Physiologically-based pharmacokinetic modeling for maribavir to inform dosing in drug-drug interaction scenarios with cyp3a4 Inducers and Inhibitors.

Maribavir, an orally available antiviral, was approved in multiple countries for the treatment of patients with refractory post-transplant cytomegalovirus (CMV) infection and/or disease. Maribavir is primarily metabolized by CYP3A4; coadministration with CYP3A4 inducers and inhibitors may significantly alter maribavir exposure, thereby affecting its efficacy and safety. The effect of CYP3A4 inducers and inhibitors on maribavir exposure was evaluated based on a drug-drug interaction (DDI) study and physiologically-based pharmacokinetic (PBPK) modeling. The effect of rifampin (a strong CYP3A4 and moderate CYP1A2 inducer), administered at a 600 mg dose once daily, on maribavir pharmacokinetics was assessed in a clinical Phase 1 DDI study in healthy participants. A full PBPK model for maribavir was developed and verified using in vitro and clinical pharmacokinetic data from Phase 1 studies. The verified PBPK model was then used to simulate maribavir DDI interactions with various CYP3A4 inducers and inhibitors. The DDI study results showed that coadministration with rifampin decreased maribavir maximum plasma concentration (C max ), area under the plasma concentration-time curve (AUC), and trough concentration (C trough ) by 39%, 60%, and 82%, respectively. Based on the results from the clinical DDI study, coadministration of maribavir with rifampin is not recommended. The PBPK model did not predict a clinically significant effect of CYP3A4 inhibitors on maribavir exposure; however, it predicted that strong or moderate CYP3A4 inducers, including phenytoin, phenobarbital, carbamazepine, and efavirenz, may reduce maribavir exposure to a clinically significant extent, and may prompt consideration of maribavir dosing increase according to the local approved labels and/or regulations. This article is protected by copyright. All rights reserved.