Short Communication Risk Assessment of Mechanism-Based Inactivation in Drug-Drug Interactions

Drug-drug interactions (DDIs) that occur via mechanism-based inactivation of cytochrome P450 are of serious concern. Although several predictive models have been published, early risk assess-ment of MBIs is still challenging. For reversible inhibitors, the DDI risk categorization using [I]/Ki ([I], the inhibitor concentration; Ki, the inhibition constant) is widely used in drug discovery and de-velopment. Although a simple and reliable methodology such as [I]/Ki categorization for reversible inhibitors would be useful for mechanism-based inhibitors (MBIs), comprehensive analysis of an analogous measure reflecting in vitro potency for inactivation has not been reported. The aim of this study was to evaluate whether the term /kdeg (, first-order inactivation rate at a given MBI concentration; kdeg, enzyme degradation rate constant) would be useful in the prediction of the in vivo DDI risk of MBIs. Twenty-one MBIs with both in vivo area under the curve (AUC) change of marker substrates and in vitro inactivation parameters were identified in the literature and analyzed. The results of this analysis show that in vivo DDIs with>2-fold change of object drug AUC can be identified with the cutoff value of /kdeg 1, where unbound steady-state Cmax is used for inhibitor concentration. However, the use of totalCmax led to great overprediction of DDI risk. The risk assessment using /kdeg coupled with unbound Cmax can be useful for the DDI risk evaluation of MBIs in drug discovery and development