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Drug Induced Liver Injury: Implications in drug discovery and development Paul B. Watkins University of North Carolina Chapel Hill, N.C.

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Drug Induced Liver Injury (DILI) is Hot FDA / Pharma steering committee Several Critical Path Initiatives $ millions spend in industry New Network (DILIN) SAE Consortium

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Industry SAE Priorities 2006 Rank Order [1 highest to 5 lowest] Overall Priority Variance Your Company's Priority Variance Hepatotoxicity1.1low1.2low QT Prolongation2.6moderate2.5high Rhabdomyolosis3.3moderate3.5mod Serious Skin Rashes [SJS]3.5high3.4high Edema4.4high4.5high SAE Consortium Survey courtesy of Arthur Holden

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Troglitazone (Rezulin) 1). PPAR agonist 2). Treats type 2 diabetes 3). Caused liver failure

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Presentation by Dr. Mark Pierce (Parke-Davis Pharmaceutical Research) March 26th 1999 - Troglitazone - FDA Advisory Panel Overall Post-Marketing Reporting Death/Transplant Rate March 1997 - March 1999 35 in 1.58 million = 1 in 45,098 Background incidence of liver failure with no known cause ~ 1 in 1 million

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Troglitazone (Rezulin) 1). Acute liver failure reports continued despite warnings and monitoring recommendations 2). Second in class (2) came on the market and appeared to be safer 3). Withdrawn from the market

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Troglitazone (Rezulin) The Rise and Fall of the Killer Drug Rezulin Los Angeles Times, June 4, 2000, p.1A. The Rise and Fall of the Killer Drug Rezulin Los Angeles Times, June 4, 2000, p.1A. a disparate collection of physicians inside the U.S. Food and Drug Administration waged a remarkable revolt that combined meticulous research and bluntly worded e-mail messages to upbraid their government superiors for contributing to the needless deaths of patients. for contributing to the needless deaths of patients.

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Why clinical drug development programs were terminated in 1991 programs were terminated in 1991 % of total terminations Nature Reviews: Drug Discovery, Aug, 2004

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Why clinical drug development programs were terminated in 2000 1991 2000 % of total terminations Nature Reviews: Drug Discovery, Aug, 2004

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Hepatotoxicity has been the most common single adverse effect causing major drug problems, including withdrawals and refusals to approve Bob Temple, M.D. FDA2/15/01

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2006 State of the Art How to avoid hepatotoxicity in drug development 1). Avoid certain molecular structures

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Compound Pair Ibuprofen Clean Compound Ibufenac Toxic Compound* *withdrawn from the market in the 1960s because of clinical liver toxicity

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2006 State of the Art How to avoid hepatotoxicity in drug development 1). Avoid certain molecular structures 2). Target daily dose to < 10 mg/day

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2006 State of the Art How to avoid hepatotoxicity in drug development 1). Avoid certain molecular structures 2). Target daily dose to < 10 mg/day 3). Low covalent binding in liver microsomes 4). Low production of glutathione conjugates

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2006 State of the Art How to avoid hepatotoxicity in drug development 1). Avoid certain molecular structures 2). Target daily dose to < 10 mg/day 3). Low covalent binding in liver microsomes 4). Low production of glutathione conjugates 5). Low incidence ( 3 X ULN in clinical trials.

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1). Avoid certain molecular structures - NO 2). Target daily dose to < 10 mg/day 4 grams/day 3). Low covalent binding in liver microsomes NO 4). Low production of glutathione conjugates NO 5). Low incidence (

Incidence of ALT elevations (>3X ULN) and clinical hepatitis ALT hepatitis troglitazone 2%