TY - JOUR T1 - Quantitative Prediction of CYP3A4 Induction: Impact of Measured, Free and Intracellular Perpetrator Concentrations from Human Hepatocyte Induction Studies on Drug-Drug Interaction Predictions JF - Drug Metabolism and Disposition JO - Drug Metab Dispos DO - 10.1124/dmd.117.075481 SP - dmd.117.075481 AU - Yongkai Sun AU - Paresh P Chothe AU - Jennifer Sager AU - Hong Tsao AU - Amanda Moore AU - Leena Laitinen AU - Niresh Hariparsad Y1 - 2017/01/01 UR - http://dmd.aspetjournals.org/content/early/2017/03/23/dmd.117.075481.abstract N2 - Typically, concentration-response curves are generated based upon nominal new chemical entity (NCE) concentrations for in-vitro-to-in-vivo extrapolation of CYP3A4 induction. These data are then used to determine the induction risk of an NCE employing various modeling approaches. The limitation to this practice is that it assumes the hepatocyte culture model to be a static system. In the current study, we assessed whether correcting for; 1) changes in perpetrator concentration in the induction medium during the assay incubation period, 2) perpetrator binding to proteins in the induction medium and 3) non-specific binding of perpetrator can improve the accuracy of CYP3A4 induction predictions. Of the seven validation compounds used in our studies, we noted significant parent loss and a high degree of medium protein binding with pioglitazone and rosiglitazone while pleconaril had very high non-specific binding. Predictions of clinical induction were determined using the relative induction score, basic-static, and mechanistic static models. In general, we observed that the precision and accuracy of our predictions improved when corrections were made for measured medium concentrations, medium protein binding, and non-specific binding of the perpetrator. As a follow-up, we noted that for substrates of uptake transporters, the use of free intracellular concentrations could result in improved predictions of CYP3A4 induction. In conclusion, our data indicates that quantifying perpetrator levels in induction medium can improve the accuracy and precision of CYP3A4 induction predictions. Continued efforts are necessary to improve our understanding of the impact of free intracellular concentrations on induction predictions. ER -