title: 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 drug-drug interactions (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 cytochromes P450 (e.g., phenytoin). In addition, methods that 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 to provide a net drug-drug interaction prediction in terms of area under the concentration-time curve 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, whereas 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.
authors.affiliation: Department of Pharmacokinetics, Dynamics, and Metabolism, Mail Stop MS-8118W-128, Pfizer Global Research & Development, Eastern Point Rd., Groton, CT 06340, USA. odette.a.fahmi@pfizer.com
authors.forename: Odette A
authors.initials: OA
authors.lastname: Fahmi
authors.forename: Tristan S
authors.initials: TS
authors.lastname: Maurer
authors.forename: Mary
authors.initials: M
authors.lastname: Kish
authors.forename: Edwin
authors.initials: E
authors.lastname: Cardenas
authors.forename: Sherri
authors.initials: S
authors.lastname: Boldt
authors.forename: David
authors.initials: D
authors.lastname: Nettleton
mesh_terms: D019540:Area Under Curve; D051544:Cytochrome P-450 CYP3A / Q000096:biosynthesis*; D065692:Cytochrome P-450 CYP3A Inhibitors; D004347:Drug Interactions; D004790:Enzyme Induction; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D008954:Models, Biological
chemical_list: D065692:Cytochrome P-450 CYP3A Inhibitors; D004791:Enzyme Inhibitors; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human