Risk Assessment Using Cytochrome P450 Time-Dependent Inhibition Assays at Single Time and Concentration in the Early Stage of Drug Discovery

In this article, we proposed a risk assessment strategy for CYP3A time-dependent inhibition (TDI) during drug discovery based on a thorough retrospective study of 13 reference drugs, some of which are known to have in vitro TDI potential but have unknown clinical relevance. First, the traditional parameter kinact/KI, recommended by regulatory authorities for necessity decision making in clinical drug-drug interaction (DDI) studies, was investigated as a predictive index for clinical TDI liability. The cutoff value of 1.1 for kinact/KI, established by the Food and Drug Administration, tended to produce false-positive prediction results for clinical DDI occurrence. The value of 1.25 recommended in the European Medicines Evaluation Agency draft guideline yielded better predictions with only 1 false negative for diltiazem. Second, to enable earlier risk assessment, remaining activity, defined as the residual CYP3A activity in vitro obtained in the screening conditions, was investigated as an alternative index. As a result, the ratios of unbound Cmax or area under the curve to remaining activity precisely predicted clinical DDI occurrence. In conclusion, we demonstrated the predictive power of kinact/KI and remaining activity values for clinical DDIs. These findings provide insights that enable TDI risk assessment, even during drug discovery.