IC50-based approaches as an alternative method for assessment of time-dependent inhibition of CYP3A4

The predictive utility of two in vitro methods (empirical IC50-based and mechanistic kinact/KI) for the assessment of time-dependent cytochrome P450 3A4 (CYP3A4) inhibition has been compared.IC50 values were determined at multiple pre-incubation time points over 30 min for five CYP3A4 time-dependent inhibitors (verapamil, diltiazem, erythromycin, clarithromycin, and azithromycin). The ability of IC50 data obtained following pre-incubation to predict kinact/KI parameters was investigated and its utility was assessed relative to the conventional kinact/KI model using 50 reported clinical drug–drug interactions (DDIs). Models with either hepatic or hepatic with intestinal components were explored.For low/medium potency time-dependent inhibitors, 81% of the predicted kinact/KI(unbound) from IC50 data were within an order of magnitude of the actual values, in contrast to 50% of potent inhibitors. An underprediction trend and > 50% of false-negatives were observed when IC50 data were used in the DDI hepatic pre...