The Utility of in Vitro Cytochrome P450 Inhibition Data in the Prediction of Drug-Drug Interactions

Abstract

The accuracy of in vitro inhibition parameters in scaling to in vivo drug-drug interactions (DDI) was examined for over 40 drugs using seven human P450-selective marker activities in pooled human liver microsomes. These data were combined with other parameters (systemic C max , estimated hepatic inlet C max , fraction unbound, and fraction of the probe drug cleared by the inhibited enzyme) to predict increases in exposure to probe drugs, and the predictions were compared with in vivo DDI gathered from clinical studies reported in the scientific literature. For drugs that had been tested as precipitants of drug interactions for more than one P450 in vivo, the order of inhibitory potencies in vitro generally aligned with the magnitude of the in vivo interactions. With the exception of many drugs known to be mechanism-based inactivators, the use of in vitro IC 50 , the fraction of the affected drug metabolized by the target enzyme [f m(CYP) ] and an estimate of free hepatic inlet C max , was generally successful in identifying those drugs that cause at least a 2-fold increase in the exposure to P450 marker substrate drugs. For CYP3A, incorporation of inhibition of both hepatic and intestinal metabolism was needed for the prediction of DDI. Many CYP3A inhibitors showed a different inhibitory potency for three different CYP3A marker activities; however, these differences generally did not alter the conclusions regarding whether a drug would cause a CYP3A DDI in vivo. Overall, these findings support the conclusion that P450 in vitro inhibition data are valuable in designing clinical DDI study strategies and can be used to predict the magnitudes of DDI.Drug-drug interactions remain an important issue in clinical practice and the discovery and development of new drugs. With our recently advanced knowledge of the human cytochrome P450 (P450) enzymes and their roles in drug metabolism, more systematic approaches to the study of drug interactions have evolved. Previous to this knowledge, studies of drug-drug interactions for new drugs were carried out empirically; combinations of drugs chosen for investigation of drug-drug interactions were selected based on the potential for alteration in the pharmacokinetics or dynamics of a narrow therapeutic index drug (e.g., digoxin, theophylline, warfarin, phenytoin, etc.) or whether there was a high likelihood that the new drug would be frequently coprescribed with another agent for a given condition. However, with an increased understanding of drug-metabolizing enzymes and their roles in the metabolism of specific drugs, a more mechanistic approach to assessing drug-drug interactions can be taken. The results of clinical drug-drug interaction studies with one drug can be extrapolated to other drugs that are cleared by the same enzyme.In vitro drug-drug interaction data are necessary for devising mechanistically based clinical drug-drug interaction study strategies. The effects of new drugs on well characterized drug metabolism reactions known to be specific for various huma...

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