Quantitative prediction of CYP3A induction-mediated drug-drug interactions in clinical practice

Abstract

There have been no reports on the quantitative prediction of CYP3A induction-mediated decreases in AUC and C_max for drug candidates identified as a “victims” of CYP3A induction. Our previous study separately evaluated the fold-induction of hepatic and intestinal CYP3A by known inducers using clinical induction data and revealed that we were able to quantitatively predict the AUC ratio (AUCR) of a few CYP3A substrates in the presence and absence of CYP3A inducers. In the present study, we investigate the predictability of AUCR and also C_max ratio (C_maxR) in additional 54 clinical studies. The fraction metabolized by CYP3A (f_m), the intestinal bioavailability (F_g), and the hepatic intrinsic clearance (CL_int) of substrates were determined by the in vitro experiments as well as clinical data used for calculating AUCR and C_maxR. The result showed that 65–69% and 65–67% of predictions were within 2-fold of observed AUCR and C_maxR, respectively. A simulation using multiple parameter combinations suggested that the variability of f_m and F_g within a certain range might have a minimal impact on the calculation output. These findings suggest that clinical AUCR and C_maxR of CYP3A substrates can be quantitatively predicted from the preclinical stage.