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AASLD-FDA-NIH-PhRMA Hepatotoxicity Steering Group Meeting, 2006 Presentations: Immunological tests for improving causality assessment

Herbert L. Bonkovsky, MD 
University of Connecticut
Immunological tests for improving causality assessment [PDF]

Some patients given drugs develop hypersensitivy-type reactions, characterized by symptoms and manifestations involving multiple organs. Rarely, patients given a variety of drugs (especially anticonvulsants like phenytoin, carbamazepine, or lamotrigine; non-steroidal anti-inflammatory drugs; or antibiotics like sulfonamides) develop fever, chills, skin rash, eosinophilia, arthralgias/arthritis, nephritis, myositis, and hepatitis. There is often a family and/or personal history of asthma, atopy, and known allergies. Based on these clinical features, it is assumed that the parent drug or a drug metabolite is the inciting antigen that causes a systemic immuno-allergic reaction. Rarely, such reactions may go on to self-sustaining hepatitis or other organ damage with hallmarks of autoimmune disease. Although detailed pharmacokinetic, pharmacogenetic, and immunologic studies of such patients are few, limited studies have identified lymphocytes in peripheral blood of such subjects that are activated by drugs and/or drug metabolites. Adequate numbers of negative controls (subjects who received the drugs for similar indications and durations without developing immuno-allergic reactions) are usually lacking, and currently there is no way to obtain such testing in clinical practice. Whether the ready availability of such testing would improve causality assessment and aid in fundamental understanding of pathogenesis of DILI remains unclear. There is a need for new and more efficient, rapid, and inexpensive methods to investigate these processes in larger numbers of well-defined, well-characterized subjects and suitable controls.

Biographical Sketch

Herbert L. Bonkovsky, M.D., Professor of Medicine and Molecular, Microbial, and Structural Biology, and Director of The Liver-Biliary-Pancreatic Center, at The University of CT Health Center, is known nationally and internationally as a clinical hepatologist, teacher, mentor, and clinical investigator. Dr. Bonkovsky is a graduate of Earlham College and Case Western Reserve University School of Medicine. His Post-graduate training was at Duke University, Case Western Reserve University School of Medicine, The U.S. National Institutes of Health, Dartmouth Medical School, and Yale University. Dr. Bonkovsky has served as Director of the Division of Digestive Disease and Nutrition at the University of Massachusetts Medical School and as Director of the Office of Clinical Research and the General Clinical Research Center at the University of Connecticut Health Center. His currently funded research is in porphyria and heme metabolism, chronic viral hepatitis, and the drug-induced liver injury. For the past twelve consecutive years, Dr. Bonkovsky has been selected by his peers as one of America’s Top Doctors.