AASLD-FDA-NIH-PhRMA*- Hepatotoxicity Special Interest Group Meeting
2008 Presentations

Drug Rechallenge [PDF]
Christine M. Hunt, MD and Julie I. Papay, Pharm.D.

Abstract

Background:   Drug rechallenge (or reinitiation), following an event of drug-induced liver injury, can lead to serious or fatal liver injury.

Methods:  Reports of possible drug-induced liver injury were examined within the GlaxoSmithKline global safety database (1958-2007) to evaluate outcome after positive rechallenge (CIOMS-defined liver injury following drug rechallenge). Among positive rechallenge events, cases were included in the analysis if:  a) the case was confirmed by a health care provider or regulatory authority, b) the event represented possible or probable drug-induced liver injury, and c) liver chemistries normalized or decreased >50% after initial event (to exclude chronic liver injury).  

Results:  36,795 hepatic adverse events were identified; 3.3% (1233) were rechallenged with the suspect drug. Of the 1233, 770 (62%) were positive rechallenges. Of these, 88 patients met inclusion criteria for analysis.  The mean age was 44 years (range 0.5-83) and 56% were male; a broad spectrum of suspect drugs was identified.  Many patients exhibited symptoms of jaundice or hepatitis on the initial and rechallenge liver event. Underlying liver disease was present in 21%.  Seventy three percent were categorized as serious adverse events (i.e. life-threatening, resulting in death, disability or hospitalization). Twelve patients (14%) exhibited severe hepatocellular injury with jaundice on either initial or rechallenge event and 2 (17%) died. The 2 patients with fatal rechallenge did not exhibit jaundice on the initial event, however developed severe hepatocellular injury with jaundice with their rechallenge. Most rechallenge events were inadvertent, occurred within one month of initial drug-induced liver injury, occurred after a shorter treatment duration than the initial injury and were generally similar or less severe.  The suspect drug was co-administered with other medications in 82% of events. 

Conclusions:  Review of a large pharmaceutical global safety database revealed that drug rechallenge following possible drug-induced liver injury resulted in a 2.3% overall fatality rate.  Most rechallenges resulted in a recurrence of liver injury.  Improved early identification and communication of possible drug-induced liver injury is needed to avoid potentially serious and/or fatal drug rechallenges. Clinicians should generally avoid such rechallenges.

References

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Biographies

Christine M. Hunt, M.D

Christine ‘Chris’ M. Hunt, M.D., F.A.C.P. obtained her B.S. in Biochemistry at the University of Massachusetts, Amherst, her M.D. at Boston University, her Internal Medicine residency at Boston VAMC, and her Gastroenterology/Hepatology fellowship at the Medical College of Virginia.  She is a board-certified in Internal Medicine and Gastroenterology/Hepatology. Dr. Hunt was on Duke University faculty for 8 years performing basic and clinical research and academic hepatology and gastroenterology practice.  Her research included the effect of aging on the human cytochromes P450, viral hepatitis, and other liver-related research. Dr. Hunt has authored more than 30 pier-reviewed publications and invited chapters.   She is a Fellow of the American College of Physicians and a member of American Association of Liver Disease and American Gastroenterological Association.

In 1996, she was recruited to GSK for Phase I-III GI and Hepatology drug development, where she contributed to or led several new drug applications. In 2005, Dr. Hunt transitioned to Clinical Safety to chair the GSK Hepatotoxicity Board and co-chair the GSK Safety Biomarker Strategy Team. She is Vice President, GSK Clinical Safety Systems, building proactive safety systems to address the key toxicities affecting drug development.  Dr. Hunt represents GSK on the FDA Hepatotoxicity Steering Committee and the Critical Path Translation Team on Predictive Biomarkers. 

Julie Papay, Pharm.D.

Julie Papay, Pharm.D. obtained a B.S. in Biology from Mississippi State University and a Doctor of Pharmacy and Drug Information Residency from Samford University.  Prior to pharmacy school, Julie’s professional experience includes research laboratory work at the University of Alabama at Birmingham, Division of Infectious Diseases under the guidance of John W. Gnann Jr and Edward Hook III.  After obtaining her Pharm.D. and residency, Julie worked for Prudential HealthCare Pharmacy Services and conducted reviews of newly approved drugs for the Prudential National Pharmacy and Therapeutics Committee. In 1998, Julie relocated to North Carolina to pursue a career with GSK during which time she has worked in several departments including Medical Information, Clinical Research, and Clinical Safety.  Julie currently works with Dr. Chris Hunt, Vice President, GSK Clinical Safety Systems building proactive safety systems to address the key toxicities affecting drug development.

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Date created: April 29, 2008

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