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The Conduct of in Vitro Studies to Address Time-Dependent Inhibition of Drug-Metabolizing Enzymes: A Perspective of the Pharmaceutical Research and Manufacturers of America

AstraZeneca Pharmaceuticals, Wilmington, Delaware (S.W.G.); Allergan Inc., Irvine, California (K.-H.J.L.); Amgen Inc., South San Francisco, California (G.R.T.); Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut (E.S.); Bristol-Myers Squibb Co., Princeton, New Jersey (K.H.); Eisai Research Institute, Andover, Massachusetts (Y.N.W.); Eli Lilly and Company, Indianapolis, Indiana (S.D.H.); GlaxoSmithKline, King of Prussia, Pennsylvania (K.W.S.); Hoffmann-La Roche, Nutley, New Jersey (T.J.Y.); Johnson & Johnson Pharmaceutical Research Institute, Raritan, New Jersey (H.-K.L.); Merck Research Laboratories, Rahway, New Jersey (R.W.W.); Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts (C.L.); Novartis Pharmaceuticals Corporation, East Hanover, New Jersey (H.J.E.); Pfizer Inc., Groton, Connecticut (R.S.O.); Sanofi-Aventis, Malvern, Pennsylvania (R.V.H.); and Schering-Plough Research Institute, Kenilworth, New Jersey (A.A.N.)

Time-dependent inhibition (TDI) of cytochrome P450 (P450) enzymes caused by new molecular entities (NMEs) is of concern because such compounds can be responsible for clinically relevant drug-drug interactions (DDI). Although the biochemistry underlying mechanism-based inactivation (MBI) of P450 enzymes has been generally understood for several years, significant advances have been made only in the past few years regarding how in vitro time-dependent inhibition data can be used to understand and predict clinical DDI. In this article, a team of scientists from 16 pharmaceutical research organizations that are member companies of the Pharmaceutical Research and Manufacturers of America offer a discussion of the phenomenon of TDI with emphasis on the laboratory methods used in its measurement. Results of an anonymous survey regarding pharmaceutical industry practices and strategies around TDI are reported. Specific topics that still possess a high degree of uncertainty are raised, such as parameter estimates needed to make predictions of DDI magnitude from in vitro inactivation parameters. A description of follow-up mechanistic experiments that can be done to characterize TDI are described. A consensus recommendation regarding common practices to address TDI is included, the salient points of which include the use of a tiered approach wherein abbreviated assays are first used to determine whether NMEs demonstrate TDI or not, followed by more thorough inactivation studies for those that do to define the parameters needed for prediction of DDI.