Methods of Administering Pirfenidone Therapy

Abstract

The present invention relates to methods involving avoiding adverse drug interactions with fluvoxamine and pirfenidone or other moderate to strong inhibitors of CYP enzymes.

What is claimed is: 
     
         1 . Pirfenidone for use in treating a patient in need of pirfenidone therapy, characterized in that the treating comprises (a) avoiding, contraindicating, discontinuing or using with caution concomitant use or co-administration of a cytochrome P450 1A2 (CYP1A2) inhibitor that is a moderate to strong inhibitor of both (i) cytochrome P450 1A2 (CYP1A2) and (ii) another CYP enzyme selected from the group consisting of CYP3A4, CYP2C9, CYP2C19, CYP2B6 and/or CYP2D6, or (b) using with caution pirfenidone in patients receiving a strong inhibitor of CYP1A2, or (c) using with caution a strong CYP1A2 inhibitor in patients receiving pirfenidone. 
     
     
         2 . Use of pirfenidone in preparation of a medicament for treating a patient in need of pirfenidone therapy, characterized in that the treating comprises (a) avoiding, contraindicating, discontinuing or using with caution concomitant use or co-administration of a cytochrome P450 1A2 (CYP1A2) inhibitor that is a moderate to strong inhibitor of both (i) cytochrome P450 1A2 (CYP1A2) and (ii) another CYP enzyme selected from the group consisting of CYP3A4, CYP2C9, CYP2C19, CYP2B6 and/or CYP2D6, or (b) using with caution pirfenidone in patients receiving a strong inhibitor of CYP1A2, or (c) using with caution a strong CYP1A2 inhibitor in patients receiving pirfenidone. 
     
     
         3 . A method of administering pirfenidone therapy to a patient in need thereof, comprising administering an effective amount of pirfenidone, and (a) avoiding, contraindicating, discontinuing or using with caution a cytochrome P450 1A2 (CYP1A2) inhibitor that is a moderate to strong inhibitor of both (i) cytochrome P450 1A2 (CYP1A2) and (ii) another CYP enzyme selected from the group consisting of CYP3A4, CYP2C9, CYP2C19, CYP2B6 and/or CYP2D6, or (b) using with caution pirfenidone in patients receiving a strong inhibitor of CYP1A2, or (e) using with caution a strong CYP1A2 inhibitor in patients receiving pirfenidone. 
     
     
         4 . The pirfenidone, use or method of any of  claims 1 - 3  wherein the CYP1A2 inhibitor is a moderate to strong inhibitor of CYP1A2 and another CYP enzyme selected from the group consisting of CYP2C9, CYP2C19 and/or CYP2D6. 
     
     
         5 . The pirfenidone, use or method of any of  claims 1 - 3  wherein the CYP1A2 inhibitor is a strong CYP1A2 inhibitor. 
     
     
         6 . The pirfenidone, use or method of any of  claims 1 - 4  wherein the CYP1A2 inhibitor is discontinued prior to starting pirfenidone therapy to avoid an adverse drug interaction with pirfenidone, or to avoid a reduced clearance of pirfenidone. 
     
     
         7 . The pirfenidone of any one of  claims 1 - 6  wherein the CYP1A2 inhibitor is discontinued within 1 month prior to starting pirfenidone therapy. 
     
     
         8 . The pirfenidone of any one of  claims 1 - 7  wherein the CYP1A2 inhibitor is discontinued within 2 weeks prior to starting pirfenidone therapy. 
     
     
         9 . The pirfenidone, use or method of any of  claims 1 - 4  wherein the CYP1A2 inhibitor is avoided during pirfenidone therapy. 
     
     
         10 . The pirfenidone, use or method of any of  claims 1 - 9  wherein the patient is in need of therapy with a CYP1A2 inhibitor. 
     
     
         11 . The pirfenidone, use or method of any of  claims 1 - 5  wherein the CYP1A2 inhibitor is used with caution. 
     
     
         12 . The pirfenidone of any one of  claims 1 - 11  wherein the patient has idiopathic pulmonary fibrosis (IPF). 
     
     
         13 . The pirfenidone of any of  claims 1 - 11  wherein the patient suffers from a disease selected from idiopathic pulmonary fibrosis, pulmonary fibrosis, idiopathic interstitial pneumonia, autoimmune lung diseases, benign prostate hypertrophy, coronary or myocardial infarction, atrial fibrillation, cerebral infarction, myocardiac fibrosis, musculoskeletal fibrosis, post-surgical adhesions, liver cirrhosis, renal fibrotic disease, fibrotic vascular disease, scleroderma, Hermansky-Pudlak syndrome, neurofibromatosis, Alzheimer's disease, diabetic retinopathy, or skin lesions, lymph node fibrosis associated with HIV, chronic obstructive pulmonary disease (COPD), inflammatory pulmonary fibrosis, rheumatoid arthritis; rheumatoid spondylitis; osteoarthritis; gout, other arthritic conditions; sepsis; septic shock; endotoxic shock; gram-negative sepsis; toxic shock syndrome; myofacial pain syndrome (MPS); Shigellosis; asthma; adult respiratory distress syndrome; inflammatory bowel disease; Crohn's disease; psoriasis; eczema; ulcerative colitis; glomerular nephritis; scleroderma; chronic thyroiditis; Grave's disease; Ormond's disease; autoimmune gastritis; myasthenia gravis; autoimmune hemolytic anemia; autoimmune neutropenia; thrombocytopenia; pancreatic fibrosis; chronic active hepatitis including hepatic fibrosis; acute or chronic renal disease; renal fibrosis; diabetic nephropathy; irritable bowel syndrome; pyresis; restenosis; cerebral malaria; stroke or ischemic injury; neural trauma; Alzheimer's disease; Huntington's disease; Parkinson's disease; acute or chronic pain; allergies, including allergic rhinitis or allergic conjunctivitis; cardiac hypertrophy, chronic heart failure; acute corollary syndrome; cachexia; malaria: leprosy; leishmaniasis; Lyme disease; Reiter's syndrome; acute synoviitis; muscle degeneration, bursitis; tendonitis; tenosynoviitis; herniated, ruptured, or prolapsed intervertebral disk syndrome; osteopetrosis; thrombosis; silicosis; pulmonary sarcosis; bone resorption diseases, such as osteoporosis or multiple myeloma-related boric disorders; cancer, including but not limited to metastatic breast carcinoma, colorectal carcinoma, malignant melanoma, gastric cancer, or non-small cell lung cancer; graft-versus-host reaction; or auto-immune diseases, such as multiple sclerosis, lupus or fibromyalgia; AIDS or other viral diseases such as Herpes Zoster, Herpes Simplex I or II, influenza virus, Severe Acute Respiratory Syndrome (SARS) or cytomegalovirus; or diabetes mellitus, proliferative disorders (including both benign or malignant hyperplasias), acute myelogenous leukemia, chronic myelogenous leukemia, Kaposi's sarcoma, metastatic melanoma, multiple myeloma, breast cancer, including metastatic breast carcinoma; colorectal carcinoma; malignant melanoma; gastric cancer; non-small cell lung cancer (NSCLC); bone metastases; pain disorders including neuromuscular pain, headache, cancer pain, dental pain, or arthritis pain; angiogenic disorders including solid tumor angiogenesis, ocular neovascularization, or infantile hemangioma; conditions associated with the cyclooxygenase or lipoxygenase signaling pathways, including conditions associated with prostaglandin endoperoxide synthase-2 (including edema, fever, analgesia, or pain); organ hypoxia; thrombin-induced platelet aggregation; or protozoal diseases. 
     
     
         14 . The pirfenidone of any one of  claims 1  through  13  wherein the pirfenidone is administered at a total daily dosage of at least 1800 mg. 
     
     
         15 . The pirfenidone of any one of  claims 1  through  13  wherein the pirfenidone is administered at a total daily dosage of about 2400 mg or 2403 mg. 
     
     
         16 . The pirfenidone of any one of  claims 1  through  13  wherein 800 or 801 mg of pirfenidone is administered to the patient three times per day, with food. 
     
     
         17 . The pirfenidone of any one of  claims 1  through  16  wherein the CYP1A2 inhibitor is fluvoxamine. 
     
     
         18 . The pirfenidone of any one of  claims 1  through  17  wherein the CYP1A2 inhibitor is ciprofloxacin, amiodarone or propafenone. 
     
     
         19 . The pirfenidone of any one of  claims 1  through  16  wherein the CYP1A2 inhibitor is grapefruit juice. 
     
     
         20 . A package or kit comprising (a) pirfenidone, optionally in a container, and (b) a package insert, package label, instructions or other labeling comprising avoiding or discontinuing or contraindicating concomitant use of or co-administration of or using with caution (1) a strong inhibitor of CYP1A2, or (2) a moderate to strong inhibitor of both (i) CYP1A2 and (ii) another CYP enzyme selected from the group consisting of CYP3A4, CYP2C9, CYP2C 19, CYP2B6 and/or CYP2D6, optionally according to any of the embodiments of  claims 1 - 19 .