NZ711312B2 - Substituted n-aryl pyridinones - Google Patents

Abstract

The disclosure relates to the use of deuterated pirfenidone (compound (I), wherein at least one of R1 – R11 is deuterium), wherein the d-pirfenidone is administered orally between 30 minutes prior to and 2 hours after consuming food. The deuterated pirfenidone may be d3-pirfenidone and the administration with food is to reduce the incidence of gastrointestinal upset, nausea, fatigue, somnolence, dizziness, headache and photosensitivity rash and to reduce the mean maximum plasma concentration. ation with food is to reduce the incidence of gastrointestinal upset, nausea, fatigue, somnolence, dizziness, headache and photosensitivity rash and to reduce the mean maximum plasma concentration.

Description

/027872 SUBSTITUTED N-ARYL PYRIDINONES This application claims the benefit of priority of United States provisional application No. 61/450,489, filed March 8, 2011, the disclosure of which is hereby incorporated by nce as if written herein in its entirety.

FIELD The t invention is directed to substituted N-Aryl pyridinones, pharmaceutically acceptable salts and prodrugs thereof, the chemical synthesis thereof, and medical use of such compounds for the treatment and/or management of idiopathic pulmonary fibrosis, uterine fibroids, le sclerosis, renal fibrosis, diabetic kidney disease, endotoxin-induced liver injury after partial hepatectomy or c ischemia, allograft injury after organ lantation, cystic fibrosis, atrial fibrilation, neutropenia, scleroderma, dermatomyositis, cirrhosis, diffuse parenchymal lung disease, mediastinal fibrosis, tuberculosis, spleen is caused by sickle-cell anemia, rheumatoid arthritis, and/or any disorder ameliorated by modulating fibrosis and/or collagen infiltration into tissues.

OUND Pirfenidone (Deskar®, EsbrietTM, a, AMR-69, F—647, 5—7701), 5-methyl- l-phenyl-lH—pyridinone, is an orally administered antifibrotic agent. Pirfenidone is effective in rodent disease models. Pirfenidone inhibits DNA synthesis in oma cells and myometrial cells (Lee et al, Journal of Clinical Endocrinology and Metabolism 1998, 83(1), 219-23). Pirfenidone has been approved for the treatment of idiopathic pulmonary fibrosis (IPF) in Japan and received positive opinion from CHMP in Europe.

Q" _\ Pirfenidone While the chemical structure of pirfenidone is relatively simple, the metabolism is only partially understood. For example, the methyl group is thought to be susceptible to oxidation which would lead to a corresponding hydroxymethyl lite, "M1." M1 is t to be further oxidized to a carboxylic acid metabolite, "M2" (Wang et al, Biomedical Chromatography 2006, 20, 1375-1379). A third detected metabolite is believed to be a phase 11 product possibly originating from M1 or M2. Pirfenidone has a very short half-life in humans and will likely be dosed at more than once per day.

The most common adverse ons or events associated with pirfenidone therapy e gastrointestinal upset, nausea, fatigue, somnolence, dizziness, headache, and photosensitivity rash. Many of these effects can interfere with everyday activities and quality of life. These effects appear to be dose related. The adverse reactions associated with pirfenidone therapy are exacerbated when pirfenidone is administered at these higher doses. al liver function is an additional adverse event that may be associated with or increase the hazards of pirfenidone therapy. Abnormal liver function may manifest as abnormalities in levels of kers of liver function, including alanine transaminase, aspartate transaminase, bilirubin, and/or alkaline phosphatase, and may be an indicator of drug-induced liver injury. See FDA Draft Guidance for ry. Drug-Induced Liver Injury: Premarketing Clinical Evaluation, October 2007.

Currently, adverse events following administration of pirfenidone are alleviated by dose reduction or tinuation of idone. In a recent study, for adverse events rated Grade 2 or worse, the dosage was reduced in a stepwise manner: from 9 tablets per day to 6 s per day and 6 tablets per day to 3 tablets per day. Azuma et al., Am. J.

Respir. Crit. Care Med, 2005, 171, 1040-47. If, after a period of 14 days of observation with reduced dosage, the adverse event persisted or sed, the dosage was further reduced by one more step-from 6 tablets per day to 3 tablets per day. If the e event persisted or increased despite reducing the dosage to 3 tablets per day, the study medication was discontinued.

There remains an unmet clinical need for a method of stering higher doses of pirfenidone to a patient in a manner that eliminates or minimizes adverse events, such as al liver function, nausea, vomiting, gastrointestinal upset, drowsiness, dizziness, headache, somnolence, and other potentially dangerous side effects that can occur with pirfenidone therapy.

SUMMARY OF THE INVENTION Disclosed herein is a enidone compound having structural Formula I: R8 R7 0 R6 R9 N \ R10 R11 R4 R3 R1R2 or a pharmaceutically acceptable salt, solvate, or prodrug thereof; wherein: R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, and R11 are selected from the group consisting of hydrogen or ium; and at least one R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, and R11 is deuterium; and In certain embodiments if R7, R8, R9, R10, and R11 are deuterium, then at least one of R1, R2, R3, R4, R5, and R6 is deuterium.

In an embodiment, a method of reducing the likelihood of adverse events in a patient receiving d-pirfenidone therapy wherein the d-pirfenidone is in the form of a pharmaceutical composition is disclosed. The method comprises, for example, administering a eutically effective amount of d-pirfenidone to a patient with food. In certain embodiments, the d-pirfenidone is d3-pirfenidone.

In an embodiment, a method of reducing the likelihood of somnolence in a t receiving d-pirfenidone therapy wherein the d-pirfenidone is in the form of a pharmaceutical ition is sed. The method comprises, for example, administering a therapeutically ive amount of d-pirfenidone to the patient with food. In certain embodiments, the d-pirfenidone is d3-pirfenidone.

In an embodiment, a method of reducing the likelihood of nausea in a patient receiving d-pirfenidone therapy n the d-pirfenidone is in the form of a pharmaceutical composition is disclosed. The method comprises, for example, administering a therapeutically effective amount of d-pirfenidone to the patient with food. In n embodiments, the d-pirfenidone is d3-pirfenidone.

In an embodiment, a method of reducing the likelihood of headaches in a patient receiving d-pirfenidone therapy wherein the d-pirfenidone is in the form of a pharmaceutical composition is sed. The method comprises, for example, administering a therapeutically effective amount of d-pirfenidone to the patient with food. In n embodiments, the d-pirfenidone is d3-pirfenidone.

WO 22165 In some embodiments, the likelihood of one or more adverse effects is reduced. For e, in some embodiments, the likelihood of nausea and ence is reduced. In other embodiments, the likelihood of nausea and headaches is reduced. In still other embodiments, the likelihood of somnolence and headaches is reduced. In some embodiments, the likelihood of nausea, somnolence and headaches is reduced.

In some embodiments, the methods e administering d-pirfenidone to a patient, wherein the administering comprises providing d-pirfenidone in about 100 milligrams to about 400 rams per unit dosage form. In some embodiments, the administering comprises providing one or more unit dosage forms one or more times per day to the patient. In an ment, the administering comprises providing one or more capsules comprising d-pirfenidone one or more times per day to the patient. In n embodiments, the d-pirfenidone is d3-pirfenidone.

In some embodiments, the food is a solid food with sufficient caloric and fat content that it is not rapidly dissolved and absorbed in the stomach. Thus, in some embodiments, the food is a meal, for example, breakfast, lunch or dinner.

In some embodiments, the therapeutically effective amount of d-pirfenidone is administered to the patient between about 1 hour prior to about 2 hours after eating a meal. In some embodiments, the d-pirfenidone is administered to the patient within about 30 minutes, about 15 minutes of consuming food. In certain embodiments, the enidone is d3- pirfenidone.

In some embodiments, the methods disclosed herein further comprise providing information to ibing physicians and patients receiving d-pirfenidone therapy useful for decreasing adverse events when taking d-pirfenidone. In preferred ments, the methods further comprise advising a patient to take d-pirfenidone with food. In some embodiments, the methods further comprise advising a patient to take d-pirfenidone with food to avoid and/or minimize adverse events associated with d-pirfenidone therapy. In n embodiments, the d-pirfenidone is d3-pirfenidone.

In some embodiments, the methods e providing the composition to the patient in a container associated with d labeling advising that the administration with food results in a reduction in the likelihood of adverse events. In some ments, the s include providing the pharmaceutical composition to the patient in a container associated with printed labeling advising the patient that the pharmaceutical composition is to be, administered between about 1 hour prior to ing food to about 2 hours after consuming food. In some embodiments, the methods include providing the pharmaceutical composition to the patient in a container associated with printed labeling advising the patient that the pharmaceutical ition is to be administered at ntially the same time as consuming food.

Another embodiment provides an article of manufacture or a kit comprising a container, wherein the container holds a pharmaceutical composition comprising d- pirfenidone in unit dosage form, and printed labeling instructions advising of the varying side effects when the composition is taken with and without food. In some embodiments, the printed instructions advise the patient to take the composition with food if stomach upset or somnolence occurs. In n embodiments, the d-pirfenidone is d3-pirfenidone.

In some embodiments, the printed instructions further advise the t that the administration of the composition with food results in a reduction in the likelihood of adverse events. In some embodiments, the printed instructions advise the patient to take the composition between about 1 hour prior to consuming food to about 2 hours after consuming food. In some embodiments, the d instructions advise the patient to take the composition at substantially the same time as consuming food. In some ments, the printed instructions advise the patent to take the composition between about 30 minutes prior to about 2 hours after consuming food. In some embodiments, the printed instructions advise the t to take the ition immediately after the consumption of food up to 1 hour after said consumption. In some embodiments, the printed instructions advise the patient to take the composition with a meal.

In some embodiments, the printed instructions advise the patient to take one or more of the capsules twice per day. In some embodiments, the printed instructions advise the patient to take one or more capsules two or three times per day.

In another embodiment, a method for ing d-pirfenidone therapy to a t is disclosed, comprising ing a therapeutic dose of d-pirfenidone to the patient, and advising the patient to take the d-pirfenidone with food. In certain embodiments, the d- pirfenidone is d3-pirfenidone.

Another disclosed embodiment is a method for providing enidone therapy to a patient, comprising providing a therapeutic dose of d-pirfenidone to the patient, and advising the patient that consuming the d-pirfenidone with food may reduce the incidence of adverse events ing from d-pirfenidone therapy. In certain embodiments, the d-pirfenidone is d3-pirfenidone.

Also disclosed is a method for providing d-pirfenidone therapy to a t, comprising providing a eutic dose of enidone to the patient; and advising the patient that ing the d-pirfenidone with food reduces mean maximum plasma concentration of d-pirfenidone. In certain embodiments, the d-pirfenidone is d3-pirfenidone.

In some embodiments, the food is a solid food with ient bulk and fat content that it is not rapidly dissolved and absorbed in the h. In certain embodiments, the food is a meal, such as breakfast, lunch, or dinner. In some embodiments, the food is at least about 100 calories, about 200 calories, about 250 calories, about 300 calories, about 400 es, about 500 calories, about 600 calories, about 700 calories, about 800 calories, about 900 calories, about 1000 calories, about 1250 calories, or about 1500 calories.

The methods disclosed herein include administering d-pirfenidone to a patient with food. The d-pirfenidone can be administered any time of day with food. For e, in some embodiments, the food can be consumed at any time during the period between from about 2 hours prior to the administration of d-pirfenidone to about 2 hours after the administration of d-pirfenidone. In some embodiments, the food can be consumed within the time period of about 2 hours, about 1.5 hours, about 1 hour, about 45 minutes, about 30 minutes, about 15 minutes, about 10 minutes, or about 5 s prior to the stration of d-pirfenidone. In some embodiments, the food can be consumed within the time period of about 5 minutes, about 10 minutes, about 15 minutes, about 30 minutes, about 45 minutes, about 1 hour, about 1.5 hours, or about 2 hours after the administration of d-pirfenidone. In some ments, the administration of d-pirfenidone to the patient is immediately after the consumption of food (e.g., within about 1 minute after food consumption) up to about 1 hour after food consumption. In some embodiments, d-pirfenidone is administered at substantially the same time as the consumption of the food. In certain embodiments, the d-pirfenidone is d3-pirfenidone.

In some embodiments, an effective daily intake of d-pirfenidone is between about 100 mg and about 200 mg per day, about 200 mg and about 300 mg per day, about 300 mg and about 400 mg per day, about 400 mg and about 500 mg per day, about 500 mg and about 600 mg per day, about 600 mg and about 700 mg per day, about 700 mg and about 800 mg per day, about 800 mg and about 900 mg per day, about 900 mg and about 1000 mg per day, about 1000 mg and about 1100 mg per day, about 1100 mg and about 1200 mg per day, about 1200 mg and about 1300 mg per day, about 1300 mg and about 1400 mg per day, about 1400 mg and about 1500 mg per day, about 1500 mg and about 1600 mg per day, about 1600 mg and about 1700 mg per day, about 1700 mg and about 1800 mg per day, about 1800 mg and about 1900 mg per day, about 1900 mg and about 2000 mg per day, about 2000 mg and about 2100 mg per day, about 2100 mg and about 2200 mg per day, about 2200 mg and about 2300 mg per day, about 2300 mg and about 2400 mg per day, about 2400 mg and about 2500 mg per day, about 2500 mg and about 2600 mg per day, about 2600 mg and about 2700 mg per day, about 2700 mg and about 2800 mg per day, about 2800 mg and about 2900 mg per day, about 2900 mg and about 3000 mg per day, about 3000 mg and about 3100 mg per day, about 3100 mg and about 3200 mg per day, about 3200 mg and about 3300 mg per day, about 3300 mg and about 3400 mg per day, about 3400 mg and about 3500 mg per day, about 3500 mg and about 3600 mg per day, about 3600 mg and about 3700 mg per day, about 3700 mg and about 3800 mg per day, about 3800 mg and about 3900 mg per day, or about 3900 mg and about 4000 mg per day. In certain ments, the d-pirfenidone is fenidone.

In an ment, d-pirfenidone is administered to the subject in a unit dosage form comprising about 100 to about 400 mg of d-pirfenidone per unit. In n embodiments, the d-pirfenidone is d3-pirfenidone.

The dosing may be once or twice or three times daily, with one or more units per dose. In some embodiments, the effective daily intake of d-pirfenidone is administered as one, two, three, four, five, six, or more doses administered separately at appropriate intervals throughout the day. In some embodiments, each dose comprises one, two, three or more unit dosage forms. For example, in some embodiments, one or more units are administered to the t one or more times per day. In some embodiments, one or more units are administered to the subject twice per day. In some embodiments, one or more units are administered to the subject two or three times per day. In some embodiments, 3 units are administered two or three times per day. In some embodiments, d-pirfenidone is administered as multiple doses spaced throughout the day and each dose ses a eutically effective amount of d- pirfenidone. In some embodiments, d-pirfenidone is administered with food once per day. In certain embodiments, the d-pirfenidone is d3-pirfenidone.

In general the daily intake will be in the range of about 100 mg/day to about g/day, or about 200 mg to about 5 g/day, or about 400 mg to about 3 g/day, or about 500 mg to about 2 g/day, in single, divided, or continuous doses for a patient weighing between about 40 to about 100 kg (which doses may be adjusted for patients above or below this weight range, particularly children under 40 kg). Generally the daily intake will be in the range of about 25 mg/kg to about 200 mg/kg of body weight per day. In some embodiments, the maximum daily intake of d-pirfenidone is 4 g/day.

The exact dosage will typically be determined by the practitioner, in light of factors related to the subject that requires treatment. Dosage and administration are generally adjusted to provide sufficient levels of d-pirfenidone or to in the desired effect. Factors which may be taken into account include the severity of the disease state, general health of the subject, age, weight, and gender of the subject, diet, time and frequency of administration, drug combination(s), reaction sensitivities, and tolerance/response to therapy. Long-acting pharmaceutical compositions may be administered every 3 to 4 days, every week, or once every two weeks depending on half-life and clearance rate of the particular formulation.

The ications for the unit dosage forms described herein depend on the ular dose employed and the effect to be achieved, and the pharmacodynamics associated with d-pirfenidone in the host.

The decrease in on or number of adverse events in a patient receiving d- pirfenidone therapy can be ced in any suitable manner. Desirably, the oral administration of d-pirfenidone with food results in a reduction in the frequency and/or severity of adverse events as evidenced by a review of adverse events ing administration of d-pirfenidone as compared to the administration of enidone without food. In certain embodiments, the d-pirfenidone is d3-pirfenidone.

In some embodiments, enidone is ed to a patient in a container associated with prescribing information that advises the t to take the pharmaceutical composition with food, and in some ments further advises the patient that taking the composition with food results in a reduction in the duration, likelihood, and/or severity of adverse events associated with d-pirfenidone therapy. In some embodiments, the prescribing information advises the patient to take the composition with food if stomach upset and/or ence occurs. In certain embodiments, the d-pirfenidone is d3-pirfenidone.

In some embodiments, the methods can include identifying a subject at risk for or suffering from an adverse event associated with d-pirfenidone therapy and administering a therapeutically effective amount of d-pirfenidone with food. In n embodiments, the d- pirfenidone is d3-pirfenidone.

In an embodiment, the methods include identifying a patient who could t from the methods disclosed herein. In some embodiments, the methods described herein include identifying a subject who has experienced or is encing an adverse event, such as gastrointestinal symptoms, somnolence, and/or headache, following administration of d- pirfenidone. Identifying such subjects may be accomplished by any means that indicates a t who may benefit from the methods disclosed herein, for example, by clinical diagnosis, laboratory testing, or any other means known to one of skill in the art, including any combination of means for identification. In certain embodiments, the d-pirfenidone is d3- pirfenidone.

The methods described herein e preventing, alleviating, and/or minimizing the duration and/or severity of e events associated with d-pirfenidone therapy. In certain embodiments, the d-pirfenidone is d3-pirfenidone.

In an embodiment, the methods sed herein result in a reduction in the likelihood of nausea in patients receiving enidone therapy with food (fed) as compared to patients receiving enidone therapy without food (fasted). In certain embodiments, the likelihood of nausea of a fed population is reduced by at least about 25% ve to the hood of nausea of a fasted population; in further embodiments, the likelihood of nausea is reduced by at least about 30%; in further embodiments, d by at least about 33%; in further embodiments, reduced by at least about 40%; in further embodiments, reduced by at least about 50%; in further embodiments, reduced by at least about 60%; in further embodiments, reduced by at least 70%; and in further embodiments, reduced by at least about 75%. hood of nausea may be measured by any reproducible means of measurement. In certain embodiments, the d-pirfenidone is d3-pirfenidone.

In an embodiment, the methods disclosed herein result in a reduction in the likelihood of somnolence in patients receiving d-pirfenidone therapy with food (fed) as compared to patients receiving d-pirfenidone therapy without food (fasted). In certain embodiments, the likelihood of somnolence of a fed population is reduced by at least about % relative to the likelihood of somnolence of a fasted population; in further embodiments, the likelihood of somnolence is reduced by at least about 30%; in further embodiments, d by at least about 33%; in further embodiments, d by at least about 40%; in further embodiments, reduced by at least about 50%; in further embodiments, reduced by at least about 60%; in further embodiments, reduced by at least 70%; and in further embodiments, reduced by at least about 75%. Likelihood of somnolence may be ed by any reproducible means of measurement. In certain ments, the d-pirfenidone is d3- pirfenidone.

In an embodiment, the methods disclosed herein result in a reduction in the hood of headache in patients receiving d-pirfenidone therapy with food (fed) as compared to patients receiving d-pirfenidone therapy without food (fasted). In certain embodiments, the likelihood of headache of a fed population is d by at least about 25% relative to the likelihood of headache of a fasted population; in further embodiments, the likelihood of headache is reduced by at least about 30%; in further embodiments, reduced by at least about 33%; in further ments, reduced by at least about 40%; in further embodiments, reduced by at least about 50%; in r embodiments, reduced by at least 2012/027872 about 60%; in further ments, d by at least 70%; and in r embodiments, reduced by at least about 75%. Likelihood of headache may be measured by any ucible means of measurement. In n embodiments, the d-pirfenidone is d3-pirfenidone.

In an embodiment, the methods disclosed herein result in a reduction in the likelihood of dizziness in patients receiving d-pirfenidone therapy with food (fed) as ed to patients receiving d-pirfenidone therapy without food (fasted). In certain embodiments, the likelihood of dizziness of a fed population is reduced by at least about 25% relative to the likelihood of dizziness of a fasted population; in further embodiments, the likelihood of dizziness is reduced by at least about 30%; in further ments, reduced by at least about 33%; in further embodiments, reduced by at least about 40%; in further embodiments, reduced by at least about 50%; in further embodiments, d by at least about 60%; in further embodiments, reduced by at least 70%; and in further embodiments, reduced by at least about 75%. Likelihood of dizziness may be measured by any reproducible means of measurement. In certain embodiments, the d-pirfenidone is d3-pirfenidone.

Also disclosed is a method for ing d-pirfenidone y to a patient, comprising providing a therapeutic dose of d-pirfenidone (usually contained within a pharmaceutical composition) to the patient; and advising the patient that consuming the d- pirfenidone with food significantly reduces mean maximum plasma concentration (Cmax) of enidone and/or significantly increases (makes longer) the mean absorption half life (t1/2, abs) of d-pirfenidone in ison to consuming the d-pirfenidone without food. In certain embodiments, the d-pirfenidone is consumed within one hour or 30 minutes ofthe food consumption. In some embodiments, the d-pirfenidone is consumed at the same time as the food consumption. In other embodiments, the d-pirfenidone is consumed during the time period from one hour prior to food consumption to two hours after food consumption. In certain embodiments, the enidone is fenidone.

In some embodiments, the patient may be advised that consuming d- pirfenidone with food significantly reduces mean maximum plasma concentration of d- pirfenidone such that the ratio of the average Cmax for the fed patient to the average Cmax of the fasted patient (Cmaxqed) : meqastedp ranges from about 0.3 to about 0.8, about 0.35 to about 0.75, about 0.4 to about 0.7, about 0.4 to about 0.6, about 0.4 to about 0.5, or about 0.45 to about 0.55. In certain embodiments, the d-pirfenidone is d3-pirfenidone. onally or alternatively, in some embodiments, the patient may be advised that consuming d-pirfenidone with food significantly increases mean absorption half life of the d-pirfenidone such that the ratio of mean t1/2, abs of the fed patient to mean t1/2,abs of the fasted t (t1/2,abs(fed) : tug, abs (lasted)) ranges from about 1.5 to about 5, about 1.75 to about 4.5, about 2 to about 4, about 2.5 to about 3.5, about 2.75 to about 3.5, or about 2.75 to 3.25. In a specific embodiment, the mean t1/2,abs increases from 0.572 hours without food to 1.78 hours with food. In certain embodiments, the d-pirfenidone is d3-pirfenidone.

In some embodiments, the t may be advised that ing d- pirfenidone with food ins at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, or 80% of the overall mean tion of enidone in comparison to consuming d-pirfenidone without food, as measured by the Area Under the Curve (AUC) of an tion profile. In certain embodiments, the d-pirfenidone is d3- pirfenidone.

In all the embodiments, it is contemplated that the patient may be advised in writing or orally, and that the written information may be contained (for example) in a label, a sticker, a product insert, product information, or prescribing information.

In related embodiments, the invention provides a method for administering d- pirfenidone to a human patient in need thereof, e.g. a patient suffering from pulmonary fibrosis, comprising administering a pharmaceutical composition comprising a therapeutic dose of d-pirfenidone with food to the patient, wherein the mean maximum plasma concentration (Cmax) of d-pirfenidone is significantly reduced and/or the mean absorption half life (t1/2,abs) of d-pirfenidone is significantly longer. In some embodiments, the ratio of the e Cmax for the fed patient to the average Cmax of the fasted patient (Cmaxqed) : Cmax(fasted)) ranges from about 0.3 to about 0.8, about 0.35 to about 0.75, about 0.4 to about 0.7, about 0.4 to about 0.6, about 0.4 to about 0.5, or about 0.45 to about 0.55, or about 0.5, and/or wherein the ratio of mean tug, abs of the fed patient to mean tug, abs of the fasted patient (t1/2,abs(fed) : tl/z, absqastedfi ranges from about 1.5 to about 5, about 1.75 to about 4.5, about 2 to about 4, about 2.5 to about 3.5, about 2.75 to about 3.5, or about 2.75 to 3.25, or about 3. In n embodiments, the d-pirfenidone is fenidone.

For fed conditions, the Cmax is typically lower that the Cmax of d-pirfenidone under fasted ions. In some ments, the ratio of Cmaxqed) to meqasted) is about 0.3 to about 0.8, about 0.35 to about 0.7, about 0.4 to about 0.65, about 0.4 to about 0.6, about 0.45 to about 0.65, or about 0.45 to about 0.55. In specific embodiments, the ratio of Cmax(fed) to Cmax(fasted) is about 0.5. In certain embodiments, the d-pirfenidone is d3-pirfenidone.

The absorption half life of d-pirfenidone when administered under fed conditions (t1/2,abs(fed)) is typically longer than the absorption half life of d-pirfenidone when administered under fasted conditions (t1/25abs(fasted)). In some embodiments, the ratio t1/2,abs(fed) to t1/2,abs (fasted) (t1/2,abs(fed) : t1/2, abs (fasted)) is about 1.5 to about 5, about 2 to about 4, or about 2.5 to about 3.5, about 2.75 to about 3.5, or about 2.75 to 3.25. In specific embodiments, t1/2,abs (fed) : t1/2, absqasted) is about 2, about 2.5, about 3, about 3.5, about 4, about 4.5, or about 5. In certain embodiments, the d-pirfenidone is d3-pirfenidone.

The total absorption of enidone under fed or fasted conditions can also be determined by ing the area under the curve (AUC) of the absorption curves. In some embodiments, the AUCfed is at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or at least about 90% that of AUCfaSted. In certain embodiments, the d-pirfenidone is d3- pirfenidone.

One aspect of the invention provides methods for stering a therapeutically effective dose of d-pirfenidone to a t that has ted al biomarkers of liver function after d-pirfenidone administration for the treatment of fibrosis, e.g. idiopathic pulmonary fibrosis (IPF). In some embodiments, a patient is identified who exhibits a significantly abnormal level of one, two, three or more biomarkers of liver function, e. g. the level of a Grade 2 abnormality, after administration of an original full target dose of enidone. In such patients, the dose of d-pirfenidone is reduced or discontinued until levels of the abnormal biomarkers approach or are within normal range, after which patients are administered increasing doses of d-pirfenidone, up to the original full target dose.

Alternatively, the dose of d-pirfenidone is not reduced at all, but liver biomarkers continue to be monitored. In r embodiment, after an optional temporary dose reduction or discontinuation, patients are administered d-pirfenidone at a permanently reduced dose. As used herein, "original full target dose" means the therapeutically effective dose ed by the U.S. Food and Drug Administration or a similar agency in a foreign country, optionally other than Japan. The total daily dose is administered one, two or three times per day. In certain embodiments, the d-pirfenidone is d3-pirfenidone.

In some embodiments of the s, enidone is administered to a patient exhibiting a liver function Grade 2 abnormality as follows: (a) administering a reduced dosage of d-pirfenidone for about one week, or until the liver on biomarkers return to Grade 0 or Grade 1, and (b) administering the original full target dose for at least one week, two weeks, three weeks, four weeks or a month, two months, or three months, or one year, or two years, or three years, or four years, or five years, or seven years, or ten years.

In certain embodiments, the total daily dose is administered two or three times per day, with food. In certain embodiments, the d-pirfenidone is d3-pirfenidone.

In some embodiments of the methods, d-pirfenidone is administered to a patient exhibiting a liver function Grade 2 abnormality as s: (a) administering a first reduced dose of d-pirfenidone for about one week, or until the liver function biomarkers return to Grade 0 or Grade 1, (b) administering a second reduced dose of enidone for about one week, and (c) administering the original full target dose for a time period of at least one week, two weeks, three weeks, four weeks or a month, two , or three months, or one year, or two years, or three years, or four years, or five years, or seven years, or ten years.

In certain embodiments, the total daily dose is administered two or three times per day, with food. In certain embodiments, the d-pirfenidone is d3-pirfenidone.

In some embodiments of the methods, d-pirfenidone is administered to a patient exhibiting a liver function Grade 2 abnormality as follows: (a) discontinuing d- pirfenidone for about one week, or until the liver function biomarkers return to Grade 0 or Grade 1, (b) administering a first reduced dose of d-pirfenidone for about one week, (c) administering a second reduced dose of d-pirfenidone for about one week, and (d) administering the original full target dose for a time period of at least one week, two weeks, three weeks, four weeks or a month, two , or three months, or one year, or two years, or three years, or four years, or five years, or seven years, or ten years. In certain embodiments, the total daily dose is administered two or three times per day, with food. In certain embodiments, the d-pirfenidone is d3-pirfenidone.

Alternatively, d-pirfenidone is administered to a patient exhibiting a liver function Grade 2 abnormality at a permanently reduced dose. In some embodiments, d- pirfenidone is administered to a patient exhibiting a liver function Grade 2 ality as s: administering a reduced dose of d-pirfenidone for a time period of at least one week, two weeks, three weeks, four weeks or a month, two months, or three months, or one year, or two years, or three years, or four years, or five years, or seven years, or ten years. In some embodiments, d-pirfenidone is administered to a patient exhibiting a liver function Grade 2 abnormality as s: (a) administering a first reduced dose of d-pirfenidone for about a week, or until biomarkers of liver function are within normal limits, and (b) administering a second reduced dose of d-pirfenidone to the patient for a time period of at least one week, two weeks, three weeks, four weeks or a month, two months, or three , or one year, or two years, or three years, or four years, or five years, or seven years, or ten years. In certain ments, the d-pirfenidone is d3-pirfenidone.

In other ments, d-pirfenidone is administered to a patient exhibiting a liver function Grade 2 abnormality as follows: (a) tinuing d-pirfenidone for about one week, or until the liver on biomarkers return to Grade 0 or Grade 1, (b) stering a first reduced dose of d-pirfenidone for about a week, or until biomarkers of liver function are within normal limits, and (C) stering a second reduced dose of d-pirfenidone to the patient for a time period of at least one week, two weeks, three weeks, four weeks or a month, two months, or three months, or one year, or two years, or three years, or four years, or five years, or seven years, or ten years. In still other ments, d-pirfenidone is administered to a patient ting a liver function Grade 2 abnormality as s: (a) discontinuing d- pirfenidone for about one week, or until the liver function biomarkers return to Grade 0 or Grade 1, and (b) administering a reduced dose of d-pirfenidone to the patient for a time period of at least one week, two weeks, three weeks, four weeks or a month, two months, or three months, or one year, or two years, or three years, or four years, or five years, or seven years, or ten years. In certain embodiments, the d-pirfenidone is d3-pirfenidone.

In some embodiments of the methods, d-pirfenidone is administered to a patient exhibiting a liver function Grade 1 abnormality as follows: (a) administering a reduced dose of d-pirfenidone for a time period, ally about one week, or until the liver function biomarkers return to Grade 0, and (b) administering the original full target dose for at least one week, two weeks, three weeks, four weeks or a month, two months, or three months, or one year, or two years, or three years, or four years, or five years, or seven years, or ten years. In n embodiments, the total daily dose is administered two or three times per day, with food. In certain embodiments, the d-pirfenidone is d3-pirfenidone.

In some embodiments of the methods, d-pirfenidone is administered to a patient exhibiting a liver on Grade 1 abnormality as follows: (a) administering a first reduced dose of d-pirfenidone for a time period, optionally about one week, or until the liver on biomarkers return to Grade 0, (b) administering a second reduced dose of d- pirfenidone for a time period, optionally about one week, and (c) administering the original full target dose for a time period of at least one week, two weeks, three weeks, four weeks or a month, two months, or three months, or one year, or two years, or three years, or four years, or five years, or seven years, or ten years. In certain embodiments, the total daily dose is administered two or three times per day, with food. In certain embodiments, the d-pirfenidone is d3-pirfenidone.

In some embodiments of the methods, d-pirfenidone is administered to a patient exhibiting a liver function Grade 1 abnormality as follows: (a) discontinuing d- pirfenidone for a time period, optionally about one week, or until the liver function biomarkers return to Grade 0, (b) administering a first reduced dose of d-pirfenidone for a time period, optionally about one week, (C) administering a second reduced dose of d- pirfenidone for a time period, optionally about one week, and (d) administering the original full target dose for a time period of at least one week, two weeks, three weeks, four weeks or a month, two months, or three months, or one year, or two years, or three years, or four years, or five years, or seven years, or ten years. In certain ments, the total daily dose is administered two or three times per day, with food. In certain embodiments, the d-pirfenidone is d3-pirfenidone.

Alternatively, d-pirfenidone is administered at a permanently reduced dose. In some embodiments, enidone is administered to a patient exhibiting a liver on Grade 1 abnormality as follows: administering a reduced dose of d-pirfenidone for a time period of at least one week, two weeks, three weeks, four weeks or a month, two months, or three months, or one year, or two years, or three years, or four years, or five years, or seven years, or ten years. In some embodiments, enidone is administered to a patient exhibiting a liver function Grade 1 abnormality as follows: (a) administering a first reduced dose of d-pirfenidone for a time period, optionally about a week, or until biomarkers of liver function are within normal limits, and (b) administering a second reduced dose of d- idone to the patient for a time period of at least one week, two weeks, three weeks, four weeks or a month, two months, or three months, or one year, or two years, or three years, or four years, or five years, or seven years, or ten years. In certain embodiments, the d- pirfenidone is d3-pirfenidone.

In other embodiments, d-pirfenidone is administered to a patient exhibiting a liver function Grade 1 ality as follows: (a) discontinuing d-pirfenidone for a time period, optionally about one week, or until the liver on biomarkers return to Grade 0, (b) administering a first d dose of d-pirfenidone for about a week, or until biomarkers of liver function are within normal limits, and (c) stering a second reduced dose of d- pirfenidone to the t for a time period of at least one week, two weeks, three weeks, four weeks or a month, two months, or three months, or one year, or two years, or three years, or four years, or five years, or seven years, or ten years. In still other embodiments, d- pirfenidone is administered to a patient exhibiting a liver function Grade 1 ality as follows: (a) discontinuing d-pirfenidone for a time period, optionally about one week, or until the liver function biomarkers return to Grade 0, and (b) administering a reduced dose of d- pirfenidone to the patient for a time period of at least one week, two weeks, three weeks, four weeks or a month, two months, or three months, or one year, or two years, or three years, or four years, or five years, or seven years, or ten years. In certain embodiments, the d- pirfenidone is d3-pirfenidone.

In any of the embodiments described , any of the reduced doses of d- pirfenidone may be administered for a time period of 2 days, 3 days, 4 days, 5 days, 6 days, one week, about two weeks, or until the level of at least one biomarker of liver function has returned to within normal limits, or until all biomarkers or liver function has returned to within normal limits. In certain embodiments, the d-pirfenidone is d3-pirfenidone.

In any of the embodiments described herein, the patient can have fibrotic lesional . Such a patient is a t who would benefit from enidone administration. In one ment, the patient is suffering from pulmonary fibrosis, idiopathic interstitial pneumonia, autoimmune lung diseases, benign prostate hypertrophy, coronary or myocardial infarction, atrial lation, cerebral tion, myocardiac fibrosis, musculoskeletal is, 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. In one embodiment, the patient is suffering from lymph node fibrosis associated with HIV. In one embodiment, the patient is ing from pulmonary fibrosis, or idiopathic pulmonary fibrosis. In another embodiment, the patient is a person who would benefit from d-pirfenidone administration, optionally with the proviso that the patient is not suffering from idiopathic pulmonary fibrosis. In certain embodiments, the d-pirfenidone is d3-pirfenidone.

In some embodiments, the biomarker of liver function is alanine transaminase, ate transaminase, bilirubin, and/or alkaline phosphatase. Elevated glutamyl erase has been observed in some patients receiving d-pirfenidone, without clinical liver impairment, and thus elevated gamma-glutamyl transferase alone is not necessarily a sign of liver impairment. In any of the ments described herein, biomarkers of liver function can exclude gamma-glutamyl transferase. In another embodiment, the al level of alanine transaminase, aspartate transaminase, or alkaline phosphatase is r than about 2.5- fold increased ed to the upper limit of normal (ULN). In a related ment, the abnormal level of alanine transaminase, aspartate transaminase, or alkaline phosphatase is greater than about 2.5- to about 5-fold increased compared to the upper limit of normal (ULN), i.e. a "liver function Grade 2 abnormality". In some embodiments, the abnormal level of bilirubin is greater than about 1.5- to about 3-fold increased compared to the upper limit of normal (ULN), i.e., a "liver function Grade 2 abnormality". -l6- In some embodiments the abnormal biomarkers of liver function, e.g. ed alanine transaminase and/or aspartate transaminase and/or elevated bilirubin, are accompanied by clinical signs of impaired liver function such as jaundice.

The invention provides s for administering a full therapeutically effective dose of enidone to a patient that has exhibited abnormal levels of biomarkers of liver function after the patient has been d with d-pirfenidone. Because liver function abnormalities can be indicative of drug-induced liver injury (hepatotoxicity), it is important to determine whether the abnormalities reflect liver injury or merely indicate limited ty that will resolve over time while continuing to take the drug. According to the present invention, even patients that exhibit abnormal liver function may continue taking d- pirfenidone at the original full target dose, optionally after a short time period of discontinuing d-pirfenidone or taking the enidone at reduced doses. This administration regimen has the advantage of maximizing the time on the full target dose of drug and therefore the potential for a beneficial therapeutic . In certain embodiments, the d- pirfenidone is d3-pirfenidone.

The t may be suffering from any disease for which enidone therapy may be useful in ameliorating symptoms. Such a patient is a patient who would benefit from d-pirfenidone administration. These diseases include, but are not limited to: chronic obstructive pulmonary disease (COPD), inflammatory pulmonary fibrosis (IPF), rheumatoid arthritis; rheumatoid spondylitis; osteoarthritis; gout, other arthritic conditions; sepsis; septic shock; endotoxic shock; gram-negative sepsis; toxic shock syndrome; ial pain syndrome (MPS); Shigellosis; asthma; adult respiratory distress me; inflammatory bowel e; Crohn's disease; psoriasis; eczema; ulcerative colitis; glomerular nephritis; derma; chronic thyroiditis; Grave's disease; Ormond's disease; autoimmune tis; myasthenia gravis; autoimmune tic anemia; mune neutropenia; thrombocytopenia; pancreatic fibrosis; chronic active hepatitis including hepatic fibrosis; acute and chronic renal disease; renal fibrosis, irritable bowel syndrome; pyresis; restenosis; cerebral malaria; stroke and ischemic injury; neural trauma; Alzheimer's disease; gton's disease; Parkinson's disease; acute and chronic pain; allergies, including allergic rhinitis and allergic conjunctivitis; c 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 sed intervertebral disk syndrome; osteopetrosis; thrombosis; silicosis; pulmonary sarcosis; bone resorption diseases, such as orosis or multiple myeloma-related bone disorders; cancer, including but not limited to metastatic breast carcinoma, ctal 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 atory Syndrome (SARS) and cytomegalovirus; and diabetes mellitus. In addition, the methods of the embodiments can be used to treat proliferative ers ding both benign and ant hyperplasias), including acute myelogenous leukemia, chronic myelogenous leukemia, Kaposi's sarcoma, metastatic melanoma, multiple myeloma, breast cancer, ing metastatic breast carcinoma; colorectal carcinoma; malignant melanoma; gastric cancer; non-small cell lung cancer (NSCLC); bone metastases, and the like; pain disorders ing neuromuscular pain, headache, cancer pain, dental pain, and tis 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 roxide synthase-2 ding edema, fever, sia, and pain); organ hypoxia; thrombin-induced platelet aggregation; protozoal diseases; e fibroids; diabetic kidney disease; endotoxin-induced liver injury after partial hepatectomy or hepatic ischemia; aft injury after organ lantation: cystic fibrosis: dermatomyositis; diffuse parenchymal lung disease; mediastinal fibrosis; tuberculosis; spleen fibrosis caused by sickle- cell anemia; rheumatoid arthritis; and/or any disorder ameliorated by modulating fibrosis and/or collagen infiltration into tissues. In certain embodiments, the d-pirfenidone is d3- pirfenidone.

The methods of the invention optionally include identifying abnormal liver function in a patient receiving d-pirfenidone, and monitoring biomarkers of liver on in a patient receiving a reduced dose of d-pirfenidone. In any of the methods described herein, AST and/or ALT may be elevated, e. g. to a Grade 2 or Grade 3 level. In some embodiments, the elevation is to a Grade 1 level. Alternatively, AST and bilirubin may be elevated, or AST or ALP may be elevated, or AST and GGT may be elevated, or ALT and bilirubin may be elevated, or ALT and ALP may be elevated, or ALT and GGT may be elevated, or bilirubin and ALP may be elevated, or bilirubin and GGT may be elevated, e.g., to a Grade 1, Grade 2, or Grade 3 level. Alternatively, three biomarkers of liver function may be elevated, e. g., ALT and AST and bilirubin, or ALT and AST and ALP, to a Grade 1, Grade 2, or Grade 3 level. In any of the embodiments described herein, biomarkers of liver on can exclude gamma- glutamyl transferase. In certain embodiments, the d-pirfenidone is d3-pirfenidone.

In some embodiments of the methods, d-pirfenidone is administered to a patient ting a liver function Grade 2 abnormality after enidone administration as follows: (a) administering a first d dose of d-pirfenidone for a time . In some embodiments, step (a) is followed by (b) administering the original full target dose. In other embodiments, the al full target dose is continued without a temporary reduction or discontinuation of the dose. In some embodiments, the time period of step (a) is 2 days, 3 days, 4 days, 5 days, 6 days, about one week, about two weeks, about three weeks, about four weeks, about 1 month, or until the level of at least one biomarker of liver function has returned to within normal limits, or until all biomarkers or liver function has returned to within normal limits. In some embodiments, step (b) is carried out for a time period of at least one week, two weeks, three weeks, four weeks or a month, two months, or three months, or one year, or two years, or three years, or four years, or five years, or seven years, or ten years, or more. Optionally the method includes measuring one or more biomarkers ofliver function during step (a) and/or step (b). In certain embodiments, the d-pirfenidone is d3-pirfenidone.

In some embodiments of the methods, d-pirfenidone is administered to a t exhibiting a liver function Grade 2 abnormality as follows: (a) administering a first reduced dose of d-pirfenidone for a time period, (b) administering a second reduced dose of for a time period, and (c) administering the original full target dose. In some ments, the time period of step (a) is 2 days, 3 days, 4 days, 5 days, 6 days, about one week, about two weeks, about three weeks, about four weeks, about 1 month, or until the level of at least one biomarker of liver function has returned to within normal limits, or to Grade 1, or until all biomarkers or liver function has ed to within normal limits, or to Grade 1. In some embodiments, the time period of step (b) is 2 days, 3 days, 4 days, 5 days, 6 days, about one week, about two weeks, about three weeks, about four weeks, about 1 month, or until the level of at least one biomarker of liver function has returned to within normal limits, or to Grade 1, or until all biomarkers or liver function has returned to within normal limits, or to Grade 1. In some embodiments, step (c) is carried out for a time period of at least one week, two weeks, three weeks, four weeks or a month, two months, or three months, or one year, or two years, or three years, or four years, or five years, or seven years, or ten years, or more.

Optionally the method includes measuring one or more biomarkers ofliver function during step (a) and/or step (b) and/or step (c). In certain embodiments, the d-pirfenidone is d3- pirfenidone.

In some ments of the s, d-pirfenidone is administered to a patient exhibiting a liver function Grade 2 abnormality as follows: (a) discontinuing d- pirfenidone for a time period, (b) administering a first reduced dose of d-pirfenidone for a time period, (C) administering a second reduced dose of d-pirfenidone for a time , and (d) administering the original full target dose. In some embodiments, the time period of step (a) is 2 days, 3 days, 4 days, 5 days, 6 days, about one week, about two weeks, about three weeks, about four weeks, about 1 month, or until the level of at least one ker of liver function has ed to within normal limits, or to Grade 1, or until all biomarkers or liver function has returned to within normal limits, or to Grade 1. In some ments, the time period of step (b) is 2 days, 3 days, 4 days, 5 days, 6 days, about one week, about two weeks, about three weeks, about four weeks, about 1 month, or until the level of at least one biomarker of liver function has returned to within normal limits, or to Grade 1, or until all biomarkers or liver function has returned to within normal limits, or to Grade 1. In some embodiments, the time period of step (c) is 2 days, 3 days, 4 days, 5 days, 6 days, about one week, about two weeks, about three weeks, about four weeks, about 1 month, or until the level of at least one biomarker of liver function has returned to within normal limits, or to Grade 1, or until all biomarkers or liver on has returned to within normal limits, or to Grade 1. In some ments, step (d) is carried out for a time period of at least one week, two weeks, three weeks, four weeks or a month, two months, or three months, or one year, or two years, or three years, or four years, or five years, or seven years, or ten years, or more. ally the method includes measuring one or more biomarkers of liver function during step (a) and/or step (b) and/or step (c) and/or step (d). In certain embodiments, the d- pirfenidone is d3-pirfenidone.

In some embodiments of the s, d-pirfenidone is administered to a patient exhibiting a liver function Grade 1 abnormality as follows: (a) administering a reduced dose of d-pirfenidone for a time period, and (b) administering the original full target dose. In some embodiments, the time period of step (a) is 2 days, 3 days, 4 days, 5 days, 6 days, about one week, about two weeks, about three weeks, about four weeks, about 1 month, or until the level of at least one biomarker of liver function has returned to within normal limits, or until all biomarkers or liver function has returned to within normal limits. In some ments, step (b) is carried out for a time period of at least one week, two weeks, three weeks, four weeks or a month, two months, or three months, or one year, or two years, or three years, or four years, or five years, or seven years, or ten years, or more. Optionally the method includes measuring one or more biomarkers ofliver function during step (a) and/or step (b). In certain embodiments, the d-pirfenidone is d3-pirfenidone.

In some embodiments of the methods, d-pirfenidone is administered to a patient exhibiting a liver function Grade 1 abnormality as follows: (a) stering a first reduced dose of d-pirfenidone for a time period, (b) administering a second reduced dose of d-pirfenidone for a time period, and (c) administering the original full target dose. In some embodiments, the time period of step (a) is 2 days, 3 days, 4 days, 5 days, 6 days, about one week, about two weeks, about three weeks, about four weeks, about 1 month, or until the level of at least one biomarker of liver function has returned to within normal limits, or to Grade 1, or until all biomarkers or liver function has returned to within normal limits, or to Grade 1. In some embodiments, the time period of step (b) is 2 days, 3 days, 4 days, 5 days, 6 days, about one week, about two weeks, about three weeks, about four weeks, about 1 month, or until the level of at least one biomarker of liver function has returned to within normal limits, or to Grade 1, or until all biomarkers or liver function has returned to within normal limits, or to Grade 1. In some ments, step (c) is carried out for a time period of at least one week, two weeks, three weeks, four weeks or a month, two months, or three months, or one year, or two years, or three years, or four years, or five years, or seven years, or ten years, or more. Optionally the method es measuring one or more biomarkers ofliver function during step (a) and/or step (b) and/or step (c). In n embodiments, the d-pirfenidone is d3-pirfenidone.

In some embodiments of the methods, d-pirfenidone is administered to a patient exhibiting a liver on Grade 1 abnormality as follows: (a) discontinuing d- pirfenidone for a time period, (b) administering a first reduced dose of d-pirfenidone for a time period, (c) administering a second reduced dose of d-pirfenidone for a time period, and (d) stering the original full target dose. In some embodiments, the time period of step (a) is 2 days, 3 days, 4 days, 5 days, 6 days, about one week, about two weeks, about three weeks, about four weeks, about 1 month, or until the level of at least one biomarker of liver function has ed to within normal limits, or to Grade 1, or until all biomarkers or liver on has returned to within normal limits, or to Grade 1. In some embodiments, the time period of step (b) is 2 days, 3 days, 4 days, 5 days, 6 days, about one week, about two weeks, about three weeks, about four weeks, about 1 month, or until the level of at least one biomarker of liver function has returned to within normal limits, or to Grade 1, or until all biomarkers or liver function has returned to within normal limits, or to Grade 1. In some embodiments, the time period of step (c) is 2 days, 3 days, 4 days, 5 days, 6 days, about one week, about two weeks, about three weeks, about four weeks, about 1 month, or until the level of at least one biomarker of liver function has returned to within normal limits, or to WO 22165 Grade 1, or until all biomarkers or liver function has returned to within normal limits, or to Grade 1. In some embodiments, step (d) is carried out for a time period of at least one week, two weeks, three weeks, four weeks or a month, two months, or three months, or one year, or two years, or three years, or four years, or five years, or seven years, or ten years, or more.

Optionally the method includes measuring one or more biomarkers of liver on during step (a) and/or step (b) and/or step (C) and/or step (d). In certain embodiments, the d- pirfenidone is d3-pirfenidone. d-Pirfenidone can be provided in tablet or capsule forms or any other oral dosage form, and typically is formulated for oral administration. Exemplary capsule formulations are described in (Int'l Appl. No. PCT/U82006/037057). enidone y can be associated with adverse effects including photosensitivity rash, anorexia (decreased te), stomach discomfort, nausea, heartburn, drowsiness (somnolence), fatigue, upper respiratory tract infection, fever, positive urinary occult blood, elevation of tive protein (CRP), sed weight, headache, constipation, and malaise. Abnormal liver function also can occur as an adverse effect (AE) in patients receiving d-pirfenidone. Prior to receiving d-pirfenidone, the baseline liver function of the patient can be, and typically is, normal. Liver function can be assessed by s means known in the art, such as blood chemistry tests ing biomarkers of liver function. Examples of biomarkers of liver function include, but are not limited to, e transaminase (ALT), ate transaminase (AST), bin, alkaline phosphatase (ALP), and lutamyl transferase (GGT).

Alanine transaminase (ALT), also called serum glutamic pyruvate transaminase (SGPT) or alanine aminotransferase , catalyzes the er of an amino group from alanine to a-ketoglutarate to produce pyruvate and glutamate. When the liver is damaged, levels of ALT in the blood can rise due to the leaking of ALT into the blood from damaged or necrosed hepatocytes.

Aspartate transaminase (AST) also called serum glutamic oxaloacetic transaminase (SGOT or GOT) or aspartate aminotransferase (ASAT), catalyzes the transfer of an amino group from aspartate to a-ketoglutarate to produce oxaloacetate and glutamate.

AST can increase in response to liver damage. Elevated AST also can result from damage to other sources, including red blood cells, cardiac muscle, skeletal muscle, kidney tissue, and brain tissue. The ratio of AST to ALT can be used as a biomarker of liver damage.

Bilirubin is a catabolite of heme that is cleared from the body by the liver.

Conjugation of bilirubin to glucuronic acid by hepatocytes produces direct bilirubin, a water soluble t that is readily cleared from the body. Indirect bilirubin is unconjugated, and the sum of direct and indirect bilirubin constitutes total bilirubin. Elevated total bilirubin can be indicative of liver impairment.

Alkaline phosphatase (ALP) hydrolyzes phosphate groups from various les and is present in the cells lining the biliary ducts of the liver. ALP levels in plasma can rise in response to liver damage, and are higher in growing children and elderly patients with Paget's disease. However, elevated ALP levels usually reflect biliary tree disease.

Adverse effect Grades for abnormal liver function are defined herein by the modified Common Toxicity ia (CTC) provided in Table 1. See the Common Terminology Criteria for Adverse Events v3.0 (CTCAE) published August 9, 2006 by the al Cancer Institute, incorporated herein by reference in its entirety.

Table 1. Modified Common Toxicity Criteria Grade Toxicity 0 l 2 3 4 ALT WNL >ULN-2.5 x ULN >2.5-5 x ULN >5-20 x ULN >20 x ULN AST WNL >ULN-2.5 x ULN >2.5-5 x ULN >5-20 x ULN >20 x ULN Bilrubin WNL >ULN-l.5 x ULN >l.5-3 x ULN >3-10 x ULN >10 x ULN ALP WNL >ULN-2.5 x ULN >2.5-5 x ULN >5-20 x ULN >20 x ULN GGT WNL >ULN-2.5 x ULN >2.5-5 x ULN >5-20 x ULN >20 x ULN (WNL =within normal limits; ULN =upper limit of normal) The ULN for various indicators of liver on s on the assay used, the patient population, and each laboratory's normal range of values for the specified ker, but can readily be determined by the skilled practitioner. Exemplary values for normal ranges for a healthy adult population are set forth in Table 2 below. See Cecil Textbook of ne, pp. 2317-2341, W.B. Saunders & Co. (1985).

Table 2 8-20 U/L 8-20 U/L Bilrubin 0 mg/dL 3.4-17.l /umol/L ALP 20-70 U/L GGT 8-40 U/L Grade 0 levels are characterized by biomarker levels within normal limits (WNL). "Normal" liver function, as used herein, refers to Grade 0 adverse effects.

"Abnormal" liver function, as used herein, refers to Grade 1 and above adverse effects.

"Grade 1 liver function alities" include elevations in ALT, AST, ALP, or GGT greater than the ULN and less than or equal to 2.5-times the ULN. Grade 1 liver function abnormalities also include elevations of bilirubin levels greater than the ULN and less than or equal to l.5-times the ULN.

"Grade 2 liver function abnormalities" e elevations in alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), or gamma- yl transferase (GGT) greater than mes and less than or equal to 5-times the upper limit of normal (ULN). Grade 2 liver function abnormalities also include elevations of bilirubin levels greater than l.5-times and less than or equal to 3-times the ULN.

"Grade 3 liver function abnormalities" include elevations in ALT, AST, ALP, or GGT greater than 5-times and less than or equal to 20-times the ULN. Grade 3 liver function abnormalities also e ions of bin levels greater than 3-times and less than or equal to lO-times the ULN.

"Grade 4 liver function abnormalities" include elevations in ALT, AST, ALP, or GGT greater than 20-times the ULN. Grade 4 liver function abnormalities also include ions of bilirubin levels greater than 10 the ULN.

The present disclosure provides methods for treating a patient having idiopathic pulmonary fibrosis and receiving a full target dose of d-pirfenidone. In accordance with the methods, a patient with abnormal liver function is administered a second reduced dose of d-pirfenidone until liver function is within normal limits, followed by administering the patient the full target dose of d-pirfenidone per day. In n embodiments, the d- pirfenidone is d3-pirfenidone.

The present sure also provides methods for treatment of patients that exhibit Grade 1 abnormality in one or more biomarkers of liver function after d-pirfenidone administration. In certain embodiments, the t may be ing d-pirfenidone for treatment of idiopathic pulmonary fibrosis. Alternatively, the patient may be suffering from a condition for which d-pirfenidone stration may be beneficial. Optionally, patients may receive reduced doses or discontinue ent for a time period, and then resume administration of d-pirfenidone. In certain embodiments, the d-pirfenidone is d3-pirfenidone.

The present invention provides an improved dose escalation scheme for the administration of d-pirfenidone. The dose escalation scheme of the t invention provides 2012/027872 d-pirfenidone in an amount such that the full maximum dosage is not reached for at least one week. In an embodiment, the full maximum dosage of d-pirfenidone is not reached until about Day 15 of treatment. The method of the present invention allows for a maximum dosage of d-pirfenidone per day to be administered to a patient and also reduces the incidence of adverse events associated with the administration of d-pirfenidone by more accurately matching dose escalation with tolerance development in the patient. Indeed, it has been observed that even as the dosage escalates using the dosing escalation scheme described herein, adverse events, such as somnolence, decrease. In certain embodiments, the d- pirfenidone is d3-pirfenidone.

The present ion discloses a method of providing d-pirfenidone therapy to a patient sing providing an initial daily dosage of d-pirfenidone to the patient in a first amount for the duration of a first period of time; ing a second daily dosage of d- pirfenidone to the patient in a second amount for a second period of time; and providing a final daily dosage of d-pirfenidone to the patient in a final amount for a final period of time, wherein the first and second periods of time together total at least about 7 days, or about 8, 9, , 11 or 12 days, or about 13 or 14 days. In some embodiments, the first and second periods can er total up to about 15 or about 20 or 21 days. In certain embodiments, the d- pirfenidone is d3-pirfenidone.

In one ment, the first period of time is about 7 days; the second period of time is about 7 days; and the third period of time is in the range of about 1 day up to an unlimited number of days. In specific embodiments, the third period of time lasts at least about 1 month, at least about 2 months, at least about 3 months, at least about a year, at least about 18 months, at least about 2 years, or more than 2 years, at least about 3 years, at least about 4 years, at least about 5 years, or as long as therapy with d-pirfenidone is needed. In certain embodiments, the d-pirfenidone is d3-pirfenidone.

The present invention also discloses a r pack comprising dosage amounts of d-pirfenidone and compartments that separate the dosage amounts according to a daily dosage of d-pirfenidone. Advantageously, the compartments can be arranged in columns and in rows, gh other arrangements are also contemplated. In certain ments, the d- pirfenidone is d3-pirfenidone.

In one exemplary embodiment, the starter pack comprises rows ating Day numbers and te columns for the number of times a dosage of d-pirfenidone is taken each day. In one embodiment, the starter pack may comprise separate rows for Days 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14 with te columns for dosage amounts to be 2012/027872 taken each day. In another ment, each week of treatment may be designated on a separate panel. In another embodiment, each panel contained within the starter pack may be approximately the same size. In another embodiment, the r pack has compartments arranged such that a user of the starter pack may administer the d-pirfenidone in accordance with the dose escalation method taught by the present invention. In certain embodiments, the d-pirfenidone is d3-pirfenidone.

Also contemplated is use of d-pirfenidone in preparation of a ment for the treatment of a fibrosis ion comprising administration of d-pirfenidone according to a dosing n as disclosed herein. In certain embodiments, the enidone is d3- pirfenidone.

The present ion discloses a method of providing d-pirfenidone therapy to a patient with an escalating dosage regimen that mitigates adverse events associated with the use of d-pirfenidone and, it is believed, better matches the development of tolerance to potentially adverse effects of the drug with increases in the dosage. In one embodiment of the present invention is a method of providing d-pirfenidone therapy to a patient comprising providing an l daily dosage of d-pirfenidone to the patient in a first amount for the duration of a first period of time; providing a second daily dosage of d-pirfenidone to the patient in a second amount for a second period of time; and providing a final daily dosage of d-pirfenidone to the patient in a final amount for a final period of time. In certain embodiments the sum of the first and second periods of time is at least about 7 days, in further embodiments about 8, 9, 10, 11, or 12 days, and in further embodiments about 13 or 14 days. In some embodiments, the first and second periods can together total up to about 15 or about 20 or 21 days. gh it is also contemplated that the first and second periods together can total more than 21 days, and can (for example) be 22, 24, 26, or 30 days, it is believed that the longer dose escalation periods are less than optimal, due to the decrease in therapeutic benefit to the patient resulting from the delay in administering the full therapeutic dosage. In certain ments, the d-pirfenidone is fenidone.

Although the present disclosure exemplifies dose escalation regimens having three steps, it is also possible to have more steps in the same amount of time, so that the dosage escalates in smaller steps. Indeed, if desired, each dose can be incrementally larger than the previous dose, or the dose can escalate every day, every two days, or every three or four days, for example. Regardless of the dose tion step size, the use of an initial dose and an ending dose in the amounts discussed below is ularly preferred.

In one embodiment, the first period of time is in the range of about 3 days to about 10 days. In another embodiment, the first period of time is about 6 to about 8 days. In another embodiment, the first period of time is about 7 days.

In one embodiment, the second period of time is in the range of about 3 days to about 10 days. In another embodiment, the second period of time is about 6 to about 8 days. In another embodiment, the second period of time is about 7 days.

In one embodiment, the final period of time is in the range of about 1 day to an unlimited number of days. In certain embodiments, the final period of time will be however long the duration of treatment with d-pirfenidone should last. In certain embodiments, the d- pirfenidone is d3-pirfenidone.

In one embodiment, a dosage amount of d-pirfenidone is taken with food. In another ment, the patient is cted to administer the dosage of d-pirfenidone with food. In certain embodiments, the d-pirfenidone is d3-pirfenidone.

In r embodiment of the present invention, there is provided a starter pack comprising d-pirfenidone. Starter packs are a relatively easy method for singulating, transporting, storing and finally dispensing oral solid drugs. Such packs include, for instance, a planar transparent piece of plastic provided with ers" or convex protrusions ured in rows and columns. Each of the blisters or convex protrusions is sized to receive a singulated dosage amount of the particular oral solid drug being dispensed. In certain embodiments, the d-pirfenidone is d3-pirfenidone.

] Typically, at least one backing layer is fastened to a solid receiving side of the blister pack. This layer is a low strength retaining r. This low strength retaining layer stretches across the backs of the blisters and retains the singulated oral dosage amounts individually sealed within each of the blisters.

Dispensing of drugs from such blister packs is easy to understand. The consumer presses down on a r from the convex side of the blister. Such pressure bears directly against the singulated oral dosage amount ned in the blister. The singulated oral solid drug is then forced through the low strength ing barrier. This low strength ing barrier at least partially tears and breaks away. During this l breaking and tearing away, the singulated oral dosage amount is partially--but typically not totally--ejected from its individual blister. In certain embodiments, it is during this partial ejection that the oral solid drug is grasped by the user and consumed as directed. The result is a safe, sterile sing of the drug in desired single dosage amounts from the blister pack.

The starter pack of the present invention may comprise various dosage amounts of d-pirfenidone designated within blisters or other individual compartments so that the patient will take the proper dosage amount of the drug each day. The starter pack may comprise many different forms. It is contemplated that a panel may be constructed to se more or less compartments. For instance, a panel may be constructed to hold dosage amounts for three days of treatment. In another embodiment, a panel may be constructed to hold dosage amounts for six days of treatment. In r embodiment, a panel may be constructed to hold dosage amounts for ten days of treatment. Any number of days and dosages in a single panel are plated by the inventors. In certain embodiments, the starter pack may be designed so that the user administers d-pirfenidone according to the dose escalation scheme of the present invention. In n embodiments, the d-pirfenidone is d3- idone.

In one ment, the starter pack comprises panels giving dosage amounts of enidone for the first week of treatment and the second week of treatment. In another embodiment, the starter pack r comprises a panel giving dosage amounts of d- pirfenidone for the third week of treatment. In another ment, the starter pack comprises a panel or an insert that gives instructions to a t for administering the proper dosage amount of d-pirfenidone. In certain embodiments, the d-pirfenidone is d3-pirfenidone.

In one embodiment, the starter pack may comprise only dosage amounts for the first week of treatment and the second week of treatment. In certain embodiments, such a r pack may also comprise instructions to the patient for administering the d-pirfenidone from a bottle for therapy after dose escalation is completed. It is contemplated that the user of the starter pack will continue therapy with d-pirfenidone pills from a bottle after dose escalation is completed. In certain embodiments, the d-pirfenidone is d3-pirfenidone.

The size of the starter pack and the panels that comprise the starter pack may be typical of similar starter packs already known. In a preferred embodiment, each panel within a starter pack is approximately of r size dimensions as the other panels of the starter pack.

In some embodiments, the starter pack comprises a unitary structure, wherein the unitary structure comprises more than one panel and each panel may comprise dosage amounts for one week of ent. In some embodiments, the starter pack comprises a panel that has printed instructions thereon. In some embodiments, the starter pack may comprise panels having tments for containing dosages of d-pirfenidone. The dosages may be WO 22165 2012/027872 pushed through the low strength retaining barrier at points opposite the location of the blisters.

In certain ments, the d-pirfenidone is d3-pirfenidone.

The Week 1 panel may have compartments that comprise a dosage amount of d-pirfenidone related to the first week of treatment. The Week 2 panel may have compartments that comprise a dosage amount of d-pirfenidone related to the second week of ent. Optionally, a panel for the dosage amounts of Week 3 may be included. The Week 3 panel may have compartments that se a dosage amount of d-pirfenidone related to the third week of usage. The other panel may be left blank or ed with instructions or any other type of indicia. In some embodiments, the starter pack may comprise an adhesive seal or a sticker that holds the starter pack in folded form until the adhesive seal or sticker is broken by a user. The starter pack may comprise regions e of folding so that the separate panels can be d upon one another while the starter pack maintains its y structure. In certain embodiments, the d-pirfenidone is d3-pirfenidone.

In one embodiment, one panel may comprise tments giving the dosage amount for Days 1-7 of the dose escalation scheme and the second panel may comprise compartments giving the dosage amount for Days 8-14 of the dose escalation scheme. In another embodiment, an optional third panel may be further provided to comprise compartments giving the dosage amount for Days 15-21 of the dose escalation scheme.

The starter pack for the first week of treatment may comprise a panel having a plurality of compartments for containing a dosage amount of d-pirfenidone. The compartments may be arranged in column and row fashion as illustrated, although other ements are also contemplated, including having all of the compartments arranged in a line, or having them arranged in a circular fashion. Additionally, instructions may be provided on the starter pack indicating the proper day and time the dosage amount should be administered. In certain embodiments, the d-pirfenidone is d3-pirfenidone.

The starter pack for the second week of treatment may comprise a panel having a plurality of compartments for containing a dosage amount of d-pirfenidone. The tments for the second week of treatment may be fashioned to hold a greater amount of d-pirfenidone than the compartments for the first week of treatment. The dosage amount of dpirfenidone for the second week may be greater than the dosage amount of the first week.

Additionally, instructions may be provided on the starter pack indicating the proper day and time the dosage amount should be administered. In certain embodiments, the d-pirfenidone is d3 -pirfenidone.

The starter pack for the third week of treatment may comprise a panel having a plurality of compartments for containing a dosage amount of d-pirfenidone. The compartments for the third week of treatment may be ned to hold a greater amount of d-pirfenidone than the compartments for the second week of treatment. The dosage amount of d-pirfenidone for the third week may be greater than the dosage amount of the second week.

Additionally, instructions may be provided on the starter pack indicating the proper day and time the dosage amount should be administered. In certain embodiments, the d-pirfenidone is d3-pirfenidone.

] In some embodiments, the starter pack may comprise a casing material that holds separate panels, wherein at least one panel comprises a plurality of compartments for containing a dosage amount of enidone. In some ments, the panel may be located within a ner having flat outer surfaces so that the container may easily be slid in and out of the casing material. In one ment, each ner may comprise a panel that comprises a plurality of compartments that hold a dosage amount of d-pirfenidone. In some embodiments, the panels may further comprise instructions or indicia so that a user can administer d-pirfenidone according to the dose escalation scheme. In some embodiments, a panel may be provided separately for providing indicia or instructions on using the drug. In some ments, indicia or instructions may be provided on one or more of the containers.

In n embodiments, the d-pirfenidone is fenidone.

In certain embodiments a starter pack comprises a casing material and at least one container. The container is partially pulled out from the casing material and may comprise a panel having a plurality of compartments for containing a dosage amount of d- pirfenidone. In certain embodiments, each panel will be approximately the same size for easy and compact insertion into the casing material. In certain embodiments, the enidone is d3-pirfenidone.

One embodiment of the present invention is a starter pack comprising dosage amounts of d-pirfenidone and compartments that separate the dosage amounts according to a daily dosage of d-pirfenidone. In one embodiment, the starter pack comprises a row designating Day numbers and te columns for the number of times a dosage of d- pirfenidone is taken each day. In one embodiment, the starter pack may se separate rows for Days 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, ll, 12, 13, and 14 with te columns for dosage amounts to be taken each day. In another embodiment, each panel contained within the starter pack may be approximately the same size. In another embodiment, the starter pack has compartments arranged such that a user of the starter pack will administer the d-pirfenidone in ance with the dose escalation method taught by the present invention. In certain embodiments, the d-pirfenidone is d3-pirfenidone.

In one embodiment, the starter pack r comprises additional rows for Days 15, 16, 17, 18, 19, 20, and 21. In another embodiment, each of the compartments corresponding to Days 15, l6, l7, l8, 19, 20, and 21 separately contain a dosage of d- pirfenidone. The addition of the rows for Days 15, l6, l7, l8, 19, 20, and 21 is for the purpose of training the patient as to the correct amount of dosage that will be needed after the r pack is finished and the patient begins taking pills from r source, such as a pill bottle. By providing the starter pack with a third week at the full dosage of d-pirfenidone, the patient will be better accustomed to taking the dosage from Day 15 and each Day thereafter as required by the d-pirfenidone y method of the present invention. In certain embodiments, the d-pirfenidone is d3-pirfenidone.

In another embodiment, the starter pack comprises a circular form. In n embodiments a container ses a base that holds at least one panel haVing a plurality of compartments for containing a dosage amount of enidone. The panel is circular in shape with compartments extending in a radial pattern from the center and wherein each radius designates its own Day for ent with d-pirfenidone. The dosages for AM, noon, and PM may be separated. The container also comprises a lid so that at least one panel containing d- pirfenidone can be stored within the container and sealed. In n embodiments, the d- pirfenidone is d3-pirfenidone.

In certain embodiments a starter pack comprises dosage amounts for the first week of therapy using d-pirfenidone. The starter pack for the first week of treatment may comprise a circular panel haVing a plurality of compartments for containing a dosage amount of d-pirfenidone. The compartments may be arranged so that they extend radially from the center of the pane. The panel may comprise indicia informing the patient which dosage to administer at the appropriate time. In certain embodiments, the d-pirfenidone is d3- pirfenidone.

In certain embodiments a starter pack comprises dosage amounts for the second week of therapy using d-pirfenidone. The r pack for the second week of treatment may comprise a circular panel haVing a plurality of compartments for containing a dosage amount of d-pirfenidone. The compartments may be ed so that they extend radially from the center or so that they fit within a panel. The panel may comprise indicia informing the patient which dosage to administer at the riate time. In certain embodiments, the d-pirfenidone is d3-pirfenidone.

In certain embodiments a starter pack comprises dosage s for the third week of therapy using d-pirfenidone. The panel for the third week of therapy is optionally provided. The starter pack for the third week of treatment may comprise a circular panel having a ity of compartments for containing a dosage amount of d-pirfenidone. The compartments may be arranged so that they extend radially from the center of the pane. The panel may comprise a informing the patient which dosage to administer at the appropriate time. In certain embodiments, the d-pirfenidone is d3-pirfenidone.

In another embodiment, the r pack has compartments arranged such that a user of the starter pack will administer the d-pirfenidone in accordance with the dose escalation method taught by the present invention. Of course, as an ative to blister packs, the doses can be contained in any other type of compartment, such as plastic bags or other containers fastened together in book form; plastic containers with snap-open lids arranged in a row or other geometric pattern, or any of a wide variety of other dosagecontaining packages. In certain embodiments, the d-pirfenidone is d3-pirfenidone.

In one ment, a method for administering d-pirfenidone therapy to a patient comprises initially administering a predetermined starting dosage of enidone to the patient and escalating the dosage stered to the patient over a predetermined time to a predetermined full dosage of d-pirfenidone. In some embodiments, the predetermined time is measured from the initial starting dosage and is between about 7 and 20 days. In some embodiments, the ermined time is 13 or 14 days. In some embodiments, the s are split into one, two, or three daily oral administrations. In certain embodiments, the d- pirfenidone is d3-pirfenidone.

ORATION BY NCE All publications and references cited herein, including those in the background section, are expressly incorporated herein by reference in their entirety. However, with respect to any similar or identical terms found in both the incorporated publications or references and those expressly put forth or defined in this document, then those terms definitions or meanings expressly put forth in this document shall control in all respects.

DETAILED DESCRIPTION To facilitate understanding of the sure set forth herein, a number of terms are defined below. Generally, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, and cology described herein are those well known and commonly employed in the art. Unless d otherwise, all technical and scientific terms used herein generally have the same meaning as ly tood in the art to which this disclosure belongs. In the event that there is a plurality of definitions for a term used herein, those in this section prevail unless stated otherwise.

As used herein, the singular forms "a," "an," and "the" may refer to plural articles unless ically stated otherwise.

The term "d-pirfenidone" refers to a compound of structural Formula 1: R8 R7 0 R6 R9 N \ R10 R11 R4 R3 R1R2 or a pharmaceutically acceptable salt, solvate, or prodrug thereof; wherein: R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, and R11 are ed from the group consisting of hydrogen or deuterium; and at least one R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, and R11 is deuterium. In certain embodiments, the d-pirfenidone is d3-pirfenidone haVing the following structural formula: GM \ d3-pirfenidone.

The term ct" refers to an animal, including, but not limited to, a primate (e. g., human monkey, chimpanzee, gorilla, and the like), rodents (e. g., rats, mice, gerbils, hamsters, ferrets, and the like), lagomorphs, swine (e. g., pig, miniature pig), equine, canine, feline, and the like. The terms "subject" and "patient" are used interchangeably herein in reference, for example, to a mammalian subject, such as a human patient.

WO 22165 The terms "treat," "treating," and "treatment" are meant to include alleviating or ting a disorder; or alleviating or abrogating one or more of the symptoms associated with the disorder; and/or alleviating or eradicating the cause(s) of the disorder itself.

The terms "prevent," "preventing," and "prevention" refer to a method of delaying or precluding the onset of a disorder; delaying or ding its attendant symptoms; g a subject from acquiring a disorder; and/or reducing a subject’s risk of acquiring a disorder.

The term "therapeutically effective amount" refers to the amount of a compound that, when administered, is ient to prevent development of, or alleviate to some extent, one or more of the symptoms of the disorder being treated. The term "therapeutically effective amount" also refers to the amount of a compound that is ient to elicit the biological or medical se of a cell, tissue, system, animal, or human that is being sought by a researcher, veterinarian, l , or clinician.

The term "pharmaceutically acceptable carrier,77 (Cpharmaceutically acceptable excipient, 77 CCphysiologically able carrier," or "physiologically acceptable excipient" refers to a pharmaceutically-acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. Each component must be "pharmaceutically acceptable" in the sense of being compatible with the other ingredients of a pharmaceutical formulation. It must also be suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenecity, or other problems or complications, commensurate with a reasonable benefit/risk ratio. See, Remington: The Science and Practice ofPharmacy, 21st Edition; Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook ofPharmaceutical Excipients, 5th Edition; Rowe et al., Eds., The Pharmaceutical Press and the American Pharmaceutical ation: 2005; and Handbook ofPharmaceutical Additives, 3rd n; Ash and Ash Eds., Gower Publishing Company: 2007; Pharmaceutical mulation and Formulation, Gibson Ed., CRC Press LLC: Boca Raton, FL, 2004).

The term "deuterium enrichment" refers to the percentage of incorporation of deuterium at a given position in a le in the place of hydrogen. For example, deuterium enrichment of 1% at a given position means that 1% of molecules in a given sample contain deuterium at the ied position. Because the lly occurring distribution of deuterium is about 0.0156%, deuterium enrichment at any position in a compound synthesized using non-enriched starting materials is about 0.0156%. The deuterium enrichment can be determined using conventional analytical s, such as mass spectrometry and nuclear magnetic resonance spectroscopy.

The term "is/are deuterium," when used to describe a given position in a molecule such as R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, and R11 or the symbol "D," when used to represent a given position in a drawing of a molecular structure, means that the specified position is enriched with deuterium above the naturally occurring distribution of deuterium. In an embodiment deuterium ment is of no less than about 1%, in another no less than about 5%, in another no less than about 10%, in another no less than about 20%, in another no less than about 50%, in another no less than about 70%, in another no less than about 80%, in another no less than about 90%, or in r no less than about 98% of ium at the specified position.

The term "isotopic enrichment" refers to the percentage of oration of a less ent isotope of an element at a given position in a molecule in the place of the more prevalent isotope of the element.

The term "non-isotopically ed" refers to a molecule in which the percentages of the various isotopes are substantially the same as the naturally ing percentages.

The terms "substantially pure" and "substantially homogeneous" mean sufficiently homogeneous to appear free of readily detectable impurities as determined by standard analytical methods, including, but not limited to, thin layer chromatography (TLC), gel electrophoresis, high performance liquid chromatography (HPLC), nuclear magnetic resonance (NMR), and mass spectrometry (MS); or sufficiently pure such that further purification would not detectably alter the physical and chemical properties, or biological and pharmacological properties, such as enzymatic and biological activities, of the substance. In n ments, antially pure" or "substantially homogeneous" refers to a collection of molecules, wherein at least about 50%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or at least about 99.5% of the les are a single compound, including a racemic mixture or single stereoisomer thereof, as determined by standard analytical methods.

] The term "about" or "approximately" means an acceptable error for a particular value, which depends in part on how the value is measured or determined. In certain embodiments, "about" can mean 1 or more standard deviations.

The terms "active ingredient" and e substance" refer to a compound, which is administered, alone or in combination with one or more pharmaceutically acceptable excipients and/or carriers, to a subject for treating, preventing, or ameliorating one or more symptoms of a disorder.

The terms "drug," "therapeutic agent," and "chemotherapeutic agent" refer to a compound, or a pharmaceutical ition f, which is administered to a subject for treating, preventing, or ameliorating one or more ms of a disorder.

The term "disorder" as used herein is intended to be generally mous, and is used interchangeably with, the terms "disease,77 CCsydrome" and "condition" (as in medical condition), in that all reflect an abnormal condition of the body or of one of its parts that impairs normal functioning and is typically manifested by guishing signs and symptoms.

The term "release controlling excipient" refers to an excipient whose primary function is to modify the duration or place of release of the active substance from a dosage form as compared with a tional immediate e dosage form.

The term "nonrelease controlling excipient" refers to an excipient whose primary function do not include modifying the duration or place of release of the active substance from a dosage form as compared with a conventional immediate release dosage form.

The term cting group" or "removable protecting group" refers to a group which, when bound to a functionality, such as the oxygen atom of a hydroxyl or carboxyl group, or the nitrogen atom of an amino group, ts reactions from occurring at that functional group, and which can be removed by a conventional chemical or enzymatic step to reestablish the functional group (Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York, NY, 1999).

] The term "fibrosis" refers to the pment of excessive fibrous connective tissue within an organ or tissue.

The term "collagen infiltration" refers to the entry of the connective tissue en into cells or into the extracellular matrix around cells. This occurs in organs and tissues naturally and under normal circumstances but can occur excessively and any or cause disease.

The terms "fibrosis" and "collagen infiltration" are not necessarily synonymous but can, in certain contexts, be used interchangeably.

As used herein, the terms "adverse event" and "adverse reactions" refer to any unfavorable, harmful, or pathologic change in a patient receiving pirfenidone therapy as indicated by physical signs, symptoms, and/or clinically significant laboratory abnormalities that occur in a patient during the treatment and post-treatment period, regardless of suspected cause. This definition es the following: intercurrent illness; injuries; exacerbation of pre-existing conditions; adverse events occurring as a result of product withdrawal, abuse, or overdose; and a change in a laboratory variable if considered by the attending physician to be clinically icant or if it caused (or should have caused) the clinician to reduce or discontinue the use of the product or initiate a nonprotocol therapy or procedure.

As used herein, the term "with food" is defined to mean, in general, the ion of having consumed food during the period n from about 1 hour prior to the administration of pirfenidone to about 2 hours after the administration of pirfenidone.

The terms "without food," "fasted," or "on an empty stomach" are defined to mean the condition of not having consumed food within the time period of about 1 hour prior to the administration of pirfenidone to about 2 hours after the administration of pirfenidone.

In some embodiments, food has not been consumed for about 10 hours, about 8 hours, about 6 hours, about 4 hours, about 2 hours prior to stration of pirfenidone.

] The term "at risk for or suffering from" as used herein, refers to ts having previously experienced, or currently experiencing, or having a high ility of experiencing an adverse event associated with pirfenidone therapy. Methods for identifying a t at risk for or ing from such adverse events are known in the art.

Deuterated Pyridinone Derivatives Pirfenidone is a substituted pyridinone-based fibrosis tor and/or collagen infiltration modulator. The carbon-hydrogen bonds of pirfenidone contain a naturally occurring distribution of hydrogen isotopes, namely 1H or protium (about 99.9844%), 2H or deuterium (about 0.0156%), and 3H or tritium (in the range between about 0.5 and 67 tritium atoms per 1018 protium atoms). Increased levels of deuterium incorporation may produce a detectable Kinetic Isotope Effect (KIE) that could affect the pharmacokinetic, pharmacologic and/or toxicologic profiles of of such fibrosis modulators and/or collagen- infiltration modulators in comparison with the compound having naturally occurring levels of deuterium.

Pirfenidone is likely metabolized in humans by oxidizing the methyl group.

Other sites on the molecule may also undergo ormations leading to lites with as- yet-unknown pharmacology/toxicology. Limiting the production of these metabolites has the potential to decrease the danger of the administration of such drugs and may even allow increased dosage and concomitant increased efficacy. All of these transformations can occur through polymorphically-expressed enzymes, thus bating the interpatient variability.

Further, disorders, such as le sclerosis, are best treated when the subject is medicated around the clock for an extended period of time. For all of foregoing reasons, there is a strong likelihood that a longer half-life ne will diminish these problems with greater efficacy and cost savings.

Various deuteration patterns can be used to a) reduce or eliminate unwanted metabolites, b) increase the half-life of the parent drug, c) decrease the number of doses needed to achieve a desired effect, d) decrease the amount of a dose needed to e a desired effect, e) increase the formation of active metabolites, if any are formed, and/or f) decrease the production of deleterious metabolites in specific tissues and/or create a more effective drug and/or a safer drug for polypharmacy, whether the polypharmacy be ional or not. The deuteration approach has strong potential to slow the metabolism via various oxidative and racemization mechanisms.

In one aspect, disclosed herein is a compound having ural Formula I: R8 R7 0 R6 R9 N R5 R10 R11 R4 R3 R1 R2 or a pharmaceutically acceptable salt, solvate, or prodrug thereof; wherein: R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, and R11 are selected from the group consisting of hydrogen and ium; and at least one of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, and R11 is deuterium; and when R7, R8, R9, R10, and R11 are deuterium, then at least one of R1, R2, R3, R4, R5, and R6 is deuterium.

In another embodiment, at least one of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, and R11 independently has deuterium enrichment of no less than about 1%, no less than about %, no less than about 10%, no less than about 20%, no less than about 50%, no less than about 70%, no less than about 80%, no less than about 90%, or no less than about 98%.

In yet another embodiment, at least one of R1, R2, and R3 is deuterium.

In yet another ment, R1, R2, and R3 are deuterium.

In yet r embodiment, R4 is ium.

In yet another embodiment, at least one of R5 and R6 is deuterium.

In yet another embodiment, R5 and R6 are deuterium.

In yet another embodiment, R5 and R6 are deuterium; and at least one of R1, R2, R3, R4, R7, R8, R9, R10, and R11, IS deuterium.

In yet another embodiment, at least one of R7, R8, R9, R10, and R11 is deuterium.

In yet another embodiment, R7, R8, R9, R10, and R11 are deuterium.

In yet another embodiment, R7, R8, and R9 are deuterium, and at least one of R1, R2, R3, R4, R5, R6, R10, and R11 is deuterium.

In yet r embodiment, at least one of R1, R2, and R3 is ium; and R4, R5, R6, R7, R8, R9, R10, and R11 are en.

In yet another embodiment, R1, R2, and R3 are ium; and R4, R5, R6, R7, R8, R9, R10, and R11 are hydrogen.

In yet another embodiment, R4 is deuterium; and R1, R2, R3, R5, R6, R7, R8, R9, R10, and R11 are hydrogen.

In yet another embodiment, at least one of R5 and R6 is ium; and R1, R2, R3, R4, R7, R8, R9, R10, and R11 are hydrogen.

In yet another embodiment, R5 and R6 are deuterium; and R1, R2, R3, R4, R7, R8, R9, R10, and R11 are hydrogen.

In yet another embodiment, at least one of R1, R2, R3, R4, R5 and R6 is deuterium; and R7, R8, R9, R10, and R11 are hydrogen.

In yet r embodiment, R1, R2, R3, R4, R5 and R6 are deuterium; and R7, R8, R9, R10, and R11 are hydrogen.

] In yet another embodiment, at least one of R7, R8, R9, R10, and R11 is deuterium; and R1, R2, R3, R4, R5, and R6 are hydrogen.

In yet another embodiment, R7, R8, R9, R10, and R11 are deuterium; and at least one of R1, R2, R3, R4, R5, and R6 is deuterium.

In other embodiments, R1 is hydrogen. In yet other embodiments, R2 is hydrogen. In still other ments, R3 is hydrogen. In yet other embodiments, R4 is hydrogen. In some embodiments, R5 is hydrogen. In yet other embodiments, R6 is hydrogen.

In still other embodiments, R7 is hydrogen. In still other embodiments, R8 is hydrogen. In some ments, R9 is hydrogen. In other embodiments, R10 is hydrogen. In yet other embodiments, R11 is hydrogen.

In other embodiments, R1 is deuterium. In yet other embodiments, R2 is deuterium. In still other embodiments, R3 is ium. In yet other embodiments, R4 is deuterium. In some embodiments, R5 is deuterium. In yet other embodiments, R6 is deuterium. In still other embodiments, R7 is deuterium. In still other embodiments, R8 is deuterium. In some embodiments, R9 is deuterium. In other embodiments, R10 is deuterium.

In yet other embodiments, R11 is deuterium.

In yet another embodiment, the compound of Formula I is selected from the group consisting of: O D D D o D D O D Chi? CD3 D D CD3 D D CD3 0 D D D o D D O D D CD3 D D CD3 D D D CD3 0 D D o D D D O D CD3 D D CD3 D D D CD3 0 D D D O D D O D D CD3 D D D CD3 D D D CD3 or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

In r embodiment, at least one of the positions represented as D independently has deuterium ment of no less than about 1%, no less than about 5%, no less than about 10%, no less than about 20%, no less than about 50%, no less than about 70%, no less than about 80%, no less than about 90%, or no less than about 98%.

] The deuterated compound as disclosed herein may also contain less ent isotopes for other elements, ing, but not limited to, 13C or 14C for carbon, 15N for nitrogen, and 17O or 18O for oxygen.

In one embodiment, the deuterated compounds disclosed herein maintain the beneficial aspects of the corresponding non-isotopically enriched molecules while substantially increasing the maximum tolerated dose, decreasing toxicity, increasing the half- life (Tl/2), lowering the maximum plasma concentration (Cmax) of the minimum cious dose (MED), lowering the efficacious dose and thus decreasing the non-mechanism-related ty, and/or lowering the probability of drug-drug interactions.

Isotopic hydrogen can be uced into a compound of a nd disclosed herein as disclosed herein by tic techniques that employ deuterated reagents, whereby incorporation rates are pre-determined; and/or by exchange ques, wherein incorporation rates are determined by equilibrium conditions, and may be highly variable depending on the reaction conditions. Synthetic techniques, where tritium or ium is directly and specifically inserted by ted or deuterated reagents of known isotopic content, may yield high tritium or deuterium abundance, but can be limited by the chemistry ed. In addition, the molecule being labeled may be changed, depending upon the severity of the synthetic reaction employed. ge techniques, on the other hand, may yield lower tritium or deuterium incorporation, often with the e being distributed over many sites on the molecule, but offer the advantage that they do not require separate synthetic steps and are less likely to disrupt the structure of the molecule being labeled.

The compounds as disclosed herein can be prepared by methods known to one of skill in the art and routine modifications thereof, and/or following procedures similar to those described in the Example section herein and routine modifications thereof, and/or procedures found in Esaki et al Tetrahedron 2006, 62, 10954-10961, Smith et al Organic ses 2002, 78, 51-56, US 3,974,281 and /Ol4087, and references cited therein and routine modifications thereof. Compounds as disclosed herein can also be prepared as shown in any of the following schemes and routine modifications thereof.

For example, n compounds as disclosed herein can be prepared as shown in Schemes l and 2.

Scheme 1 H R9 0 N R4 R8 R10 I + R5 \ R1 —R\6 R2 R7 R11 R5 R3 X R10 R11 R4 1 2 Aminopyridone 1 when treated with a base, such as potassium carbonate, and in the presence of a copper ning reagent, such as copper powder, reacts with benzene 2 (wherein X is either Bromine or Iodine) at an ed temperature with or without solvent to afford N—aryl pyridinone 3 of Formula 1.

Deuterium is incorporated into different positions synthetically, according to the synthetic procedures as shown in Scheme 1, by using appropriate deuterated intermediates. For example, to introduce ium at ons R1, R2, R3, R4, R5, and R6, 2- hydroxypicoline with the corresponding deuterium substitutions can be used. To introduce deuterium at one or more positions ed from R7, R8, R9, R10 and R11, the riate halobenzene with the corresponding deuterium substitutions can be used. These deuterated intermediates are either commercially available, or are prepared by methods known to one of skill in the art or ing procedures similar to those described in the e section herein and routine modifications thereof.

Deuterium can also be incorporated to various positions having an exchangeable proton via proton-deuterium equilibrium exchange. Such protons may be replaced with deuterium selectively or non-selectively through a proton-deuterium exchange method known in the art.

Scheme 2 o n o N QM I —* U Q \ \ o N COZH COzMe U\ COzMe o N o N 0 N ; | I | o N OH \ Br \ \ c02H I D D D D CD 7 3 8 9 1o 6-Hydroxynicotinic acid (4) reacts with thionyl chloride and methanol to give methyloxo-l,6-dihydropyridinecarboxylate (5), which is coupled with phenylboronic acid in the ce of (II) acetate monohydrate, pyridine and molecular sieves in dichloromethane to give methyloxo-l-phenyl-l,6-dihydropyridinecarboxylate (6).

Compound 6 is hydrolyzed with lithium hydroxide monohydrate in tetrahydrofuran water, to give 6-oxo-l-phenyl-l ydropyridinecarboxylic acid 7. Acid 7 reacts with isobutyl chloroformate in the presence of N-methylmorpholine in tetrahydrofuran to give a mixed ide which is reduced with sodium borodeuteride in tetrahydrofuran to give d2 (hydroxymethyl)-l-phenylpyridine-2(lH)-one (8). Compound 8 is converted to d2 bromomethyl-l-phenyl-lH-pyridinone (9) by reacting with phosphorus tribromide in dichloromethane. e 9 is reduced with m aluminum deuteride to give d3 (methyl)-l-phenylpyridine-2(lH)-one (10) of a (I).

It is to be understood that the compounds disclosed herein may contain one or more chiral centers, chiral axes, and/or chiral planes, as described in "Stereochemistry of Carbon Compounds" Eliel and Wilen, John Wiley & Sons, New York, 1994, pp. 1119-1190.

Such chiral centers, chiral axes, and chiral planes may be of either the (R) or (S) configuration, or may be a mixture thereof.

Another method for characterizing a composition containing a compound having at least one chiral center is by the effect of the composition on a beam of polarized light. When a beam of plane polarized light is passed h a solution of a chiral compound, the plane of polarization of the light that emerges is rotated relative to the original plane. This phenomenon is known as optical activity, and compounds that rotate the plane of polarized light are said to be optically active. One enantiomer of a compound will rotate the beam of polarized light in one direction, and the other enantiomer will rotate the beam of light in the opposite direction. The enantiomer that s the polarized light in the clockwise ion is the (+) enantiomer, and the enantiomer that rotates the polarized light in the counterclockwise direction is the (-) enantiomer. Included within the scope of the compositions described herein are compositions ning n 0 and 100% of the (+) and/or (-) enantiomer of compounds sed herein.

Where a compound as disclosed herein contains an alkenyl or alkenylene group, the compound may exist as one or mixture of geometric cis/trans (or Z/E) isomers.

Where structural isomers are interconvertible via a low energy barrier, the compound disclosed herein may exist as a single tautomer or a mixture of tautomers. This can take the form of proton erism in the compound disclosed herein that contains for example, an imino, keto, or oxime group; or so-called valence tautomerism in the compound that contain an aromatic moiety. It follows that a single compound may exhibit more than one type of isomerism.

The compounds disclosed herein may be enantiomerically pure, such as a single enantiomer or a single diastereomer, or be stereoisomeric mixtures, such as a mixture of enantiomers, a racemic e, or a diastereomeric mixture. As such, one of skill in the art will recognize that administration of a compound in its (R) form is lent, for compounds that undergo epimerization in vivo, to administration of the compound in its (S) form. Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable lly pure precursor or resolution of the racemate using, for example, chiral chromatography, recrystallization, resolution, diastereomeric salt formation, or derivatization into diastereomeric adducts followed by separation.

When the compound disclosed herein contains an acidic or basic moiety, it may also disclosed as a pharmaceutically able salt (See, Berge et al., J. Pharm. Sci. 1977, 66, l-l9; and ook of Pharmaceutical Salts, Properties, and Use," Stah and Wermuth, Ed.; Wiley-VCH and VHCA, Zurich, 2002).

Suitable acids for use in the preparation of pharmaceutically acceptable salts include, but are not limited to, acetic acid, chloroacetic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 4- acetamidobenzoic acid, boric acid, (+)-camphoric acid, camphorsulfonic acid, (+)-(lS)- camphor-lO-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, cyclohexanesulfamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, formic acid, c acid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucuronic acid, L-glutamic acid, oc-oxo-glutaric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, (+)-L-lactic acid, (i)-DL-lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, (i)-DL-mandelic acid, esulfonic acid, naphthalenesulfonic acid, naphthalene-l,5-disulfonic acid, l-hydroxynaphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, perchloric acid, phosphoric acid, L-pyroglutamic acid, saccharic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid, undecylenic acid, and c acid.

Suitable bases for use in the preparation of pharmaceutically acceptable salts, including, but not limited to, inorganic bases, such as magnesium hydroxide, calcium ide, potassium hydroxide, zinc hydroxide, or sodium hydroxide; and organic bases, such as primary, ary, tertiary, and quaternary, aliphatic and aromatic amines, including L-arginine, benethamine, hine, choline, deanol, diethanolamine, diethylamine, dimethylamine, dipropylamine, diisopropylamine, 2-(diethylamino)-ethanol, ethanolamine, ethylamine, ethylenediamine, isopropylamine, N-methyl-glucamine, hydrabamine, 1H- imidazole, L-lysine, line, 4-(2-hydroxyethyl)-morpholine, methylamine, piperidine, piperazine, propylamine, pyrrolidine, 1-(2-hydroxyethyl)-pyrrolidine, pyridine, quinuclidine, quinoline, isoquinoline, secondary amines, triethanolamine, trimethylamine, triethylamine, N-methyl-D-glucamine, o(hydroxymethyl)-1,3-propanediol, and tromethamine.

The compound as disclosed herein may also be designed as a prodrug, which mammmmdmmwmwdmewmmmflfidedemmmMmmMMmemmbmw the parent compound in Vivo. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent compound. They may, for ce, be bioavailable by oral administration whereas the parent compound is not. The prodrug may also have enhanced solubility in pharmaceutical compositions over the parent nd. A prodrug may be converted into the parent drug by various mechanisms, including enzymatic processes and metabolic hydrolysis. See Harper, Progress in Drug Research 1962, 4, 221- 294; wich et al. in "Design of Biopharmaceutical Properties through Prodrugs and Analogs," Roche Ed., APHA Acad. Pharm. Sci. 1977; "Bioreversible rs in Drug in Drug Design, Theory and Application," Roche Ed., APHA Acad. Pharm. Sci. 1987; "Design of Prodrugs," Bundgaard, ElseVier, 1985; Wang et al., Curr. Pharm. Design 1999, 5, 265- 287; ti et al., Adv. Drug. Delivery Rev. 1997, 27, 6; Mizen et al., Pharm.

Biotech. 1998, 11, 345-365; Gaignault et al., Pract. Med. Chem. 1996, 671-696; Asghamejad in "Transport ses in Pharmaceutical Systems," Amidon et al., Ed., Marcell Dekker, 185-218, 2000; Balant et al., Eur. J. Drug Metab. Pharmacokinet. 1990, 15, 143-53; Balimane and Sinko, Adv. Drug Delivery Rev. 1999, 39, 183-209; Browne, Clin.

Neuropharmacol. 1997, 20, 1-12; Bundgaard, Arch. Pharm. Chem. 1979, 86, 1-39; Bundgaard, Controlled Drug Delivery 1987, 17, 179-96; Bundgaard, Adv. Drug Delivery Rev.1992, 8, 1-38; Fleisher et al., Adv. Drug Delivery Rev. 1996, 19, 115-130; Fleisher et al., Methods Enzymol. 1985, 112, 360-381; Farquhar et al., J. Pharm. Sci. 1983, 72, 324-325; fkeenuu1etal,J.C7unn.Socu Cheni Connnun.1991,875-877;PrhsandlBundgaard,Ear.J Pharm. Sci. 1996, 4, 49-59; Gangwar et al., Des. Biopharm. Prop. Prodrugs Analogs, 1977, 409-421; Nathwani and Wood, Drugs 1993, 45, 866-94; Sinhababu and Thakker, Adv. Drug Delivery Rev. 1996, 19, 241-273; Stella et al., Drugs 1985, 29, 455-73; Tan et al., Adv. Drug Delivery Rev. 1999, 39, 117-151; Taylor, Adv. Drug Delivery Rev. 1996, 19, 131-148; ino and Borchardt, Drug Discovery Today 1997, 2, 5; Wiebe and Knaus, Adv.

Drug Delivery Rev. 1999, 39, 63-80; Waller et al., Br. J. Clin. Pharmac. 1989, 28, 497-507.

Pharmaceutical ition Disclosed herein are pharmaceutical compositions comprising a nd as disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, as an active ingredient, combined with a pharmaceutically acceptable vehicle, carrier, diluent, or ent, or a mixture thereof; in combination with one or more pharmaceutically able excipients or rs.

Disclosed herein are pharmaceutical compositions in modified release dosage forms, which comprise a compound as disclosed herein, or a pharmaceutically able salt, solvate, or prodrug thereof; and one or more release controlling excipients or rs as described herein. Suitable modified release dosage vehicles e, but are not limited to, hydrophilic or hydrophobic matrix s, water-soluble separating layer coatings, enteric coatings, osmotic devices, multiparticulate devices, and combinations thereof. The pharmaceutical compositions may also comprise non-release controlling excipients or carriers.

Further disclosed herein are ceutical compositions in enteric coated dosage forms, which comprise a compound as disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof; and one or more release controlling excipients or carriers for use in an enteric coated dosage form. The pharmaceutical compositions may also comprise non-release controlling excipients or rs.

] Further disclosed herein are pharmaceutical compositions in escent dosage forms, which se a compound as disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof; and one or more release lling excipients or carriers for use in an effervescent dosage form. The pharmaceutical compositions may also comprise non-release lling excipients or carriers.

Additionally disclosed are pharmaceutical compositions in a dosage form that has an instant releasing component and at least one delayed releasing component, and is capable of giving a discontinuous release of the compound in the form of at least two consecutive pulses separated in time from 0.1 up to 24 hours. The pharmaceutical compositions comprise a compound as disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof; and one or more release controlling and non-release controlling excipients or carriers, such as those excipients or carriers suitable for a disruptable semi-permeable ne and as swellable substances.

Disclosed herein also are pharmaceutical compositions in a dosage form for oral administration to a subject, which comprise a compound as disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof; and one or more pharmaceutically acceptable excipients or carriers, enclosed in an intermediate reactive layer comprising a gastric resistant polymeric layered al lly neutralized with alkali and having cation exchange capacity and a gastric juice-resistant outer layer.

Disclosed herein are pharmaceutical compositions that comprise about 0.1 to about 1000 mg, about 1 to about 500 mg, about 2 to about 100 mg, about 1 mg, about 10 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg of one or more compounds as disclosed herein in the form of film-coated immediate-release tablets for oral stration. The pharmaceutical compositions further comprise hypromellose, hydroxypropyl cellulose, croscarmellose sodium, magnesium stearate, microcrystalline cellulose, povidone, pregelatinized starch, propylene glycol, silicon dioxide, sorbic acid, sorbitan monooleate, stearic acid, talc, titanium dioxide, and vanillin. ed herein are pharmaceutical compositions that comprise about 0.1 to about 1000 mg, about 1 to about 500 mg, about 2 to about 250 mg, about 1 mg, about 10 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg of one or more compounds as disclosed herein in the form of film-coated immediate-release tablets for oral administration. The pharmaceutical compositions further comprise hypromellose, hydroxypropyl cellulose, colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, microcrystalline ose, povidone, propylene , sorbic acid, sorbitan monooleate, titanium e, and vanillin.

Provided herein are pharmaceutical compositions that comprise about 0.1 to about 1000 mg, about 1 to about 500 mg, about 2 to about 250 mg, about 1 mg, about 10 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg of one or more nds as disclosed herein in the form of oated ed-release tablets for oral administration. The pharmaceutical compositions further se cellulosic polymers, lactose monohydrate, magnesium stearate, propylene glycol, sorbic acid, sorbitan monooleate, talc, titanium dioxide, and vanillin.

Provided herein are pharmaceutical compositions that comprise about 0.1 to about 1000 mg, about 1 to about 500 mg, about 2 to about 250 mg, about 1 mg, about 10 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg of one or WO 22165 more compounds as disclosed herein in the form of granules for oral suspension. The pharmaceutical compositions further se carbomer, castor oil, citric acid, hypromellose phthalate, maltodextrin, potassium sorbate, povidone, silicon dioxide, sucrose, n gum, titanium e and fruit punch flavor.

The pharmaceutical itions disclosed herein may be disclosed in unit- dosage forms or multiple-dosage forms. osage forms, as used herein, refer to physically discrete units suitable for administration to human and animal subjects and ed individually as is known in the art. Each unit-dose contains a predetermined quantity of the active ingredient(s) sufficient to produce the desired therapeutic effect, in association with the required pharmaceutical carriers or excipients. Examples of unit-dosage forms include ampouls, syringes, and individually packaged tablets and capsules. Unit- dosage forms may be administered in fractions or multiples thereof. A multiple-dosage form is a plurality of identical unit-dosage forms packaged in a single ner to be administered in segregated unit-dosage form. Examples of multiple-dosage forms include vials, bottles of tablets or capsules, or bottles of pints or gallons.

The compound as disclosed herein may be administered alone, or in combination with one or more other compounds disclosed herein, one or more other active ingredients. The pharmaceutical compositions that comprise a compound disclosed herein may be formulated in various dosage forms for oral, parenteral, and topical administration.

The pharmaceutical itions may also be formulated as a modified release dosage form, including delayed-, extended-, prolonged-, sustained-, pulsatile-, lled-, accelerated- and fast-, targeted-, programmed-release, and gastric retention dosage forms. These dosage forms can be prepared ing to conventional methods and techniques known to those skilled in the art (see, Remington: The Science and ce of Pharmacy, supra; Modified-Release Drug Deliver logy, Rathbone et al., Eds., Drugs and the Pharmaceutical Science, Marcel Dekker, Inc.: New York, NY, 2002; Vol. 126).

The pharmaceutical compositions disclosed herein may be administered at once, or multiple times at intervals of time. It is understood that the precise dosage and duration of treatment may vary with the age, weight, and condition of the patient being treated, and may be determined empirically using known g protocols or by extrapolation from in vivo or in vitro test or diagnostic data. It is further understood that for any particular individual, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the formulations.

WO 22165 In the case wherein the patient’s condition does not improve, upon the doctor’s discretion the administration of the compounds may be administered chronically, that is, for an extended period of time, including throughout the duration of the patient’s life in order to ameliorate or otherwise l or limit the symptoms of the patient’s disease or condition.

In the case wherein the patient’s status does improve, upon the doctor’s discretion the administration of the compounds may be given continuously or temporarily suspended for a certain length of time (i.e., a "drug holiday").

Once improvement of the patient's conditions has occurred, a maintenance dose is administered if ary. Subsequently, the dosage or the frequency of administration, or both, can be reduced, as a function of the symptoms, to a level at which the improved e, disorder or condition is retained. Patients can, however, e intermittent treatment on a long-term basis upon any recurrence of symptoms.

A. Oral Administration The pharmaceutical compositions disclosed herein may be formulated in solid, semisolid, or liquid dosage forms for oral administration. As used herein, oral administration also include buccal, lingual, and sublingual administration. le oral dosage forms include, but are not limited to, tablets, capsules, pills, troches, lozenges, pastilles, cachets, pellets, medicated chewing gum, granules, bulk powders, effervescent or non-effervescent powders or granules, solutions, emulsions, suspensions, solutions, wafers, sprinkles, elixirs, and . In addition to the active ingredient(s), the pharmaceutical itions may contain one or more ceutically acceptable carriers or excipients, including, but not limited to, binders, fillers, diluents, disintegrants, wetting agents, lubricants, glidants, ng agents, dye-migration inhibitors, sweetening agents, and flavoring agents.

Binders or granulators impart cohesiveness to a tablet to ensure the tablet remaining intact after compression. le binders or granulators include, but are not limited to, starches, such as corn , potato starch, and latinized starch (e. g., STARCH 1500); gelatin; sugars, such as sucrose, e, dextrose, molasses, and lactose; natural and synthetic gums, such as acacia, c acid, alginates, extract of Irish moss, Panwar gum, ghatti gum, mucilage of isabgol husks, carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone (PVP), Veegum, larch arabogalactan, powdered anth, and guar gum; celluloses, such as ethyl cellulose, cellulose acetate, ymethyl cellulose calcium, sodium carboxymethyl cellulose, methyl cellulose, hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropyl methyl cellulose ; rystalline celluloses, such as AVICEL-PH-lOl, AVICEL-PH-103, AVICEL RC-581, -PH-105 (FMC Corp., Marcus Hook, PA); and mixtures thereof.

Suitable fillers include, but are not limited to, talc, calcium carbonate, microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre- gelatinized starch, and mixtures thereof. The binder or filler may be present from about 50 to about 99% by weight in the pharmaceutical compositions disclosed herein.

Suitable diluents include, but are not limited to, dicalcium phosphate, calcium sulfate, lactose, sorbitol, sucrose, inositol, cellulose, kaolin, ol, sodium chloride, dry starch, and powdered sugar. Certain diluents, such as mannitol, lactose, sorbitol, e, and inositol, when present in sufficient quantity, can impart properties to some compressed s that permit disintegration in the mouth by chewing. Such compressed tablets can be used as chewable tablets.

Suitable disintegrants include, but are not limited to, agar; bentonite; celluloses, such as cellulose and carboxymethylcellulose; wood products; natural sponge; cation-exchange resins; alginic acid; gums, such as guar gum and Veegum HV; citrus pulp; cross-linked celluloses, such as croscarmellose; linked rs, such as crospovidone; cross-linked starches; calcium carbonate; microcrystalline cellulose, such as sodium starch ate; polacrilin potassium; starches, such as corn starch, potato starch, tapioca , and pre-gelatinized starch; clays; aligns; and mixtures thereof. The amount of disintegrant in the ceutical compositions disclosed herein varies upon the type of formulation, and is readily discernible to those of ordinary skill in the art. The pharmaceutical compositions disclosed herein may n from about 0.5 to about 15% or from about 1 to about 5% by weight of a disintegrant.

Suitable lubricants include, but are not limited to, calcium stearate; magnesium stearate; mineral oil; light mineral oil; glycerin; sorbitol; mannitol; s, such as glycerol behenate and polyethylene glycol (PEG); stearic acid; sodium lauryl sulfate; talc; hydrogenated vegetable oil, including peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil; zinc stearate; ethyl oleate; ethyl laureate; agar; starch; lycopodium; silica or silica gels, such as AEROSIL® 200 (W.R. Grace Co., Baltimore, MD) and CAB-O-SIL® (Cabot Co. of Boston, MA); and mixtures thereof. The pharmaceutical compositions disclosed herein may contain about 0.1 to about 5% by weight of a lubricant.

Suitable glidants include colloidal silicon e, CAB-O-SIL® (Cabot Co. of Boston, MA), and asbestos-free talc. ng agents include any of the approved, certified, water soluble FD&C dyes, and water insoluble FD&C dyes suspended on alumina hydrate, and color lakes and mixtures thereof. A color lake is the combination by adsorption of a water-soluble dye to a hydrous oxide of a heavy metal, resulting in an insoluble form of the dye. Flavoring agents include l flavors extracted from plants, such as fruits, and synthetic blends of compounds which produce a pleasant taste sensation, such as peppermint and methyl late. Sweetening agents e e, e, ol, syrups, glycerin, and artificial sweeteners, such as saccharin and aspartame. Suitable emulsifying agents include gelatin, acacia, tragacanth, bentonite, and tants, such as yethylene sorbitan eate (TWEEN® 20), polyoxyethylene sorbitan monooleate 80 (TWEEN® 80), and triethanolamine . Suspending and dispersing agents include sodium carboxymethylcellulose, pectin, tragacanth, Veegum, , sodium carbomethylcellulose, hydroxypropyl methylcellulose, and polyvinylpyrolidone. Preservatives include glycerin, methyl and propylparaben, benzoic add, sodium benzoate and alcohol. Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, and polyoxyethylene lauryl ether. ts include glycerin, sorbitol, ethyl alcohol, and syrup. Examples of non-aqueous liquids utilized in emulsions include mineral oil and cottonseed oil. Organic acids include citric and tartaric acid. Sources of carbon dioxide include sodium bicarbonate and sodium carbonate.

It should be understood that many carriers and excipients may serve several functions, even within the same formulation.

The pharmaceutical compositions disclosed herein may be formulated as compressed tablets, tablet triturates, chewable lozenges, rapidly dissolving tablets, multiple compressed tablets, or enteric-coating tablets, sugar-coated, or film-coated tablets. Enteric- coated tablets are ssed tablets coated with substances that resist the action of stomach acid but dissolve or disintegrate in the intestine, thus ting the active ingredients from the acidic environment of the stomach. Enteric-coatings include, but are not limited to, fatty acids, fats, salicylate, waxes, shellac, ammoniated shellac, and cellulose acetate phthalates. Sugar-coated tablets are compressed tablets surrounded by a sugar g, which may be cial in covering up objectionable tastes or odors and in protecting the tablets from oxidation. Film-coated tablets are compressed tablets that are covered with a thin layer or film of a water-soluble material. Film coatings include, but are not limited to, hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000, and cellulose acetate phthalate. Film coating imparts the same general characteristics as sugar coating. Multiple compressed tablets are compressed tablets made by more than one compression cycle, including layered tablets, and coated or dry-coated tablets.

The tablet dosage forms may be prepared from the active ingredient in powdered, lline, or granular forms, alone or in combination with one or more carriers or excipients described herein, including s, disintegrants, controlled-release polymers, lubricants, diluents, and/or colorants. Flavoring and sweetening agents are especially useful in the formation of chewable tablets and lozenges.

The pharmaceutical compositions disclosed herein may be formulated as soft or hard capsules, which can be made from gelatin, methylcellulose, starch, or calcium alginate. The hard gelatin capsule, also known as the dry-filled capsule (DFC), consists of two ns, one slipping over the other, thus completely enclosing the active ingredient.

The soft c capsule (SEC) is a soft, globular shell, such as a gelatin shell, which is plasticized by the addition of glycerin, sorbitol, or a similar polyol. The soft gelatin shells may contain a preservative to prevent the growth of microorganisms. le preservatives are those as described herein, ing methyl- and propyl-parabens, and sorbic acid. The liquid, lid, and solid dosage forms disclosed herein may be encapsulated in a capsule.

Suitable liquid and semisolid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils, or triglycerides. Capsules ning such solutions can be prepared as bed in U.S. Pat. Nos. 4,328,245; 4,409,239; and 4,410,545. The capsules may also be coated as known by those of skill in the art in order to modify or n dissolution of the active ient.

The pharmaceutical compositions disclosed herein may be ated in liquid and semisolid dosage forms, including ons, solutions, suspensions, elixirs, and . An emulsion is a two-phase system, in which one liquid is dispersed in the form of small globules throughout another liquid, which can be oil-in-water or water-in-oil.

Emulsions may include a pharmaceutically acceptable non-aqueous liquids or solvent, emulsifying agent, and preservative. Suspensions may include a ceutically acceptable suspending agent and preservative. Aqueous alcoholic ons may include a pharmaceutically acceptable acetal, such as a di(lower alkyl) acetal of a lower alkyl aldehyde (the term "lower" means an alkyl having between 1 and 6 carbon atoms), e. g., acetaldehyde diethyl acetal; and a water-miscible solvent having one or more hydroxyl groups, such as propylene glycol and ethanol. Elixirs are clear, sweetened, and hydroalcoholic solutions.

Syrups are concentrated aqueous solutions of a sugar, for example, sucrose, and may also contain a preservative. For a liquid dosage form, for e, a solution in a polyethylene glycol may be d with a sufficient quantity of a ceutically acceptable liquid carrier, e. g., water, to be measured iently for administration.

Other useful liquid and semisolid dosage forms include, but are not limited to, those containing the active ingredient(s) disclosed herein, and a dialkylated mono- or poly- alkylene glycol, including, l,2-dimethoxymethane, e, triglyme, tetraglyme, polyethylene glycoldimethyl ether, polyethylene glycoldimethyl ether, hylene glycoldimethyl ether, wherein 350, 550, and 750 refer to the approximate average molecular weight of the hylene glycol. These formulations may further comprise one or more antioxidants, such as butylated hydroxytoluene (BHT), ted hydroxyanisole (BHA), propyl gallate, n E, hydroquinone, hydroxycoumarins, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, bisulfite, sodium metabisulfite, thiodipropionic acid and its esters, and dithiocarbamates.

The pharmaceutical itions disclosed herein for oral administration may be also formulated in the forms of liposomes, micelles, microspheres, or nanosystems.

Micellar dosage forms can be prepared as described in U.S. Pat. No. 6,350,458.

The pharmaceutical compositions disclosed herein may be formulated as non- effervescent or effervescent, granules and powders, to be reconstituted into a liquid dosage form. Pharmaceutically acceptable rs and excipients used in the non-effervescent es or powders may include diluents, sweeteners, and wetting agents. ceutically acceptable carriers and excipients used in the effervescent granules or powders may include organic acids and a source of carbon e.

Coloring and flavoring agents can be used in all of the above dosage forms.

The pharmaceutical compositions disclosed herein may be formulated as immediate or modified release dosage forms, including delayed-, sustained, pulsed-, controlled, targeted-, and mmed-release forms.

The pharmaceutical compositions disclosed herein may be co-formulated with other active ingredients which do not impair the d therapeutic action, or with substances that supplement the desired action, such as drotrecogin- and hydrocortisone.

B. Parenteral Administration The pharmaceutical compositions disclosed herein may be administered parenterally by injection, infusion, or implantation, for local or systemic stration.

Parenteral administration, as used herein, include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial, and subcutaneous administration.

The pharmaceutical compositions disclosed herein may be formulated in any dosage forms that are suitable for parenteral administration, including solutions, suspensions, emulsions, es, liposomes, microspheres, nanosystems, and solid forms suitable for solutions or suspensions in liquid prior to injection. Such dosage forms can be prepared according to conventional methods known to those skilled in the art of pharmaceutical science (see, Remington: The Science and Practice ofPharmacy, supra).

The pharmaceutical compositions intended for parenteral administration may include one or more pharmaceutically acceptable carriers and ents, including, but not limited to, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles, crobial agents or preservatives against the growth of microorganisms, stabilizers, lity enhancers, isotonic agents, buffering agents, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or ing agents, cryoprotectants, lyoprotectants, thickening agents, pH adjusting agents, and inert gases.

Suitable aqueous vehicles include, but are not limited to, water, saline, physiological saline or phosphate buffered saline (PBS), sodium chloride injection, Ringers injection, isotonic se ion, sterile water ion, dextrose and lactated Ringers injection. ueous vehicles include, but are not limited to, fixed oils of vegetable origin, castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, enated ble oils, hydrogenated soybean oil, and -chain cerides of coconut oil, and palm seed oil. Water-miscible vehicles include, but are not limited to, ethanol, l,3-butanediol, liquid polyethylene glycol (e. g., polyethylene glycol 300 and polyethylene glycol 400), propylene glycol, glycerin, N-methylpyrrolidone, dimethylacetamide, and dimethylsulfoxide.

] Suitable antimicrobial agents or preservatives include, but are not limited to, phenols, cresols, mercurials, benzyl alcohol, chlorobutanol, methyl and propyl phydroxybenzates , thimerosal, benzalkonium chloride, benzethonium chloride, methyl- and propyl-parabens, and sorbic acid. Suitable isotonic agents include, but are not limited to, sodium chloride, glycerin, and dextrose. Suitable ing agents include, but are not d to, phosphate and citrate. Suitable antioxidants are those as described herein, including bisulfite and sodium sulfite. Suitable local anesthetics include, but are not limited to, procaine hydrochloride. Suitable suspending and dispersing agents are those as described herein, ing sodium carboxymethylcelluose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone. Suitable emulsifying agents e those described herein, including polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan eate 80, and triethanolamine oleate. Suitable sequestering or chelating agents include, but are not limited to EDTA. Suitable pH adjusting agents include, but are not limited to, sodium hydroxide, hloric acid, citric acid, and lactic acid. Suitable compleXing agents include, but are not limited to, cyclodextrins, including oc-cyclodextrin, B-cyclodextrin, hydroxypropyl-B-cyclodextrin, sulfobutylether-B-cyclodextrin, and sulfobutylether 7-[3- cyclodextrin (CAPTISOL®, CyDeX, Lenexa, KS).

The pharmaceutical compositions sed herein may be formulated for single or multiple dosage stration. The single dosage formulations are packaged in an ampule, a vial, or a e. The multiple dosage parenteral ations must contain an antimicrobial agent at bacteriostatic or fungistatic concentrations. All parenteral formulations must be sterile, as known and practiced in the art.

In one embodiment, the pharmaceutical compositions are formulated as ready- to-use sterile solutions. In another embodiment, the pharmaceutical compositions are formulated as sterile dry soluble products, including lyophilized powders and hypodermic tablets, to be reconstituted with a vehicle prior to use. In yet another embodiment, the pharmaceutical compositions are formulated as ready-to-use sterile suspensions. In yet r embodiment, the pharmaceutical compositions are formulated as sterile dry insoluble products to be reconstituted with a vehicle prior to use. In still another embodiment, the ceutical compositions are formulated as ready-to-use sterile emulsions.

The pharmaceutical itions disclosed herein may be formulated as immediate or modified release dosage forms, including delayed-, sustained, pulsed-, controlled, targeted-, and programmed-release forms.

The pharmaceutical itions may be formulated as a suspension, solid, semi-solid, or thixotropic liquid, for administration as an implanted depot. In one embodiment, the pharmaceutical compositions disclosed herein are dispersed in a solid inner matrix, which is surrounded by an outer polymeric ne that is insoluble in body fluids but allows the active ingredient in the pharmaceutical compositions diffuse through.

Suitable inner matrixes include polymethylmethacrylate, polybutylmethacrylate, plasticized or ticized polyvinylchloride, plasticized nylon, plasticized polyethyleneterephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinylacetate copolymers, silicone rubbers, polydimethylsiloxanes, silicone carbonate copolymers, hydrophilic polymers, such as hydrogels of esters of acrylic and methacrylic acid, collagen, cross-linked polyvinylalcohol, and cross-linked partially hydrolyzed polyvinyl acetate.

Suitable outer polymeric membranes include polyethylene, polypropylene, ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers, ethylene/vinylacetate mers, silicone rubbers, methyl siloxanes, neoprene rubber, chlorinated hylene, nylchloride, hloride copolymers with vinyl acetate, vinylidene de, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber epichlorohydrin rubbers, ethylene/vinyl alcohol copolymer, ethylene/vinyl acetate/vinyl alcohol terpolymer, and ne/vinyloxyethanol copolymer.

D. ed Release The ceutical compositions disclosed herein may be formulated as a modified release dosage form. As used herein, the term "modified release" refers to a dosage form in which the rate or place of release of the active ingredient(s) is different from that of an immediate dosage form when administered by the same route. ed release dosage forms include delayed-, extended-, prolonged-, sustained-, pulsatile-, controlled-, accelerated- and fast-, targeted-, programmed-release, and gastric retention dosage forms. The pharmaceutical compositions in modified release dosage forms can be prepared using a variety of ed release devices and methods known to those skilled in the art, ing, but not limited to, matrix controlled e devices, osmotic controlled release devices, multiparticulate controlled release devices, ion-exchange resins, enteric coatings, multilayered coatings, microspheres, liposomes, and combinations thereof. The release rate of the active ingredient(s) can also be modified by varying the particle sizes and polymorphorism of the active ingredient(s).

Examples of modified release include, but are not limited to, those described in U.S. Pat. Nos.: 3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719; 5,674,533; ,059,595; 5,591,767; 5,120,548; 5,073,543; 5,639,476; 5,354,556; 480; 5,733,566; 108; 5,891,474; 5,922,356; 5,972,891; 5,980,945; 5,993,855; 6,045,830; 6,087,324; 943; 6,197,350; 6,248,363; 6,264,970; 981; 461; 6,419,961; 6,589,548; 6,613,358; and 6,699,500. 1. Matrix Controlled Release Devices The pharmaceutical compositions disclosed herein in a modified release dosage form may be fabricated using a matrix controlled release device known to those d in the art (see, Takada et al in "Encyclopedia of Controlled Drug Delivery," Vol. 2, witz ed., Wiley, 1999).

In one embodiment, the pharmaceutical compositions disclosed herein in a modified release dosage form is formulated using an erodible matrix device, which is water- swellable, erodible, or soluble polymers, ing synthetic polymers, and naturally occurring polymers and derivatives, such as polysaccharides and proteins.

Materials useful in forming an erodible matrix include, but are not limited to, chitin, chitosan, dextran, and pullulan; gum agar, gum arabic, gum karaya, locust bean gum, gum tragacanth, carrageenans, gum ghatti, guar gum, xanthan gum, and scleroglucan; starches, such as n and maltodextrin; hydrophilic colloids, such as pectin; phosphatides, such as lecithin; alginates; propylene glycol alginate; gelatin; collagen; and cellulosics, such as ethyl cellulose (EC), methylethyl cellulose (MEC), carboxymethyl cellulose (CMC), CMEC, yethyl ose (HEC), hydroxypropyl cellulose (HPC), cellulose acetate (CA), ose propionate (CP), cellulose butyrate (CB), cellulose e te (CAB), CAP, CAT, hydroxypropyl methyl cellulose (HPMC), HPMCP, HPMCAS, hydroxypropyl methyl cellulose acetate trimellitate (HPMCAT), and ydroxy ethylcellulose (EHEC); nyl pyrrolidone; polyvinyl l; polyvinyl acetate; glycerol fatty acid esters; polyacrylamide; polyacrylic acid; copolymers of ethacrylic acid or methacrylic acid (EUDRAGIT®, Rohm America, Inc., Piscataway, NJ); poly(2-hydroxyethyl-methacrylate); polylactides; copolymers of L-glutamic acid and ethyl-L-glutamate; degradable lactic acid- glycolic acid mers; poly-D-(-)hydroxybutyric acid; and other acrylic acid derivatives, such as homopolymers and copolymers of butylmethacrylate, methylmethacrylate, ethylmethacrylate, ethylacrylate, (2-dimethylaminoethyl)methacrylate, and (trimethylaminoethyl)methacrylate chloride.

In further ments, the pharmaceutical compositions are formulated with a non-erodible matrix device. The active ingredient(s) is dissolved or dispersed in an inert matrix and is released primarily by diffusion through the inert matrix once administered.

Materials suitable for use as a non-erodible matrix device included, but are not limited to, insoluble plastics, such as polyethylene, polypropylene, polyisoprene, obutylene, polybutadiene, polymethylmethacrylate, polybutylmethacrylate, chlorinated polyethylene, nylchloride, methyl acrylate-methyl methacrylate copolymers, ethylene-Vinylacetate mers, ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers, vinylchloride copolymers with vinyl acetate, dene de, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber epichlorohydrin s, ethylene/vinyl alcohol copolymer, ethylene/vinyl acetate/vinyl alcohol terpolymer, and ethylene/vinyloxyethanol copolymer, polyvinyl chloride, plasticized nylon, plasticized polyethyleneterephthalate, natural rubber, silicone rubbers, polydimethylsiloxanes, silicone carbonate copolymers; hydrophilic polymers, such as ethyl cellulose, cellulose acetate, crospovidone, and cross-linked lly hydrolyzed polyvinyl acetate; and fatty compounds, such as carnauba wax, microcrystalline wax, and triglycerides.

In a matrix controlled e system, the desired release kinetics can be controlled, for example, via the polymer type employed, the polymer viscosity, the particle sizes of the polymer and/or the active ingredient(s), the ratio of the active ingredient(s) versus the polymer, and other excipients or carriers in the compositions.

The pharmaceutical compositions disclosed herein in a modified release dosage form may be prepared by methods known to those skilled in the art, ing direct compression, dry or wet granulation followed by compression, melt-granulation followed by compression. 2. c Controlled Release s The pharmaceutical itions disclosed herein in a modified e dosage form may be fabricated using an osmotic controlled release device, including one- chamber system, two-chamber system, asymmetric membrane technology (AMT), and extruding core system (ECS). In general, such devices have at least two components: (a) the core which contains the active ingredient(s) and (b) a semipermeable membrane with at least one delivery port, which encapsulates the core. The semipermeable membrane controls the influx of water to the core from an aqueous environment of use so as to cause drug release by extrusion through the delivery port(s).

In on to the active ingredient(s), the core of the osmotic device optionally includes an osmotic agent, which creates a driving force for transport of water from the nment of use into the core of the device. One class of osmotic agents water- swellable hydrophilic polymers, which are also referred to as "osmopolymers" and gels," including, but not limited to, hydrophilic vinyl and acrylic polymers, polysaccharides such as calcium alginate, polyethylene oxide (PEO), polyethylene glycol (PEG), polypropylene glycol (PPG), -hydroxyethyl methacrylate), poly(acrylic) acid, poly(methacrylic) acid, polyvinylpyrrolidone (PVP), crosslinked PVP, polyvinyl alcohol (PVA), P copolymers, PVA/PVP copolymers with hydrophobic monomers such as methyl methacrylate and vinyl acetate, hilic polyurethanes containing large PEO blocks, sodium rmellose, carrageenan, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), carboxymethyl cellulose (CMC) and carboxyethyl, cellulose (CEC), sodium alginate, polycarbophil, gelatin, xanthan gum, and sodium starch glycolate.

The other class of osmotic agents are osmogens, which are capable of imbibing water to affect an osmotic pressure gradient across the barrier of the surrounding coating. Suitable osmogens include, but are not limited to, inorganic salts, such as magnesium sulfate, magnesium chloride, calcium de, sodium chloride, lithium chloride, potassium sulfate, potassium phosphates, sodium carbonate, sodium sulfite, lithium e, potassium chloride, and sodium sulfate; sugars, such as dextrose, fructose, glucose, inositol, lactose, maltose, ol, ose, sorbitol, sucrose, trehalose, and xylitol; c acids, such as ascorbic acid, c acid, fumaric acid, citric acid, maleic acid, sebacic acid, sorbic acid, adipic acid, edetic acid, glutamic acid, nesulfonic acid, succinic acid, and tartaric acid; urea; and mixtures f.

Osmotic agents of different dissolution rates may be employed to influence how rapidly the active ingredient(s) is initially delivered from the dosage form. For example, amorphous , such as Mannogeme EZ (SP1 Pharma, Lewes, DE) can be used to provide faster delivery during the first couple of hours to promptly produce the desired therapeutic effect, and gradually and continually release of the remaining amount to maintain the desired level of therapeutic or prophylactic effect over an extended period of time. In this case, the active ingredient(s) is released at such a rate to replace the amount of the active ingredient metabolized and excreted.

The core may also include a wide variety of other excipients and carriers as bed herein to e the performance of the dosage form or to promote stability or processing.

Materials useful in forming the semipermeable membrane include various grades of acrylics, vinyls, ethers, polyamides, polyesters, and cellulosic tives that are water-permeable and water-insoluble at logically relevant pHs, or are susceptible to being rendered water-insoluble by chemical alteration, such as crosslinking. Examples of suitable polymers useful in forming the coating, include plasticized, unplasticized, and reinforced cellulose e (CA), cellulose diacetate, cellulose triacetate, CA propionate, cellulose e, ose acetate butyrate (CAB), CA ethyl carbamate, CAP, CA methyl carbamate, CA succinate, cellulose acetate trimellitate (CAT), CA dimethylaminoacetate, CA ethyl carbonate, CA chloroacetate, CA ethyl oxalate, CA methyl sulfonate, CA butyl sulfonate, CA p-toluene sulfonate, agar e, amylose triacetate, beta glucan acetate, beta glucan triacetate, acetaldehyde dimethyl acetate, tate of locust bean gum, hydroxlated ethylene-vinylacetate, EC, PEG, PPG, PEG/PPG copolymers, PVP, HEC, HPC, CMC, CMEC, HPMC, HPMCP, HPMCAS, HPMCAT, poly(acrylic) acids and esters and poly- crylic) acids and esters and copolymers thereof, starch, dextran, dextrin, chitosan, collagen, gelatin, polyalkenes, polyethers, polysulfones, polyethersulfones, polystyrenes, nyl s, nyl esters and , natural waxes, and synthetic waxes.

Semipermeable membrane may also be a hydrophobic microporous membrane, wherein the pores are substantially filled with a gas and are not wetted by the aqueous medium but are permeable to water vapor, as disclosed in U.S. Pat. No. 5,798,119.

Such hydrophobic but water-vapor permeable ne are typically composed of hydrophobic rs such as polyalkenes, polyethylene, polypropylene, polytetrafluoroethylene, polyacrylic acid derivatives, polyethers, polysulfones, polyethersulfones, polystyrenes, polyvinyl halides, polyvinylidene fluoride, polyvinyl esters and ethers, l waxes, and synthetic waxes.

The delivery port(s) on the semipermeable membrane may be formed post- coating by mechanical or laser drilling. Delivery port(s) may also be formed in situ by erosion of a plug of water-soluble material or by rupture of a thinner portion of the membrane over an indentation in the core. In addition, delivery ports may be formed during coating process, as in the case of asymmetric ne coatings of the type disclosed in U.S. Pat.

Nos. 5,612,059 and 5,698,220.

The total amount of the active ingredient(s) released and the release rate can substantially by modulated via the thickness and porosity of the semipermeable membrane, the composition of the core, and the , size, and position of the delivery ports.

The pharmaceutical compositions in an osmotic controlled-release dosage form may further se additional conventional excipients or carriers as described herein to promote performance or processing of the formulation.

The osmotic controlled-release dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art (see, Remington: The Science and Practice ofPharmacy, supra; Santus and Baker, J. lled Release 1995, 35, 1-21; Verma et al., Drug Development and rial Pharmacy 2000, 26, 695-708; Verma et al., J. Controlled Release 2002, 79, 7-27).

] In n embodiments, the pharmaceutical compositions disclosed herein are formulated as AMT lled-release dosage form, which comprises an asymmetric osmotic membrane that coats a core comprising the active ingredient(s) and other pharmaceutically acceptable excipients or carriers. See, U.S. Pat. No. 5,612,059 and WC 2002/ 17918. The AMT controlled-release dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art, including direct compression, dry granulation, wet granulation, and a dip-coating method.

In certain embodiments, the pharmaceutical compositions disclosed herein are formulated as ESC controlled-release dosage form, which comprises an osmotic membrane that coats a core comprising the active ingredient(s), a hydroxylethyl ose, and other pharmaceutically acceptable excipients or carriers. 3. Multiparticulate Controlled Release Devices The pharmaceutical itions disclosed herein in a modified release dosage form may be fabricated a multiparticulate controlled release device, which comprises a multiplicity of particles, granules, or pellets, ranging from about 10 pm to about 3 mm, about 50 pm to about 2.5 mm, or from about 100 pm to about 1 mm in diameter. Such multiparticulates may be made by the processes know to those skilled in the art, including wet-and dry-granulation, extrusion/spheronization, roller-compaction, melt-congealing, and by spray-coating seed cores. See, for example, Multiparticulate Oral Drug Delivery; Marcel : 1994; and Pharmaceutical ization Technology; Marcel Dekker: 1989.

Other excipients or carriers as described herein may be blended with the pharmaceutical compositions to aid in processing and forming the multiparticulates. The resulting les may themselves constitute the multiparticulate device or may be coated by various film-forming materials, such as enteric polymers, water-swellable, and water-soluble polymers. The multiparticulates can be r sed as a capsule or a tablet.

The invention is further illustrated by the following examples: EXAMPLE 1 S-Methylphenylpyridin-2(1H)-0ne l / HO 0 5-Meth l hen l-1H- ridinone: A finely ized mixture of 2- hydroxymethylpyridine (0.500 g, 4.58 mmol), anhydrous potassium carbonate (0.693 g, 6.41 mmol), copper powder (0.006 g, 0.09 mmol) and nzene (1.68 g, 8.26 mmol) was heated at 180-190 0C for 7 hours. The mixture was cooled, and standard extractive workup was performed to afford a brown residue which was triturated with petroleum ether and recrystallized from hot water to yield the title nd as a white solid (0.470 g, 56%). mp. 105-107 0C; 1H NMR (400 MHz, DMSO-d6) 8 2.50 (s, 3H), 6.43 (d, J = 9.3 Hz, 1H), 7.36- 7.53 (m, 7H); IR (KBr) 1) 3045,1675,1611,1531,1270 cm'l; MS 186 (M +1).

EXAMPLE 2 d3(Methyl-)phenylpyridine-2(1H)-0ne Step1 O H O N UCOZHI —* U COZMe Methyloxo-1,6-dihydropyridinecarboxylate Thionyl chloride (6.3 mL, 86.33 mmol) was added dropwise to a solution of 6-hydroxynicotinic acid (10.0 g, 71.94 mmol) in ol at 00C. The mixture was heated to reflux for 6 hours, the solvent was removed and standard extractive work up provided the title compound as a brown solid (7.5 g, 68%). mp. 166-172 0C; 1H NMR (400 MHz, DMSO-d6) 8 3.77 (s, 3H), 6.37 (d, J = 9.3 Hz, 1H), 7.79 (dd, J = 2.7, 9.5 Hz, 1H), 8.04 (d, J = 2.4 Hz, 1H); IR (KBr) 1) 3050, 2965, 1712,1651,1433,1300,1106 cm'l; MS 154 (M +1).

Step 2 H QBOH( )2 0U o | —’ \ 9| COZMe COZMe Meth loxo hen l-1 6-dih dro ridinecarbox late Methyloxo-1,6- opyridinecarboxylate (6.0 g, 39.22 mmol), phenylboronic acid (5.74 g, 47.06 mmol), copper(H) acetate monohydrate (11.76 g, 58.82 mmol), pyridine (6.32 mL, 78.43 mmol) and molecular sieves (4A, 6.0 g) in dichloromethane (100 mL) was stirred at ambient temperature for 12 hours and filtered. Standard extractive work up provided a crude residue which was purified by silica gel column tography 00 mesh) (1—2% methanol in chloroform) to give the title compound as a brown solid (5.0 g, 56%). mp. 100-105 0C; 1H NMR (400 MHz, CDCl3) 8 3.86 (s, 3H), 6.63 (d, J = 9.5 Hz, 1H), 7.36-7.55 (m, 5H), 7.91 (dd, J = 2.5, 9.9 Hz, 1H), 8.23 (d, J = 2.5 Hz, 1H); IR (KBr) 1) 3058, 2924, 2854, 1721, 1675, 1540,1446,1313,1271,1103 cm'l; MS 230 (M +1).

Step 3 6-Oxophenyl-1,6-dihydropyridinecarboxylic acid: Lithium hydroxide monohydrate (0.366 g, 8.73 mmol) was added to a mixture of methyloxophenyl-1,6- dihydropyridinecarboxylate (1.0 g, 4.37 mmol), tetrahydrofuran (9 mL) and water (6 mL) at 0 OC. The mixture was stirred for 1 hour, diluted with water and washed with ethyl acetate.

The pH of the aqueous layer was adjusted to 2 using 2 N hydrochloric acid and the precipitate was filtered to give the title compound as a brown solid (0.740 g, 79%). mp. 256-263 0C; 1H NMR (400 MHz, DMSO-d6) 8 6.53 (d, J = 9.4 Hz, 1H), 7.40-7.49 (m, 5H), 7.87 (dd, J: 2.5, 9.8 Hz, 1H), 8.23 (d, J: 2.5 Hz, 1H); IR (KBr) 1) 3446, 1708, 1645, 1577, 1263, 1228 cm'l; MS 214 (M — 1). ] d2 H drox meth l hen l ridine-2 1 -one: Isobutyl formate (0.45 mL, 3.49 mmol) was added to a solution of 6-oxophenyl-1,6-dihydropyridine carboxylic acid (0.500 g, 2.32 mmol) and N—methylmorpholine (0.38 mL, 3.49 mmol) in tetrahydrofuran (10 mL) at -5 OC. The mixture was stirred for 3 hours at the same temperature, diluted with tetrahydrofuran and filtered over a pad of Celite under argon. The te containing the mixed anhydride was added dropwise to a suspension of sodium uteride (0.117 g, 2.79 mmol) in tetrahydrofuran at -10 OC. The reaction mixture was allowed to warm to room temperature and stirred for 16 hours, after which D20 (1 mL) was added. Standard extractive work up gave a crude residue which was purified by ative HPLC to give the title compound as a white solid (0.290 g, 61%). mp. 115-120 0C; 1H NMR (400 MHz, CDC13) 8 2.05 (br, 1H), 6.66 (d, J = 9.1 Hz, 1H), 7.25-7.51 (m, 7H); IR (KBr) 1) 3337, 1665, 1586, 1535, 1257 cm'l; MS 204 (M + 1).

Step 5 O N —> O N <8rI U\\ CD3 D D d3 Meth l hen l ridine-2 1 -one: Phosphorus tribromide (0.07 mL, 0.738 mmol) was added dropwise to a solution of d2(hydroxymethyl)phenylpyridine- 2(1H)-one (0.300 g, 1.47 mmol) in dichloromethane at -10 OC and the mixture was stirred for s. Dichloromethane and excess phosphorus tribromide were flushed out by a stream of argon and the residue was dissolved in tetrahydrofuran. This solution of the bromide was added dropwise to a suspension of lithium aluminum deuteride (0.092 g, 2.2 mmol) in ydrofuran at -78 OC and the e was stirred for 1 hour. D20 was added, and standard extractive work up gave a crude residue which was purified by preparative HPLC to give the title compound as a pale brown solid (0.070 g, 25%). mp. 103-107 0C; 1H NMR (400 MHz, DMSO-d6) 8 6.42 (d, J = 9.2 Hz, 1H), 7.36-7.53 (m, 7H); IR (KBr) 1) 3045, 2925, 1673, 1607, 1488, 1272 cm'l; MS 189 (M +1).

EXAMPLE 3 dn-S-Methyl-l-phenyl-1H-pyridin0ne D O D D D / N D D3C DD D H D (lgmethyl-pyridinylamine: The procedure is carried out using the methods described by by Esaki et al edron 2006, 62, 10954-10961.

H2N N D o N D | | D D ethyl-lH-pyridinone: The procedure is carried out using the s described by Smith et al Organic Syntheses 2002, 78, 51-56, but substituting d2- sulfuric acid in deuterium oxide for sulfuric acid in water, and substituting ethyl- pyridinylamine for 5-methyl-pyridinylamine.

Step 3 H D o D D O N D D D | + —> / D N D D CD3 _ D D D X D3C D D D dfl-S-Methyl-l-phenyl-lH-pyridinone: The procedure is carried out using the methods described in WO2003/014087 wherein the Ullmann coupling is run substituting d6methyl-lH-pyridinone for 5-methyl-lH-pyridinone and also substituting d5- bromobenzene (commercially available from multiple sources) for bromobenzene.

EXAMPLE 4 Human Dose-Escalation Study The procedure is carried out as described in US 7,635,707, which is hereby incorporated by nce in its entirety.

Modified Dosing in Response to Liver Function Test Elevations The procedure is carried out as described in US 7,635,707, which is hereby incorporated by nce in its entirety.

EXAMPLE 6 Multiple-Dose Study The procedure is carried out as described in US 20070203202, which is hereby incorporated by reference in its entirety.

EXAMPLE 7 Single-Dose Study The procedure is carried out as described in US 87508, which is hereby incorporated by nce in its entirety.

EXAMPLE 8 Multiple-Dose Study The procedure is carried out as described in US 20080287508, which is hereby incorporated by reference in its entirety.

Claims (15)

What is claimed

1. Use of d-pirfenidone in the manufacture of a ment for treating a liver function Grade 2 abnormality, wherein the medicament is formulated for: (a) administering a reduced dosage of d-pirfenidone for about one week, or until one or more liver function kers return to Grade 0 or Grade 1; and (b) administering an original full target dose of d-pirfenidone for a period of at least one week.

2. The use of claim 1, wherein the one or more biomarkers of liver function are selected from the group consisting of alanine transaminase, ate transaminase, bilirubin, and alkaline phosphatase.

3. The use of claim 1 or claim 2, wherein the liver function abnormality includes a level of alanine transaminase, aspartate transaminase, and/or alkaline phosphatase greater than about 2.5- fold increase compared to an upper limit of normal (ULN).

4. The use of any one of the preceding claims, wherein the liver function ality includes a level of alanine transaminase, aspartate minase, and/or ne phosphatase greater than about 2.5- to about 5-fold se compared to an upper limit of normal (ULN).

5. The use of any one of the preceding claims, wherein the liver function abnormality includes a level of bilirubin greater than about 1.5- to about 3-fold increase compared to an upper limit of normal (ULN).

6. Use of d-pirfenidone in the manufacture of a medicament for treating a liver function Grade 1 abnormality, wherein the medicament is formulated for: (a) administering a reduced dose of d-pirfenidone for about one week, or until one or more liver function biomarkers return to Grade 0; and (b) administering an al full target dose of d-pirfenidone for a period of at least one week.

7. The use of claim 6, wherein the one or more biomarkers of liver function are selected from the group consisting of alanine transaminase, aspartate transaminase, bilirubin and/or alkaline atase.

8. The use of claim 6 or claim 7, wherein the liver function abnormality includes a level of alanine transaminase, aspartate transaminase, and/or alkaline phosphatase greater than an upper limit of normal (ULN) and equal to or less than about a 2.5- fold increase compared to the ULN.

9. The use of any one of claims 6 to 8, wherein the liver function abnormality includes a level of bilirubin greater than an upper limit of normal (ULN) and equal to or less than about a 1.5-fold increase compared to the ULN.

10. The use of any one of the preceding claims, wherein at least one position of the dpirfenidone has deuterium enrichment of no less than about 10%.

11. The use of any one of the preceding claims, wherein the enidone is d3- pirfenidone.

12. The use of claim 11, wherein the d3-pirfenidone is

13. The use of any one of the preceding , wherein the medicament is formulated to provide a total daily dose of d-pirfenidone over two or three administrations a day, with food.

14. The use of claim 1, ntially as herein described with reference to any one of the Examples.

15. The use of claim 6, substantially as herein described with reference to any one of the Examples.