Quantitative prediction of drug-drug interactions arising from CYP3A4 induction using chimeric mice with humanized liver.

Abstract

We aimed to establish an approach to quantitatively predict drug-drug interactions arising from cytochrome P450 (CYP) 3A4 induction using chimeric mice with humanised liver.After repeated administration of rifampicin or efavirenz as CYP inducers to chimeric mice, the relative expression of human CYP3A4 in their livers was measured and plotted against the area under the concentration-time curve (AUC) of rifampicin and efavirenz, respectively, in plasma on the final day of administration. Induction curves were obtained by fitting the plots.Assuming a similar relationship of relative CYP3A4 expression to AUC in chimeric mice as in humans, the relative CYP3A4 expression by clinical doses of rifampicin and efavirenz were calculated from the estimated clinical exposure.The calculated relative CYP3A4 expression was reflected in the intrinsic clearance of midazolam or alfentanil coadministered with a CYP inducer. The intrinsic clearance was incorporated into a constructed physiologically based pharmacokinetic model, which successfully predicted the pk change of midazolam or alfentanil coadministered with a CYP inducer or not. The results confirmed that our approach is useful to improve the prediction accuracy of CYP3A4 induction in the preclinical phase.