Received for publication September 4, 2007.
Revised May 15, 2008.
Accepted for publication May 16, 2008.

A COMBINED MODEL FOR PREDICTING CYP3A4 CLINICAL NET DRUG-DRUG INTERACTION BASED ON CYP3A4 INHIBITION, INACTIVATION, AND INDUCTION DETERMINED IN VITRO

Abstract

Although approaches to the prediction of DDIs arising via time-dependent inactivation have recently been developed, such approaches do not account for simple competitive inhibition or induction. Accordingly, these approaches do not provide accurate predictions of DDIs arising from simple competitive inhibition (e.g. ketoconazole) or induction of P450s (e.g. phenytoin). In addition, methods which focus upon a single interaction mechanism are likely to yield misleading predictions in the face of mixed mechanisms (e.g. ritonavir). As such, we have developed a more comprehensive mathematical model that accounts for the simultaneous influences of competitive inhibition, time-dependent inactivation and induction of CYP3A in both the liver and intestine in order to provide a net drug-drug interaction prediction in terms of AUC ratio. This model provides a framework by which readily obtained in vitro values for competitive inhibition, time-dependent inactivation and induction for the precipitant compound as well as literature values for f_m and F_G for the object drug can be used to provide quantitative predictions of DDIs. Using this model, DDIs arising via inactivation (e.g. erythromycin) continue to be well predicted, while those arising via competitive inhibition (e.g. ketoconazole); induction (e.g. phenytoin) and mixed mechanisms (e.g. ritonavir) are also predicted within the ranges reported in the clinic. This comprehensive model quantitatively predicts clinical observations with reasonable accuracy and can be a valuable tool to evaluate candidate drugs and rationalize clinical DDIs.

Key words: CYP induction, CYP inhibition, CYP3A, hepatocytes, human CYP enzymes, in vitro-in vivo prediction, inactivation, induction, liver microsomes, mechanism-based inhibition

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