A Combined Model for Predicting CYP3A4 Clinical Net Drug-Drug Interaction Based on CYP3A4 Inhibition, Inactivation, and Induction Determined in Vitro

• DOI: 10.1124/dmd.107.018663
• Publication Date: 2008-05-20T00:34:26Z
• Authors: Odette A. Fahmi; Tristan S. Maurer; Mary Kish; Edwin Cardenas; Sherri Boldt; David Nettleton
• Keywords: Drug-drug interaction

Although approaches to the prediction of drug-drug interactions (DDIs) arising via time-dependent inactivation have recently been developed, such do not account for simple competitive inhibition or induction. Accordingly, these provide accurate predictions DDIs from (e.g., ketoconazole) induction cytochromes P450 phenytoin). In addition, methods that focus upon a single interaction mechanism are likely yield misleading in face mixed mechanisms ritonavir). As such, we developed more comprehensive mathematical model accounts simultaneous influences inhibition, inactivation, and CYP3A both liver intestine net terms area under concentration-time curve ratio. This provides framework by which readily obtained vitro values precipitant compound as well literature f_m F_G object drug can be used quantitative DDIs. Using this model, erythromycin) continue predicted, whereas those ketoconazole), phenytoin), ritonavir) also predicted within ranges reported clinic. quantitatively predicts clinical observations with reasonable accuracy valuable tool evaluate candidate drugs rationalize