 and/or CYP3A4
is contraindicated. In some embodiments, the patient is advised
that pirfenidone should be used with caution in patients taking a
drug that is a moderate-strong inhibitor of both CYP1A2 and another
CYP enzyme selected from the group consisting of CYP2C9, CYP2C19
and/or CYP3A4.
[0089] In some embodiments, the patient is advised that use of
pirfenidone in patients being treated with a drug that is a
moderate-strong inhibitor of both CYP1A2 and another CYP enzyme
selected from the group consisting of CYP2C9, CYP2C19, CYP3A4,
CYP2B6 and/or CYP2D6 is contraindicated. In some embodiments, the
patient is advised that pirfenidone should be used with caution in
patients taking a drug that is a moderate-strong inhibitor of both
CYP1A2 and another CYP enzyme selected from the group consisting of
CYP2C9, CYP2C19, CYP3A4, CYP2B6 and/or CYP2D6.
Dosing and Dose Modifications
[0090] In various embodiments, a method of administering
pirfenidone and fluvoxamine concurrently is provided wherein the
patient is administered a therapeutically effective amount of
fluvoxamine and a dosage of pirfenidone that is decreased relative
to a patient not taking fluvoxamine. In some aspects, such a
decreased dosage of pirfenidone is less than 2400 mg/day. For
example, the decreased dosage is about 2136 mg per day, 1869 mg per
day, 1602 mg per day, 1335 mg per day, or 1068 mg per day (e.g., 8,
7, 6, 5, 4, or 3 capsules per day where each capsule is
approximately 267 mg). In some embodiments, the patient is already
being administered fluvoxamine. In other embodiments, the patient
is already being administered pirfenidone. In related embodiments,
the dosage of pirfenidone is decreased prior to administration of
fluvoxamine.
[0091] In other aspects, a method of administering pirfenidone and
a drug that is a moderate-strong inhibitor of both CYP1A2 and
another CYP enzyme selected from the group consisting of CYP1A1,
CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1,
CYP2J2 CYP3A4, CYP3A5, CYP4A11 and/or CYP4F2 concurrently is
provided wherein the patient is administered a therapeutically
effective amount of the drug that is a CYP inhibitor and a dosage
of pirfenidone that is decreased relative to a patient not taking
such drug that is a CYP inhibitor. In some aspects, such a
decreased dosage of pirfenidone is less than 2400 mg/day. For
example, the decreased dosage is about 2136 mg per day, 1869 mg per
day, 1602 mg per day, 1335 mg per day, or 1068 mg per day (e.g., 8,
7, 6, 5, 4, or 3 capsules per day where each capsule is
approximately 267 mg). In some embodiments, the patient is already
being administered the drug that is a CYP inhibitor. In other
embodiments, the patient is already being administered pirfenidone.
In related embodiments, the dosage of pirfenidone is decreased
prior to administration of the drug that is a CYP inhibitor.
[0092] In other aspects, a method of administering pirfenidone and
a drug that is a moderate-strong inhibitor of both CYP1A2 and
another CYP enzyme selected from the group consisting of CYP2C9,
CYP2C19 and/or CYP3A4 concurrently is provided, wherein the patient
is administered a therapeutically effective amount of the drug that
is a CYP inhibitor and a dosage of pirfenidone that is decreased
relative to a patient not taking such drug that is a CYP inhibitor.
In related aspects, a method of administering pirfenidone and a
drug that is a moderate-strong inhibitor of both CYP1A2 and another
CYP enzyme selected from the group consisting of CYP2C9, CYP2C19,
CYP3A4, CYP2B, and/or CYP2D6 concurrently is provided, wherein the
patient is administered a therapeutically effective amount of the
drug that is a CYP inhibitor and a dosage of pirfenidone that is
decreased relative to a patient not taking such drug that is a CYP
inhibitor. In some aspects, such a decreased dosage of pirfenidone
is less than 2400 mg/day. For example, the decreased dosage is
about 2136 mg per day, 1869 mg per day, 1602 mg per day, 1335 mg
per day, or 1068 mg per day (e.g., 8, 7, 6, 5, 4, or 3 capsules per
day where each capsule is approximately 267 mg). In some
embodiments, the patient is already being administered the drug
that is a CYP inhibitor. In other embodiments, the patient is
already being administered pirfenidone. In related embodiments, the
dosage of pirfenidone is decreased prior to administration of the
drug that is a CYP inhibitor.
[0093] In yet other aspects, a method of administering pirfenidone
and a strong CYP1A2 inhibitor concurrently is provided wherein the
patient is administered a therapeutically effective amount of the
strong CYP1A2 inhibitor and a dosage of pirfenidone that is
decreased relative to a patient not taking the strong CYP1A2
inhibitor. In some aspects, such a decreased dosage of pirfenidone
is less than 2400 mg/day. For example, the decreased dosage is
about 2136 mg per day, 1869 mg per day, 1602 mg per day, 1335 mg
per day, or 1068 mg per day (e.g., 8, 7, 6, 5, 4, or 3 capsules per
day where each capsule is approximately 267 mg). In some
embodiments, the patient is already being administered the strong
CYP1A2 inhibitor. In other embodiments, the patient is already
being administered pirfenidone. In related embodiments, the dosage
of pirfenidone is decreased prior to administration of the strong
CYP1A2 inhibitor.
[0094] In various embodiments, a method of administering
pirfenidone and a CYP1A2 substrate concurrently is provided wherein
the patient is administered a therapeutically effective amount of
the CYP1A2 substrate and a dosage of pirfenidone that is decreased
relative to a patient not taking the CYP1A2 substrate. In some
aspects, such a decreased dosage of pirfenidone is less than 2400
mg/day. For example, the decreased dosage is about 2136 mg per day,
1869 mg per day, 1602 mg per day, 1335 mg per day, or 1068 mg per
day (e.g., 8, 7, 6, 5, 4, or 3 capsules per day where each capsule
is approximately 267 mg). In some embodiments, the patient is
already being administered the CYP1A2 substrate. In other
embodiments, the patient is already being administered pirfenidone.
In related embodiments, the dosage of pirfenidone is decreased
prior to administration of the CYP1A2 substrate.
[0095] In some embodiments, the amount of pirfenidone being
administered is 2400 or 2403 mg/day. Pirfenidone can be dosed at a
total amount of about 50 to about 2400 mg per day. The dosage can
be divided into two or three doses over the day or given in a
single daily dose. Specific amounts of the total daily amount of
the therapeutic contemplated for the disclosed methods include
about 50 mg, about 100 mg, about 15t mg, about 200 mg, about 250
mg, about 267 mg, about 300 mg, about 350 mg, about 400 mg, about
450 mg, about 500 mg, about 534 mg, about 550 mg, about 600 mg,
about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850
mg, about 900 mg, about 950 mg, about 1000 mg, about 1050 mg, about
1068 mg, about 1100 mg, about 1150 mg, about 1200 mg, about 1250
mg, about 1300 mg, about 1335 mg, about 1350 mg, about 1400 mg,
about 1450 mg, about 1500 mg, about 1550 mg, about 1600 mg, about
1650 mg, about 1700 mg, about 1750 mg, about 1800 mg, about 1850
mg, about 1869 mg, about 1900 mg, about 1950 mg, about 2000 mg,
about 2050 mg, about 2100 mg, about 2136 mg, about 2150 mg, about
2200 mg, about 2250 mg, about 2300 mg, about 2350 mg, and about
2400 mg.
[0096] Dosages of pirfenidone can alternately be administered as a
dose measured in mg/kg. Contemplated mg/kg doses of the disclosed
therapeutics include about 1 mg/kg to about 40 mg/kg. Specific
ranges of doses in mg/kg include about 1 mg/kg to about 20 mg/kg,
about 5 mg/kg to about 20 mg/kg, about 10 mg/kg to about 20 mg/kg,
about 10 mg/kg to about 30 mg/kg, and about 15 mg/kg to about 25
mg/kg.
[0097] In one embodiment, a dosage amount of pirfenidone is taken
with food. In another embodiment, the patient is instructed to
administer the dosage of pirfenidone with food.
[0098] In some embodiments, a method of administering a SSRI to a
patient in need thereof is provided, the improvement comprising
discontinuing administration of fluvoxamine, for example,
concurrent with starting administration of pirfenidone, and
optionally administering an SSRI that is not a moderate to strong
inhibitor of both CYP1A2, and a CYP enzyme selected from the group
consisting of CYP2C9, CYP2C19 and/or CYP3A4.
[0099] In some embodiments, a method of optimizing pirfenidone
therapy is provided comprising titrating the dosage of pirfenidone
administered to a patient downward relative to a previously
administered dosage in the patient, wherein co-administration of
fluvoxamine to the patient does not result in an increased exposure
to pirfenidone. In some embodiments, the dose is reduced by about
100 mg/day. In other embodiments, the dose is reduced by about 150
mg/day, or about 200 mg/day, or about 250 mg/day, or about 267
mg/day, or about 300 mg day, or about 350 mg/day, or about 400
mg/day, or about 450 mg/day, or about 500 mg day, or about 550
mg/day, or about 600 mg/day, or about 650 mg/day, or about 700 ng
day, or about 750 mg/day, or about 800 mg/day (to a total daily
dose of about 1600 mg day or 1602 mg/day), or about 850 mg/day, or
about 900 mg day, or about 950 mg/day, or about 1000 mg/day, or
about 1050 mg/day, or about 1100 mg day, or about 1150 mg/day, or
about 1200 mg/day, or about 1250 mg/day, or about 1300 mg/day, or
about 1350 mg/day, or about 1400 mg/day, or about 1450 mg/day, or
about 1500 mg/day, or about 1600 mg/day (to a total daily dose of
about 800 mg/day or 801 mg/day) or more.
[0100] In some embodiments, a method of optimizing pirfenidone
therapy is provided comprising titrating the dosage of pirfenidone
administered to a patient downward relative to a previously
administered dosage in the patient, wherein co-administration of a
drug that is a moderate-strong inhibitor of both CYP1A2 and another
CYP enzyme selected from the group consisting of CYP1A1, CYP2A6,
CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP2J2
CYP3A4, CYP3A5, CYP4A11 and/or CYP4F2 to the patient does not
result in an increased exposure to pirfenidone. In some
embodiments, the dose is reduced by about 100 mg/day. In other
embodiments, the dose is reduced by about 150 mg/day, or about 200
mg/day, or about 250 mg/day, or about 267 mg/day, or about 300
mg/day, or about 350 mg/day, or about 400 mg/day, or about 450
mg/day, or about 500 mg/day, or about 550 mg/day, or about 600
mg/day, or about 650 mg/day, or about 700 mg/day, or about 750
mg/day, or about 800 mg/day (to a total daily dose of about 1600
mg/day or 1602 mg/day, or about 850 mg/day, or about 900 mg/day, or
about 950 mg/day, or about 1000 mg/day, or about 1050 mg/day, or
about 1100 mg/day, or about 1150 mg/day, or about 1200 mg/day, or
about 1250 mg/day, or about 1300 mg/day, or about 1350 mg/day, or
about 1400 mg/day, or about 1450 mg/day, or about 1500 mg/day, or
about 1600 mg/day (to a total daily dose of about 800 mg/day or 801
mg/day) or more.
[0101] In some embodiments, a method of optimizing pirfenidone
therapy is provided comprising titrating the dosage of pirfenidone
administered to a patient downward relative to a previously
administered dosage in the patient, wherein co-administration of a
drug that is a moderate-strong inhibitor of both CYP1A2 and another
CYP enzyme selected from the group consisting of CYP2C9, CYP2C19
and/or CYP3A4 to the patient does not result in an increased
exposure to pirfenidone. In some embodiments, a method of
optimizing pirfenidone therapy is provided comprising titrating the
dosage of pirfenidone administered to a patient downward relative
to a previously administered dosage in the patient, wherein
co-administration of a drug that is a moderate-strong inhibitor of
both CYP1A2 and another CYP enzyme selected from the group
consisting of CYP2C9, CYP2C19, CYP3A4, CYP2B6 and, or CYP2D6 to the
patient does not result in an increased exposure to pirfenidone. In
some embodiments, the dose is reduced by about 100 mg/day. In other
embodiments, the dose is reduced by about 150 mg; day, or about 200
mg/day, or about 250 mg/day, or about 267 mg/day, or about 300
mg/day, or about 350 mg/day, or about 400 mg/day, or about 450
mg/day, or about 500 mg/day, or about 550 mg/day, or about 600
mg/day, or about 650 mg/day, or about 700 mg/day, or about 750
mg/day, or about 800 mg/day (to a total daily dose of about 1600
mg/day or 1602 mg/day), or about 850 mg/day, or about 900 mg/day,
or about 950 mg/day, or about 1000 mg/day, or about 1050 mg/day, or
about 1100 mg/day, or about 1150 mg/day, or about 1200 mg/day, or
about 1250 mg/day, or about 1300 mg/day, or about 1350 mg/day, or
about 1400 mg/day, or about 1450 mg/day, or about 1500 mg/day, or
about 1600 mg/day (to a total daily dose of about 800 mg/day or 801
mg/day) or more.
[0102] In some embodiments, a method of optimizing pirfenidone
therapy is provided comprising titrating the dosage of pirfenidone
administered to a patient downward relative to a previously
administered dosage in the patient, wherein co-administration of a
strong CYP1 A2 inhibitor to the patient does not result in an
increased exposure to pirfenidone. In some embodiments, the dose is
reduced by about 100 mg/day. In other embodiments, the dose is
reduced by about 150 mg/day, or about 200 mg/day, or about 250
mg/day, or about 267 mg/day, or about 300 mg/day, or about 350
mg/day, or about 400 mg/day, or about 450 mg/day, or about 500
mg/day, or about 550 mg/day, or about 600 mg/day, or about 650
mg/day, or about 700 mg/day, or about 750 mg/day, or about 800
mg/day (to a total daily dose of about 1600 mg/day or 1602 mg/day),
or about 850 mg/day, or about 900 mg/day, or about 950 mg/day, or
about 1000 mg/day, or about 1050 mg/day, or about 1100 mg/day, or
about 1150 mg/day, or about 1200 mg/day, or about 1250 mg/day, or
about 1300 mg/day, or about 1350 mg/day, or about 1400 mg/day, or
about 1450 mg/day, or about 1500 mg/day, or about 1600 mg/day (to a
total daily dose of about 800 mg/day or 801 mg/day) or more.
[0103] In some embodiments, a method of optimizing pirfenidone
therapy is provided comprising titrating the dosage of pirfenidone
administered to a patient downward relative to a previously
administered dosage in the patient, wherein co-administration of a
CYP1A2 substrate to the patient does not result in an increased
exposure to pirfenidone. In some embodiments, the dose is reduced
by about 100 mg/day. In other embodiments, the dose is reduced by
about 150 mg/day, or about 200 mg/day, or about 250 mg/day, or
about 267 mg/day, or about 300 mg/day, or about 350 mg/day, or
about 400 m day, or about 450 mg day, or about 500 mg/day, or about
550 mg/day, or about 600 mg day, or about 650 mg/day, or about 700
mg/day, or about 750 mg/day, or about 800 mg/day (to a total daily
dose of about 1600 mg/day or 1602 mg/day), or about 850 mg/day, or
about 900 mg/day, or about 950 mg/day, or about 1000 mg day, or
about 1050 mg/day, or about 1100 mg/day, or about 1150 mg/day, or
about 1200 mg day, or about 1250 mg/day, or about 1300 mg/day, or
about 1350 mg/day, or about 1400 mg/day, or about 1450 mg/day, or
about 1500 mg/day, or about 1600 mg/day (to a total daily dose of
about 800 mg/day or 801 mg/day) or more.
[0104] In some embodiments, a method of administering pirfenidone
therapy to a patient receiving fluvoxamine therapy is provided,
comprising administering to the patient a therapeutically effective
amount of fluvoxamine and administering to the patient a daily
dosage of pirfenidone that is less than 2400 mg or 2403 mg per day,
e.g. 1600 mg or 1602 mg per day. In some embodiments, the dosage of
pirfenidone is decreased prior to administration of fluvoxamine.
Similarly, in any of the foregoing embodiments relating to other
CYP inhibitors or CYP substrates, the daily dosage of pirfenidone
that is less than 2400 mg or 2403 mg per day may be, e.g. 1600 mg
or 1602 mg per day.
[0105] In some embodiments, a method of optimizing pirfenidone
therapy is provided comprising titrating the dosage of pirfenidone
administered to a patient downward relative to a previously
administered dosage in the patient, wherein co-administration of
fluvoxamine to the patient does not result in an increased exposure
to pirfenidone. It is understood that, in such embodiments
comprising dose titration downwards, upon discontinuation of
fluvoxamine, the dosage is titrated back up to a dose that is not
less than 2400 or 2403 mg/day. As noted above, in any of the
embodiments described herein, including but not limited to
discontinuation or dose titration downwards, the packages and kits,
and/or the methods of preparing or packaging pirfenidone, the
pirfenidone, uses, methods, packages, kits, advice, warnings,
discontinuation or dose titration may apply not only to fluvoxamine
but also to (a) any other drug that is a moderate to strong
inhibitor of both CYP1 A2 and another CYP enzyme selected from the
group consisting of CYP3A4, CYP2C9, and/or CYP2C19, or (b) a drug
that is a strong inhibitor of CYP1A2 that also has inhibitory
effects on other CYP isozymes [2C9, 2C19, and/or 3A4]), or (c) any
other drug that is a moderate to strong inhibitor of both CYP1 A2
and another CYP enzyme selected from the group consisting of
CYP3A4, CYP2C9, CYP2C19, CYP2B6, and/or CYP2D6, or (d) any other
drug that is a moderate to strong inhibitor of both CYP1A2 and
another CYP enzyme that metabolizes pirfenidone, e.g. selected from
the group consisting of CYP1A1, CYP2A6, CYP2B6, CYP2C8, CYP2C9,
CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP2J2 CYP3A4, CYP3A5, CYP4A11
and/or CYP4F2, or (e) any other drug that is a strong inhibitor of
CYP1A2 or (f) any other drug that is a substrate for CYP1A2.
Packages, Kits, Methods of Packaging, and Methods of Delivering
[0106] In another aspect, a package or kit is provided comprising
pirfenidone, optionally in a container, and a package insert,
package label, instructions or other labeling including any one,
two, three or more of the following information or
recommendations:
[0107] (a) use of fluvoxamine should be avoided or
discontinued,
[0108] (b) co-administration of pirfenidone with drugs that are
moderate to strong inhibitors of both CYP1A2 and another CYP enzyme
selected from the group consisting of CYP3A4, CYP2C9, and/or
CYP2C19, can alter the therapeutic effect or adverse reaction
profile of pirfenidone,
[0109] (c) co-administration of pirfenidone with fluvoxamine can
alter the therapeutic effect or adverse reaction profile of
pirfenidone,
[0110] (d) use of pirfenidone in patients being treated with
fluvoxamine is contraindicated,
[0111] (e) co-administration of pirfenidone and fluvoxamine
resulted in an average 6-fold increase in exposure to pirfenidone,
and/or
[0112] (f) strong CYP1A2 inhibitors should be used with caution in
patients receiving pirfenidone due to the potential for reduced
pirfenidone clearance.
[0113] In some embodiments, the information or recommendation may
include that co-administration of pirfenidone and fluvoxamine
resulted in a 2-fold increase in average peak serum concentration
of pirfenidone (Cmax).
[0114] In other embodiments, the information or recommendation may
include that co-administration of pirfenidone with drugs that are
moderate to strong inhibitors of both CYP1A2 and another CYP enzyme
selected from the group consisting of CYP3A4, CYP2C9, CYP2C19,
CYP2B6, and/or CYP2D6 can alter the therapeutic effect or adverse
reaction profile of pirfenidone. In other embodiments, the
information or recommendation may include that co-administration of
pirfenidone with drugs that are moderate to strong inhibitors of
both CYP1A2 and another CYP enzyme selected from the group
consisting of CYP1A1, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C18,
CYP2C19, CYP2D6, CYP2E1, CYP2J2 CYP3A4, CYP3A5, CYP4A11 and/or
CYP4F2 can alter the therapeutic effect or adverse reaction profile
of pirfenidone. In other embodiments, the information or
recommendation may include that co-administration of pirfenidone
with drugs that are strong CYP1A2 inhibitors can alter the
therapeutic effect or adverse reaction profile of pirfenidone. In
other embodiments, the information or recommendation may include
that co-administration of pirfenidone with drugs that are CYP1A2
substrates can alter the therapeutic effect or adverse reaction
profile of pirfenidone.
[0115] In other embodiments, the information or recommendation may
include that drugs that are moderate to strong inhibitors of both
CYP1A2 and another CYP enzyme selected from the group consisting of
CYP3A4, CYP2C9, and/or CYP2C19 should be avoided or discontinued,
or are contraindicated, or should be used with caution. In yet
further embodiments, the information or recommendation may include
that administering a strong CYP1A2 inhibitor should be avoided or
discontinued, or are contraindicated, or should be used with
caution. In other embodiments, the information or recommendation
may include that drugs that are CYP1A2 substrates should be avoided
or discontinued, or are contraindicated, or should be used with
caution.
[0116] The package insert, package label, instructions or other
labeling may further comprise directions for treating IPF by
administering pirfenidone, e.g., at a dosage of 2400 mg or 2403 mg
per day.
[0117] In related aspect, the invention provides a method of
preparing or packaging a pirfenidone medicament comprising
packaging pirfenidone, optionally in a container, together with a
package insert or package label or instructions including any one,
two, three or more of the foregoing information or
recommendations.
[0118] In some embodiments, a method of treating IPF is disclosed
comprising providing, selling or delivering any of the kits of
disclosed herein to a hospital, physician or patient.
[0119] In some embodiments, a kit is provided comprising
fluvoxamine and a package insert, package label, instructions, or
other labeling comprising any one, two, three or more of the
following warnings:
[0120] (a) use of fluvoxamine and pirfenidone is
contraindicated
[0121] (b) use of pirfenidone in patients being treated with
fluvoxamine is contraindicated, and/or
[0122] (c) co-administration of pirfenidone and fluvoxamine
resulted in an average 6-fold increase in exposure to
pirfenidone.
[0123] (d) co-administration of pirfenidone and fluvoxamine
resulted in an average 2-fold increase in peak serum concentration
of pirfenidone.
[0124] In some embodiments, a method of treating a patient in need
of fluvoxamine is provided comprising providing or delivering any
of the kits disclosed herein comprising fluvoxamine to a hospital,
physician or patient.
[0125] In related aspects, the invention provides a method of
administering a SSRI to a patient in need thereof, the improvement
comprising discontinuing administration of fluvoxamine, for
example, concurrent with starting administration of pirfenidone,
and optionally administering an SSRI that is not a moderate to
strong inhibitor of both CYP1A2 and another CYP enzyme selected
from the group consisting of CYP3A4, CYP2C9, and/or CYP2C19.
[0126] The invention will be more fully understood by reference to
the following examples which detail exemplary embodiments of the
invention. They should not, however, be construed as limiting the
scope of the invention. All citations throughout the disclosure are
hereby expressly incorporated by reference.
EXAMPLES
Example 1
[0127] An open-label Phase 1 study was performed to determine the
impacts of fluvoxamine on the pharmacokinetics and safety of
pirfenidone in healthy subjects.
[0128] Study Design.
[0129] The study was a Phase 1, open-label, parallel-group study in
healthy subjects. Fifty-four subjects were to be enrolled in two
groups, consisting of 27 subjects who were smokers (Group 1) and 27
subjects who were nonsmokers (Group 2). Smoking induces CYP1A2
activity. Each group (smokers and nonsmokers) was to include a
minimum of nine females and nine males, and attempts were to be
made to enroll equal numbers of each sex in each group. Each
subject was to receive a single 801-mg dose of pirfenidone on Days
1 and 11. Fluvoxamine dosing was started on Day 2 and titrated to
the final dose according to the following schedule: [0130] Days
2-4: fluvoxamine 50 mg at bedtime [0131] Days 5-7: fluvoxamine 50
mg twice a day (in the morning and at bedtime) [0132] Days 8-11:
fluvoxamine 50 mg in the morning and 100 mg at bedtime
[0133] All pharmacokinetic (PK) analyses were conducted using
population PK methods using Monte-Carlo parametric expectation
maximization as implemented in the open-source software program S
ADAPT 1.5.6 (Bauer et al., AAPS Journal 9(1):E(0-83, 2007). The
structural model for the analysis was obtained from a preliminary
population PK analysis. This population PK model was fit to the
pirfenidone and 5 carboxy-pirfenidone plasma concentration-time
data from Days 1 and 11 separately. Once a final population PK
model was defined, AUC.sub.0-28 estimates were generated by
simulating plasma PK profiles and compared for statistically
significant differences between days (to test the effect of
fluvoxamine co-administration) and between groups (to test the
effect of smoking status).
[0134] As the primary endpoint of the study, differences in the
pirfenidone and 5 carboxy pirfenidone AUC.sub.0-28 estimates
between Days 1 and 1, and between smokers and nonsmokers were
tested for significance. The analysis of the effect of fluvoxamine
(i.e., Day 1 versus Day 11) was analyzed using the FDA criteria for
bioequivalence for paired data (FDA 2003). The ratio of
AUC.sub.0-28 on Day 11 to that on Day 1 was used to test for the
interaction between smoking status and fluvoxamine
coadministration. If other subject characteristics (such as body
size or age) were also associated with the ratio of AUC.sub.0-28 on
Day 11 to that on Day 1, the significance of these covariates was
also tested. The significance of differences in pirfenidone and
5-carboxy-pirfenidone AUC.sub.0-28 estimates on Day 1 in smokers
and nonsmokers was tested using multivariable linear regression in
order to take into account the effects of other significant
covariates.
[0135] Pharmacokinetic Results. Fifty-one of the 54 subjects
enrolled in the study were included in the PK analyses. Three
subjects were removed from the PK analyses as they did not meet the
protocol-specified requirement for adequate compliance with the
fluvoxamine dosing regimen. Two subjects discontinued the study
early due to adverse events, and one subject only took 73% of the
protocol-required fluvoxamine dose. All 51 subjects had the full
complement of PK samples available for analysis. Each subject had
two profiles on each day: one for pirfenidone and one for 5-carboxy
pirfenidone. There were a total of 1224 samples (12 per subject per
day); each sample was assayed for pirfenidone and
5-carboxy-pirfenidone for a total of 2448 concentrations.
[0136] A robust fit to the data was obtained using the population
PK structural model. In general, the fits of the data were
excellent: 98% of the individual profiles had r.sup.2 values above
0.9 and there was no systematic bias in the fits.
[0137] The summary statistics of AUC.sub.0-28 stratified by study
day are provided in Table 1. Symmetrical dot density plots of
pirfenidone and 5-carboxy pirfenidone AUC.sub.0-28 values versus
study day, identified by smoking status, are provided in FIG. 1.
The co-administration of fluvoxamine resulted in a significant
increase in the AUC.sub.0-28 of pirfenidone (p<0.00001). There
was not a statistically significant effect of fluvoxamine
co-administration on 5-carboxy pirfenidone AUC.sub.0-28.
TABLE-US-00001 TABLE 1 Comparison of AUC.sub.0-.infin. Between
Study Days (n = 51) AUC.sub.0-.infin. (mg hr/L) 5-Carboxy- Study
Day Statistic Pirfenidone.sup.a Pirfenidone.sup.b 1:
Pre-Fluvoxamine Mean (SD) 34.9 (16.9) 29.3 (8.22) Median 34.7
(21.4-45.9) 26.9 (22.0-33.7) (25.sup.th-75.sup.th) 11: Mean (SD)
171 (47.7) 31.7 (8.96) Post-Fluvoxamine Median 167 (126-206) 29.4
(25.4-36.5) (25.sup.th-75.sup.th) .sup.ap-value <0.00001 (paired
t-test) .sup.bp-value = 0.168 (paired t-test) AUC.sub.0-.infin. =
area under the concentration-time curve from time zero to infinity;
SD = standard deviation.
[0138] There was also a large apparent difference in the C.sub.max
estimates pre- and post-fluvoxamine; the pirfenidone C.sub.max was
higher after administration of fluvoxamine while the 5-carboxy
pirfenidone C.sub.max was lower after administration of
fluvoxamine. The mean (95% CI) for the ratio of C.sub.max on Day 11
to the C.sub.max on Day 1 was 2.09 (1.94-2.25) for pirfenidone and
0.369 (0.349-0.390) for 5-carboxy-pirfenidone.
[0139] The summary statistics of the ratio of the AUC.sub.0-28 on
Day 11 to the AUC.sub.0-28 on Day 1, stratified by smoking status,
are provided in Table 2. While both smokers and nonsmokers were
affected by the coadministration of fluvoxamine, smokers appeared
to have a more pronounced increase in exposure to pirfenidone, as
evidenced by the higher ratio of Day 11 to Day 1 AUC. Given that
there was an imbalance in the demographics between smokers and
nonsmokers (smokers were younger, heavier and predominantly male),
the impact of these variables on the ratio of the pirfenidone
AUC.sub.0-28 on Day 11 to the AUC.sub.0-28 on Day 1 was tested
using multiple linear regression. Using backward elimination
(p-value for removal=0.10), smoking status was the only significant
predictor of the ratio of the pirfenidone AUC.sub.0-28 on Day 11 to
the AUC.sub.0-28 on Day 1; body size, sex, and age were not
significant.
TABLE-US-00002 TABLE 2 Comparison of Ratio of Day 11
AUC.sub.0-.infin. to Day 1 AUC.sub.0-.infin. by Smoking Status
Smoking Status Statistic Pirfenidone 5-Carboxy-Pirfenidone Smokers
N 26 76 Mean (SD) 7.32 (2.12) 1.12 (0.0951) Median 7.07 (6.12-8.25)
1.13 (1.04-1.19) (25.sup.th-75.sup.th) Nonsmokers N 25 25 Mean (SD)
4.13 (1.15) 1.05 (0.114) Median 3.99 (3.26-4.68) 1.03 (0.978-1.11)
(25.sup.th-75.sup.th) AUC.sub.0-.infin. = area under the
concentration-time curve from time zero to infinity; SD = standard
deviation.
[0140] In summary, the design and execution of this study allowed
for a robust and informative analysis of the effects of CYP1A2
inhibition on the pharmacokinetics of pirfenidone. Administration
of the potent CYP inhibitor fluvoxamine resulted in a significant
drug interaction and markedly increased pirfenidone exposure.
Smokers were likely to experience significantly lower pirfenidone
exposure (in the absence of the drug interaction) presumably due to
the inductive effects of smoking.
[0141] The coadministration of fluvoxamine resulted in a
significant drug interaction such that exposure (AUC.sub.0-28) to
pirfenidone was, on average, nearly 6 times higher after ten days
of dosing with fluvoxamine. Subjects also experienced, on average,
a two-fold increase in C.sub.max after administration of
fluvoxamine.
[0142] While the present invention has been described in terms of
various embodiments and examples, it is understood that variations
and improvements will occur to those skilled in the art.
EXAMPLES OF EMBODIMENTS OF THE INVENTION INCLUDE
[0143] 1. Pirfenidone for use in treating a patient in need of
pirfenidone therapy, characterized in that the treating comprises
avoiding, contraindicating or discontinuing concomitant use of
fluvoxamine. 2. The use of pirfenidone in the manufacture of a
medicament for treating a patient in need of pirfenidone therapy,
characterized in that the treating comprises avoiding,
contraindicating or discontinuing concomitant use of fluvoxamine.
3. The pirfenidone of paragraph 1 or use of paragraph 2 wherein the
patient is a patient who is avoiding concomitant use of fluvoxamine
because concomitant use of pirfenidone with fluvoxamine is
contraindicated. 4. The pirfenidone of paragraph 1 or use of
paragraph 2 wherein the patient is a patient who has discontinued
use of fluvoxamine prior to the initiation of pirfenidone therapy
in order to avoid reduced clearance of [or increased exposure to]
pirfenidone. 5. Pirfenidone or use of any one of paragraphs 1 to 3,
wherein administration of fluvoxamine to the patient is
contraindicated or avoided in order to avoid reduced clearance of
[or increased exposure to] pirfenidone. 6. The pirfenidone or use
of paragraph 4, wherein the patient has discontinued administration
of fluvoxamine within 1 month prior to starting pirfenidone
therapy. 7. The pirfenidone or use of paragraph 4, wherein the
patient has discontinued administration of fluvoxamine within 2
weeks prior to starting pirfenidone therapy. 8. The pirfenidone or
use of any one of paragraphs 1 to 7 wherein the patient suffers
from a disease selected from pulmonary fibrosis, idiopathic
pulmonary fibrosis, idiopathic interstitial pneumonia, autoimmune
lung diseases, benign prostate hypertrophy, coronary or myocardial
infarction, atrial fibrillation, cerebral infarction, myocardiac
fibrosis, musculoskeletal fibrosis, post-surgical adhesions, liver
cirrhosis, renal fibrotic disease, fibrotic vascular disease,
scleroderma, Hermansky-Pudlak syndrome, neurofibromatosis,
Alzheimer's disease, diabetic retinopathy, or skin lesions, lymph
node fibrosis associated with HIV, chronic obstructive pulmonary
disease (COPD), inflammatory pulmonary fibrosis, rheumatoid
arthritis; rheumatoid spondylitis; osteoarthritis; gout, other
arthritic conditions; sepsis; septic shock; endotoxic shock;
gram-negative sepsis; toxic shock syndrome; myofacial pain syndrome
(MPS); Shigellosis; asthma; adult respiratory distress syndrome;
inflammatory bowel disease; Crohn's disease; psoriasis; eczema;
ulcerative colitis; glomerular nephritis; scleroderma; chronic
thyroiditis; Grave's disease; Ormond's disease; autoimmune
gastritis; myasthenia gravis; autoimmune hemolytic anemia;
autoimmune neutropenia; thrombocytopenia; pancreatic fibrosis;
chronic active hepatitis including hepatic fibrosis; acute or
chronic renal disease; renal fibrosis; diabetic nephropathy;
irritable bowel syndrome; pyresis; restenosis; cerebral malaria;
stroke or ischemic injury; neural trauma; Alzheimer's disease;
Huntington's disease; Parkinson's disease; acute or chronic pain;
allergies, including allergic rhinitis or allergic conjunctivitis;
cardiac hypertrophy, chronic heart failure; acute coronary
syndrome; cachexia; malaria; leprosy; leishmaniasis; Lyme disease;
Reiter's syndrome; acute synovitis; muscle degeneration, bursitis;
tendonitis; tenosynoviitis; herniated, ruptured, or prolapsed
intervertebral disk syndrome; osteopetrosis; thrombosis; silicosis;
pulmonary sarcosis; bone resorption diseases, such as osteoporosis
or multiple myeloma-related bone disorders; cancer, including but
not limited to metastatic breast carcinoma, colorectal carcinoma,
malignant melanoma, gastric cancer, or non-small cell lung cancer;
graft-versus-host reaction; or auto-immune diseases, such as
multiple sclerosis, lupus or fibromyalgia; AIDS or other viral
diseases such as Herpes Zoster, Herpes Simplex I or II, influenza
virus, Severe Acute Respiratory Syndrome (SARS) or cytomegalovirus;
or diabetes mellitus, proliferative disorders (including both
benign or malignant hyperplasias), acute myelogenous leukemia,
chronic myelogenous leukemia, Kaposi's sarcoma, metastatic
melanoma, multiple myeloma, breast cancer, including metastatic
breast carcinoma; colorectal, carcinoma: malignant melanoma;
gastric cancer; non-small cell lung cancer (NSCLC); bone
metastases; pain disorders including neuromuscular pain, headache,
cancer pain, dental pain, or arthritis pain; angiogenic disorders
including solid tumor angiogenesis, ocular neovascularization, or
infantile hemangioma: conditions associated with the cyclooxygenase
or lipoxygenase signaling pathways, including conditions associated
with prostaglandin endoperoxide synthase-2 (including edema, fever,
analgesia, or pain); organ hypoxia; thrombin-induced platelet
aggregation; or protozoal diseases. 9. The pirfenidone or use of
any one of paragraphs 1 to 7 wherein the patient has Idiopathic
Pulmonary Fibrosis (IPF). 10. The pirfenidone or use of any one of
paragraphs 1 to 9, wherein the pirfenidone is administered at a
total daily dosage of 2400 mg or 2403 mg per day. 11. The
pirfenidone or use of any one of paragraphs 1 to 10, wherein each
dose of pirfenidone administered is 801 mg. 12. The pirfenidone or
use of paragraph 11, wherein the pirfenidone is for administration
to the patient three times per day, with food.
OTHER EXAMPLES OF EMBODIMENTS OF THE INVENTION INCLUDE
[0144] 1A. A method of administering pirfenidone therapy to a
patient in need thereof, comprising administering to the patient a
therapeutically effective amount of pirfenidone, and avoiding
administration of fluvoxamine.
[0145] 2A. The method of paragraph 1A wherein the patient has
idiopathic pulmonary fibrosis (IPF).
[0146] 3A. The method of paragraph 1A wherein the therapeutically
effective amount of pirfenidone is a daily dosage of 2400 mg or
2403 mg per day.
[0147] 4A. The method of paragraph 1A wherein 800 or 801 mg of
pirfenidone is administered to the patient three times per day,
with food.
[0148] 5A. A method of administering pirfenidone therapy to a
patient in need thereof, comprising discontinuing administration of
fluvoxamine to avoid an adverse drug interaction, and administering
to the patient a therapeutically effective amount of
pirfenidone.
[0149] 6A. The method of paragraph 5A wherein the patient has
idiopathic pulmonary fibrosis (IPF).
[0150] 7A. The method of paragraph 5A wherein the therapeutically
effective amount of pirfenidone is a daily dosage of 2400 mg or
2403 mg per day.
[0151] 8A. The method of paragraph 5A wherein 800 or 801 mg of
pirfenidone is administered to the patient three times per day,
with food.
[0152] 9A. The method of paragraph 5A wherein the fluvoxamine is
discontinued within 1 month prior to starting pirfenidone
therapy.
[0153] 10A. The method of paragraph 5A wherein the fluvoxamine is
discontinued within 2 weeks prior to starting pirfenidone
therapy.
[0154] 11A. A method of administering pirfenidone therapy to a
patient in need thereof, comprising administering to the patient a
therapeutically effective amount of pirfenidone, and any one or
more of the following:
[0155] (a) advising the patient that fluvoxamine should be avoided
or discontinued,
[0156] (b) advising the patient that co-administration of
pirfenidone with drugs that are moderate to strong inhibitors of
both CYP1 A2 and another CYP enzyme selected from the group
consisting of CYP2C9, CYP2C19 and CYP3A4 can alter the therapeutic
effect or adverse reaction profile of pirfenidone,
[0157] (c) advising the patient that co-administration of
pirfenidone with fluvoxamine can alter the therapeutic effect or
adverse reaction profile of pirfenidone,
[0158] (d) advising the patient that use of pirfenidone in patients
being treated with fluvoxamine is contraindicated,
[0159] (e) advising the patient that co-administration of
pirfenidone and fluvoxamine resulted in a 6-fold increase in
exposure to pirfenidone, or
[0160] f) advising the patient that strong CYP1A2 inhibitors should
be used with caution in patients receiving pirfenidone due to the
potential for reduced pirfenidone clearance.
[0161] 12A. The method of paragraph 11A wherein the patient is
advised that fluvoxamine should be avoided or discontinued.
[0162] 13A. The method of paragraph 11A wherein the patient is
advised that co-administration of pirfenidone with drugs that are
moderate to strong inhibitors of both CYP1A2 and another CYP enzyme
selected from the group consisting of CYP2C9, CYP2C19 and CYP3A4
can alter the therapeutic effect or adverse reaction profile of
pirfenidone.
[0163] 14A. The method of paragraph 11A wherein the patient is
advised that co-administration of pirfenidone with fluvoxamine can
alter the therapeutic effect or adverse reaction profile of
pirfenidone.
[0164] 15A. The method of paragraph 1A wherein the patient is
advised that use of pirfenidone in patients being treated with
fluvoxamine is contraindicated.
[0165] 16A. The method of paragraph 11A wherein the patient is
advised that co-administration of pirfenidone and fluvoxamine
resulted in a 6-fold increase in exposure to pirfenidone.
[0166] 17A. The method of paragraph 16A further comprising advising
the patient that co-administration of pirfenidone and fluvoxamine
resulted in a 2-fold increase in average peak serum concentration
of pirfenidone (Cmax).
[0167] 18A. The method of paragraph 11A wherein the patient is
advised that strong CYP1A2 inhibitors should be used with caution
in patients receiving pirfenidone due to the potential for reduced
pirfenidone clearance.
[0168] 19A. The method of paragraph 18A further comprising avoiding
administering a strong CYP1A2 inhibitor.
[0169] 20A. The method of paragraph 18A further comprising
discontinuing administration of a strong CYP1A2 inhibitor.
* * * * *