Prediction of time-dependent CYP3A4 drug-drug interactions: Impact of enzyme degradation, parallel elimination pathways, and intestinal inhibition

Time-dependent inhibition of CYP3A4 often results in clinically significant drug-drug interactions. In the current study, 37 in vivo cases of irreversible inhibition were collated, focusing on macrolides ( erythromycin, clarithromycin, and azithromycin) and diltiazem as inhibitors. The interactions included 17 different CYP3A substrates showing up to a 7-fold increase in AUC ( 13.5% of studies were in the range of potent inhibition). A systematic analysis of the impact of CYP3A4 degradation half-life ( mean t(1/2deg) = 3 days, ranging from 1 to 6 days) on the prediction of the extent of interaction for compounds with a differential contribution from CYP3A4 to the overall elimination ( defined by fm(CYP3A4)) was performed. Although the prediction accuracy was very sensitive to the CYP3A4 degradation rate for substrates mainly eliminated by this enzyme ( fm(CYP3A4) >= 0.9), minimal effects are observed when CYP3A4 contributes less than 50% to the overall elimination in cases when the parallel elimination pathway is not subject to inhibition. Use of the mean CYP3A4 t(1/2deg) ( 3 days), average unbound systemic plasma concentration of the inhibitor, and the corresponding fm(CYP3A4) resulted in 89% of studies predicted within 2-fold of the in vivo value. The impact of the interaction in the gut wall was assessed by assuming maximal intestinal inhibition of CYP3A4. Although a reduced number of false-negative predictions was observed, there was an increased number of over-predictions, and generally, a loss of prediction accuracy was observed. The impact of the possible interplay between CYP3A4 and efflux transporters on the intestinal interaction requires further evaluation.