RT Journal Article SR Electronic T1 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 JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP 1355 OP 1370 DO 10.1124/dmd.109.026716 VO 37 IS 7 A1 Scott W. Grimm A1 Heidi J. Einolf A1 Steven D. Hall A1 Kan He A1 Heng-Keang Lim A1 Kah-Hiing John Ling A1 Chuang Lu A1 Amin A. Nomeir A1 Eleanore Seibert A1 Konstantine W. Skordos A1 George R. Tonn A1 Robert Van Horn A1 Regina W. Wang A1 Y. Nancy Wong A1 Tian J. Yang A1 R. Scott Obach YR 2009 UL http://dmd.aspetjournals.org/content/37/7/1355.abstract AB 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.