Vector Analysis to Detect Hepatotoxicity Signals in Drug Development
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Donald C. Trost, MD, PhD Senior Director. Translational and
Molecular Medicine. Pfizer Global Research and Development, Groton. Connecticuf
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Vector Analysis to Detect Hepatotoxicity Signals in Drug Development
Jams W. Frrston, MD, PhD Professor of Medicine and Boehringer lngelheim Chair of Clinical Pharmacologv. University ofConnecticut Healfh Cenfer. Farmingfon. Connecticut
Koy Words Hepatotaxicity; Vector analysis; Liver cell injury: Adverse events; Pafhodynamics
Corrrspondonre Addrors Donald C. Trost. MS 8260-2301, Eastem Point Road, Pfizer Global Research and Development. Grofon, CT 06340 (e-mail: Trost ResearchOaol.corn).
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Hepatotaxicityis a leading cause of discontinuing drugs in development and withdmwing drugs from clinical use. Most withdrmvals are due to idiosyncrntichepatotaxici@which usually escapes detection in clinical trials because of its m'iyWe investigatedthe potential of vector analysis of liverfinction tests to detect an Omj. signal of idiosyncmtichepatotaxicityin clinical t i a l s using data with an obvious druginduced liver response. Serum samples collected serially during mndomized, placebo-contrdledtrials of a compound that was subsequentlydiscontinued because of hepatotaxicitywere an4zedfor alanine aminotnansfemse,aspartateaminotmns-
femse, y-glutmybmsfm and &dine phosphahe. Vectm for d i n a t i o n s of tests were computed and dispiayed in two a thra dimmsions ova the 6-weekcause ofthe trids. At baseline, shod vectors wac d u s t d within the n d mngc in the active- a
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