TY - JOUR T1 - Evaluation of CYP2B6 Induction and Prediction of Clinical DDI: Considerations from the IQ Consortium Induction Working Group- An Industry Perspective JF - Drug Metabolism and Disposition JO - Drug Metab Dispos DO - 10.1124/dmd.116.071076 SP - dmd.116.071076 AU - Odette A. Fahmi AU - Mohamad Shebley AU - Jairam Palamanda AU - Michael Sinz AU - Diane Ramsden AU - Heidi J Einolf AU - Liangfu Chen AU - Hongbing Wang Y1 - 2016/01/01 UR - http://dmd.aspetjournals.org/content/early/2016/07/15/dmd.116.071076.abstract N2 - Drug-drug interactions (DDI) due to CYP2B6 induction have recently gained prominence and clinical induction risk assessment is recommended by regulatory agencies. The objective of this work was to evaluate the potency of CYP2B6 vs CYP3A4 induction in vitro and from clinical studies, and to assess the predictability of efavirenz vs bupropion as clinical probe substrates of CYP2B6 induction. The analysis indicates that the magnitude of CYP3A4 induction was higher than CYP2B6 both in vitro and in vivo. The magnitude of DDI caused by induction could not be predicted for bupropion with static or dynamic models. On the other hand, the RIS, Net Effect, and SimCYP models using efavirenz resulted in improved DDI predictions. Although bupropion and efavirenz have been used and are recommended by regulatory agencies as clinical CYP2B6 probe substrates for DDI studies, CYP3A4 contributes to the metabolism of both probes and is induced by all reference CYP2B6 inducers. Therefore, caution must be taken when interpreting clinical induction results due to lack of selectivity of these probes. While IVIVE for efavirenz performed better than bupropion, interpretation of the clinical change in exposure is confounded by the co-induction of CYP2B6 and CYP3A4, and the increased contribution of CYP3A4 to efavirenz metabolism under induced conditions. Current methods and probe substrates preclude accurate prediction of CYP2B6 induction. Identification of a sensitive and selective clinical substrate for CYP2B6 (fm > 0.9) is needed to improve IVIVE for characterizing the potential for CYP2B6 mediated DDI. Alternative strategies and a framework for evaluating the CYP2B6 induction risk were proposed. ER -