Pirfenidone Treatment for Patients with Atypical Liver Function

Abstract

Methods are provided for administering pirfenidone to a patient that has exhibited abnormal biomarkers of liver function in response to pirfenidone administration. The methods include administering to a patient pirfenidone at doses lower than the full target dosage for a time period, followed by administering to the patient pirfenidone at the full target dosage. The methods also include administering pirfenidone at the full target dose with no reduction and administering permanently reduced doses of pirfenidone.

What is claimed is: 
     
         1 . A method of administering pirfenidone to treat a patient who would benefit from pirfenidone administration, optionally a patient with idiopathic pulmonary fibrosis (IPF), said patient having exhibited a Grade 2 abnormality in one or more biomarkers of liver function after pirfenidone administration, comprising (a) administering to said patient pirfenidone at doses of at least 1600 mg/day or 1602 mg/day. 
     
     
         2 . A method of  claim 1  comprising (a) administering to said patient pirfenidone at doses of 2400 mg/day or 2403 mg/day. 
     
     
         3 . The method of  claim 1  or  2  further comprising, prior to step (a), administering to said patient pirfenidone at doses lower than 2400 mg/day for a time period. 
     
     
         4 . The method of any of  claims 1 - 3  wherein prior to step (a) pirfenidone is discontinued until biomarkers of liver function are within normal limits. 
     
     
         5 . The method of any of  claims 1 - 4  further comprising, prior to step (a), administering about 1600 mg/day or 1602 mg/day pirfenidone for a period of time, optionally about one week, or until biomarkers of liver function are within normal limits. 
     
     
         6 . The method of any of  claims 1 - 5  further comprising, prior to step (a), administering about 800 mg/day or 801 mg/day pirfenidone for a period of time, optionally about one week, or until biomarkers of liver function are within normal limits, followed by administering about 1600 mg/day or 1602 mg/day pirfenidone for a period of time, optionally about one week, or until biomarkers of liver function are within normal limits. 
     
     
         7 . The method of any of  claims 1 - 6  further comprising, prior to step (a), discontinuing pirfenidone for a period of time, optionally about one week, or until biomarkers of liver function are within normal limits. 
     
     
         8 . The method of any of  claims 1 - 7 , wherein the pirfenidone is administered three times per day with food. 
     
     
         9 . The method of any of  claims 1 - 8 , wherein said one or more biomarkers of liver function is selected from the group consisting of alanine transaminase, aspartate transaminase, and bilirubin. 
     
     
         10 . The method of any of  claims 1 - 9  further comprising the step of measuring one or more biomarkers of liver function. 
     
     
         11 . The method of any of  claims 1 - 10 , wherein said one or more biomarkers of liver function are alanine transaminase and aspartate transaminase. 
     
     
         12 . Pirfenidone for use in treating a patient who would benefit from pirfenidone administration, optionally a patient with idiopathic pulmonary fibrosis (IPF), said patient having exhibited a Grade 2 abnormality in one or more biomarkers of liver function after pirfenidone administration, wherein (a) said patient is administered pirfenidone at doses of 2400 mg/day or 2403 mg/day. 
     
     
         13 . Pirfenidone for use in treating a patient according to  claim 11 , wherein, prior to step (a), said patient is administered pirfenidone at doses lower than 2400 mg/day for a time period. 
     
     
         14 . Pirfenidone for use in treating a patient according to  claim 11  or  12 , wherein, prior to step (a), pirfenidone administration to the patient is discontinued for a time period, optionally about one week, or until biomarkers of liver function are within normal limits. 
     
     
         15 . Pirfenidone for use in treating a patient according to any of  claims 11 - 13 , wherein, prior to step (a), about 1600 mg/day or 1602 mg/day pirfenidone is administered to the patient for a time period, optionally about one week, or until biomarkers of liver function are within normal limits. 
     
     
         16 . Pirfenidone for use in treating a patient according to any of  claims 11 - 14 , wherein, prior to step (a), about 800 mg/day or 801 mg/day pirfenidone is administered to the patient for a time period, optionally about one week, or until biomarkers of liver function are within normal limits, and then about 1600 mg/day or 1602 mg/day pirfenidone is administered to the patient for a time period, optionally about one week or until biomarkers of liver function are within normal limits. 
     
     
         17 . Pirfenidone for use in treating a patient according to any of  claims 11 - 15 , wherein, prior to step (a), administration of pirfenidone is discontinued for a time period, optionally about one week, or until biomarkers of liver function are within normal limits, and then about 800 mg/day or 801 mg/day pirfenidone is administered for a time period, optionally about one week or until biomarkers of liver function are within normal limits, and then about 1600 mg/day or 1602 mg/day pirfenidone is administered for a time period, optionally about one week or until biomarkers of liver function are within normal limits. 
     
     
         18 . Pirfenidone for use in treating a patient according to any of  claims 11 - 16 , wherein the pirfenidone is administered three times per day with food. 
     
     
         19 . Pirfenidone for use in treating a patient according to any of  claims 11 - 17 , wherein said one or more biomarkers of liver function is selected from the group consisting of alanine transaminase, aspartate transaminase, and bilirubin. 
     
     
         20 . Pirfenidone for use in treating a patient according to any of  claims 11 - 18  further comprising measuring one or more biomarkers of liver function. 
     
     
         21 . Pirfenidone for use in treating a patient according to any of  claims 11 - 19 , wherein said one or more biomarkers of liver function are alanine transaminase and aspartate transaminase. 
     
     
         22 . Use of pirfenidone in the manufacture of a medicament for treating a patient who would benefit from pirfenidone administration, optionally a patient with idiopathic pulmonary fibrosis (IPF), said patient having exhibited a Grade 2 abnormality in one or more biomarkers of liver function after pirfenidone administration, wherein (a) said patient is administered pirfenidone at doses of 2400 mg/day or 2403 mg/day. 
     
     
         23 . Use according to  claim 21 , wherein, prior to step (a), said patient is administered pirfenidone at doses lower than 2400 mg/day for a time period. 
     
     
         24 . Use according to  claim 21  or  22 , wherein, prior to step (a), pirfenidone administration to the patient is discontinued for a time period, optionally about one week or until biomarkers of liver function are within normal limits. 
     
     
         25 . Use according to any of  claims 21 - 23 , wherein, prior to step (a), about 1600 mg/day or 1602 mg/day pirfenidone is administered to the patient for a time period, optionally about one week, or until biomarkers of liver function are within normal limits. 
     
     
         26 . Use according to any of  claims 21 - 24 , wherein, prior to step (a), about 800 mg/day or 801 mg/day pirfenidone is administered to the patient for a time period, optionally about one week, or until biomarkers of liver function are within normal limits, and then about 1600 mg/day or 1602 mg/day pirfenidone is administered to the patient for a time period, optionally about one week, or until biomarkers of liver function are within normal limits. 
     
     
         27 . Use according to any of  claims 21 - 25 , wherein, prior to step (a), administration of pirfenidone is discontinued for a time period, optionally about one week, or until biomarkers of liver function are within normal limits, and then about 800 mg/day or 801 mg/day pirfenidone is administered for a time period, optionally about one week or until biomarkers of liver function are within normal limits, and then about 1600 mg/day or 1602 mg/day pirfenidone is administered for a time period, optionally about one week or until biomarkers of liver function are within normal limits. 
     
     
         28 . Use according to any of  claims 21 - 26 , wherein the pirfenidone is administered three times per day with food. 
     
     
         29 . Use according to any of  claims 21 - 27 , wherein said one or more biomarkers of liver function is selected from the group consisting of alanine transaminase, aspartate transaminase, and bilirubin. 
     
     
         30 . Use according to any of  claims 21 - 28  further comprising measuring one or more biomarkers of liver function during administration of pirfenidone. 
     
     
         31 . Use according to any of  claims 21 - 29 , wherein said one or more biomarkers of liver function are alanine transaminase and aspartate transaminase. 
     
     
         32 . The method according to  claim 1 , wherein, prior to step (a), said patient is administered pirfenidone at doses lower than 1600 mg/day for a time period. 
     
     
         33 . The method according to  claim 1  or  32 , wherein, prior to step (a), pirfenidone administration to the patient is discontinued for a time period, optionally about one week or until biomarkers of liver function are within normal limits. 
     
     
         34 . The method according to any of  claim 1  or  32 - 33 , wherein, prior to step (a), about 800 mg/day or 801 mg/day pirfenidone is administered to the patient for a time period, optionally about one week, or until biomarkers of liver function are within normal limits. 
     
     
         35 . The method according to any of  claim 1  or  32 - 34 , wherein the pirfenidone is administered three times per day with food. 
     
     
         36 . The method according to any of  claim 1  or  32 - 35 , wherein said one or more biomarkers of liver function is selected from the group consisting of alanine transaminase, aspartate transaminase, and bilirubin. 
     
     
         37 . The method according to any of  claim 1  or  32 - 36  further comprising measuring one or more biomarkers of liver function during administration of pirfenidone. 
     
     
         38 . The method according to any of  claim 1  or  32 - 37 , wherein said one or more biomarkers of liver function are alanine transaminase and aspartate transaminase. 
     
     
         39 . Pirfenidone for use in treating a patient who would benefit from pirfenidone administration, optionally a patient with idiopathic pulmonary fibrosis (IPF), said patient having exhibited a Grade 2 abnormality in one or more biomarkers of liver function after pirfenidone administration, wherein (a) said patient is administered pirfenidone at doses of at least 1600 mg/day or 1602 mg/day. 
     
     
         40 . Pirfenidone for use in treating a patient according to  claim 39 , wherein, prior to step (a), said patient is administered pirfenidone at doses lower than 1600 mg/day for a time period. 
     
     
         41 . Pirfenidone for use in treating a patient according to  claim 39  or  40 , wherein, prior to step (a), pirfenidone administration to the patient is discontinued for a time period, optionally about one week or until biomarkers of liver function are within normal limits. 
     
     
         42 . Pirfenidone for use in treating a patient according to any of  claims 39 - 41 , wherein, prior to step (a), about 800 mg/day or 801 mg/day pirfenidone is administered to the patient for a time period, optionally about one week, or until biomarkers of liver function are within normal limits. 
     
     
         43 . Pirfenidone for use in treating a patient according to any of  claims 39 - 42 , wherein the pirfenidone is administered three times per day with food. 
     
     
         44 . Pirfenidone for use in treating a patient according to any of  claims 39 - 43 , wherein said one or more biomarkers of liver function is selected from the group consisting of alanine transaminase, aspartate transaminase, and bilirubin. 
     
     
         45 . Pirfenidone for use in treating a patient according to any of  claims 39 - 44  further comprising measuring one or more biomarkers of liver function during administration of pirfenidone. 
     
     
         46 . Pirfenidone for use in treating a patient according to any of  claims 39 - 45 , wherein said one or more biomarkers of liver function are alanine transaminase and aspartate transaminase. 
     
     
         47 . Use of pirfenidone in the manufacture of a medicament for treating a patient who would benefit from pirfenidone administration, optionally a patient with idiopathic pulmonary fibrosis (IPF), said patient having exhibited a Grade 2 abnormality in one or more biomarkers of liver function after pirfenidone administration, wherein (a) said patient is administered pirfenidone at doses of at least 1600 mg/day or 1602 mg/day. 
     
     
         48 . The use according to  claim 47 , wherein, prior to step (a), said patient is administered pirfenidone at doses lower than 1600 mg/day for a time period. 
     
     
         49 . The use according to  claim 47  or  48 , wherein, prior to step (a), pirfenidone administration to the patient is discontinued for a time period, optionally about one week or until biomarkers of liver function are within normal limits. 
     
     
         50 . The use according to any of  claims 47 - 49 , wherein, prior to step (a), about 800 mg/day or 801 mg/day pirfenidone is administered to the patient for a time period, optionally about one week, or until biomarkers of liver function are within normal limits. 
     
     
         51 . The use according to any of  claims 47 - 50 , wherein the pirfenidone is administered three times per day with food. 
     
     
         52 . The use according to any of  claims 47 - 51 , wherein said one or more biomarkers of liver function is selected from the group consisting of alanine transaminase, aspartate transaminase, and bilirubin. 
     
     
         53 . The use according to any of  claims 47 - 52  further comprising measuring one or more biomarkers of liver function during administration of pirfenidone. 
     
     
         54 . The use according to any of  claims 47 - 53 , wherein said one or more biomarkers of liver function are alanine transaminase and aspartate transaminase. 
     
     
         55 . The method or use of any of the preceding claims, wherein the patient who would benefit from pirfenidone administration suffers from a condition selected from the group consisting of pulmonary fibrosis, idiopathic interstitial pneumonia, autoimmune lung diseases, benign prostate hypertrophy, coronary or myocardial infarction, atrial fibrillation, cerebral infarction, myocardiac fibrosis, musculoskeletal fibrosis, post-surgical adhesions, liver cirrhosis, renal fibrotic disease, fibrotic vascular disease, scleroderma, Hermansky-Pudlak syndrome, neurofibromatosis, Alzheimer's disease, diabetic retinopathy, skin lesions, and lymph node fibrosis associated with HIV. 
     
     
         56 . The method or use of any of the preceding claims wherein the patient who would benefit from pirfenidone administration suffers from a condition selected from the group consisting of chronic obstructive pulmonary disease (COPD), inflammatory pulmonary fibrosis (IPF), rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gout, sepsis, septic shock, endotoxic shock, gram-negative sepsis, toxic shock syndrome, myofacial pain syndrome (MPS), Shigellosis, asthma, adult respiratory distress syndrome, inflammatory bowel disease, Crohn's disease, psoriasis, eczema, ulcerative colitis, glomerular nephritis, scleroderma, chronic thyroiditis, Grave's disease, Ormond's disease, autoimmune gastritis, myasthenia gravis, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, pancreatic fibrosis, chronic active hepatitis, acute and chronic renal disease, renal fibrosis, irritable bowel syndrome, pyresis, restenosis, cerebral malaria, stroke and ischemic injury, neural trauma, Huntington's disease, Parkinson's disease, acute and chronic pain, allergies, cardiac hypertrophy, chronic heart failure, acute coronary syndrome, cachexia, malaria, leprosy, leishmaniasis, Lyme disease, Reiter's syndrome, acute synoviitis, muscle degeneration, bursitis; tendonitis, tenosynoviitis, herniated, ruptured, or prolapsed intervertebral disk syndrome, osteopetrosis, thrombosis, silicosis, pulmonary sarcosis, bone resorption diseases, cancer, graft-versus-host reaction; and auto-immune diseases, AIDS, Herpes Zoster, Herpes Simplex I or II, influenza virus, Severe Acute Respiratory Syndrome (SARS), cytomegalovirus, and diabetes mellitus.