Drug Induced Liver Injury: Implications in drug discovery and
development Paul B. Watkins University of North Carolina Chapel
Hill, N.C.
Slide 2
Drug Induced Liver Injury (DILI) is Hot FDA / Pharma steering
committee Several Critical Path Initiatives $ millions spend in
industry New Network (DILIN) SAE Consortium
Slide 3
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
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
Slide 6
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Withdrawn from the market
Slide 7
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.
Slide 8
Why clinical drug development programs were terminated in 1991
programs were terminated in 1991 % of total terminations Nature
Reviews: Drug Discovery, Aug, 2004
Slide 9
Why clinical drug development programs were terminated in 2000
1991 2000 % of total terminations Nature Reviews: Drug Discovery,
Aug, 2004
Slide 10
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
Slide 11
2006 State of the Art How to avoid hepatotoxicity in drug
development 1). Avoid certain molecular structures
Slide 12
Compound Pair Ibuprofen Clean Compound Ibufenac Toxic Compound*
*withdrawn from the market in the 1960s because of clinical liver
toxicity
Slide 13
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
Slide 14
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
Slide 15
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.
Slide 16
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%