Pirfenidone Treatment for Patients with Atypical Liver Function

• US 20110263656A1
• Filed: 11/09/2009
• Published: 10/27/2011
• Est. Priority Date: 11/10/2008
• Status: Active Grant

• Current Assignee: Intermune Incorporated (Roche Holding AG)
• Original Assignee: Intermune Incorporated (Roche Holding AG)
• Inventors: Szwarcberg, Javier, Bradford, Williamson Z.
• Granted Patent: US 8,609,701 B2
• Time in Patent Office: Days
• US Class Current: 514/345
• CPC Class Codes: A61K 31/4412 having oxo groups directly attached to the heterocyclic ring
• CPC Class Codes: A61K 31/4418 having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 11/16 Central respiratory analeptics
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/04 for non-specific disorders of the connective tissue
• CPC Class Codes: A61P 19/06 Antigout agents, e.g. antihyperuricemic or uricosuric agents
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/14 : for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 : Anti-Parkinson drugs
• CPC Class Codes: A61P 25/28 : for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 27/02 : Ophthalmic agents
• CPC Class Codes: A61P 29/00 : Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/00 : Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/10 : for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/04 : Antibacterial agents
• CPC Class Codes: A61P 31/08 : for leprosy
• CPC Class Codes: A61P 31/16 : for influenza or rhinoviruses
• CPC Class Codes: A61P 31/18 : for HIV
• CPC Class Codes: A61P 31/22 : for herpes viruses
• CPC Class Codes: A61P 33/06 : Antimalarials
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 37/02 : Immunomodulators
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 : Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 39/02 : Antidotes
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/14 : of the thyroid hormones, e.g. T3, T4
• CPC Class Codes: A61P 7/00 : Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/02 : Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 7/06 : Antianaemics
• CPC Class Codes: A61P 7/08 : Plasma substitutes; Perfusion solutions; Dialytics or haemodialytics; Drugs for electrolytic or acid-base disorders, e.g. hypovolemic shock artificial tears A61P27/04
• CPC Class Codes: A61P 9/04 : Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: G01N 2800/52 : Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis
• CPC Class Codes: G01N 33/576 : for hepatitis
• CPC Class Codes: G01N 33/6893 : related to diseases not provided for elsewhere
• CPC Class Codes: Y02A 50/30 : Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

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.

Claims

1. A method of administering pirfenidone to treat a patient who would benefit from pirfenidone administration, 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. The 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 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 claim 1 further comprising, prior to step (a), discontinuing pirfenidone for a time period, optionally about one week, or until biomarkers of liver function are within normal limits.

5. The method of claim 2 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 claim 1 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 claim 2 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 claim 1, wherein the pirfenidone is administered three times per day with food.

10. The method of claim 1 further comprising the step of measuring one or more biomarkers of liver function.

11. The method of claim 1, wherein said one or more biomarkers of liver function are alanine transaminase and/or 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 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 claim 1, 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 claim 32, wherein the pirfenidone is administered three times per day with food.

37. The method according to claim 32 further comprising measuring one or more biomarkers of liver function during administration of pirfenidone.

38. The method according to claim 32, wherein said one or more biomarkers of liver function are alanine transaminase and/or aspartate transaminase.

55. The method of claim 1, 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 of claim 1 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.

57. The method of claim 2 further comprising, prior to step (a), administering about 800 mg/day or 801 mg/day pirfenidone for a period of time, optionally 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.

58. The method of claim 1, wherein step (a) comprises administering to said patient pirfenidone at a dose of about 1800 mg/day.

9. (canceled)

12-31. -31. (canceled)

36. (canceled)

39-54. -54. (canceled)