In Vitro Profiling for Potential Cytochrome P450 and P-Glycoprotein–Mediated Drug–Drug Interaction By Maribavir (Shp620)

Abstract

Introduction Maribavir is a potent and orally bioavailable antiviral with a novel mechanism of action against cytomegalovirus (CMV). The efficacy and safety of maribavir for treatment of CMV infections are being evaluated in ongoing Phase 3 trials. Characterization of drug–drug interaction (DDI) properties of maribavir is necessary in informing potential DDIs with co-medications. Objective To evaluate the potential cytochrome p450 and p-glycoprotein–mediated drug–drug interaction by maribavir. Methods Cytochrome P450 (CYP) reversible inhibition: Probe substrates of CYPs were incubated with human liver microsomes (HLM) and maribavir. Percent remaining CYP activity was plotted against maribavir concentrations for IC50 determination. Time-dependent inhibition (TDI) for CYPs: After pre-incubation with maribavir for varying durations, percent remaining CYP activity in HLM was measured. The concentration at half-maximal inactivation (KI) and maximum inactivation rate constant (kinact) were calculated. CYP induction: After treating human hepatocytes with maribavir for three days, CYP mRNA expression was plotted against maribavir concentrations to determine half-maximal induction concentration (EC50) and maximal fold induction (Emax). P-glycroprotein (P-gp) inhibition: Bi-directional transport of digoxin in Caco-2 cells with maribavir was measured and IC50 calculated by plotting percent transporter activity against maribavir concentration. Results Maribavir is not a reversible inhibitor of CYP2A6, CYP2B6, CYP2C8, CYP2D6, CYP2E1, or CYP3A4 and is a weak inhibitor of CYP1A2, CYP2C9, and CYP2C19 (IC50 40, 18, and 35 µM). Maribavir is not a TDI of CYP1A2, CYP2C8, CYP2C9, CYP2C19, or CYP2D6 but a weak TDI for CYP3A (KI 41.2 μM, kinact 0.0117 min−1). Maribavir is not an inducer of CYP1A2 or CYP2B6 mRNA but is a weak, possibly donor-dependent inducer of CYP3A4 mRNA. Maribavir is a weak inhibitor of P-gp (IC50 33.7 µM). Conclusions Maribavir is not expected to affect exposures of substrates of major CYPs or P-gp when co-administered at therapeutic dose of 400 mg BID, based on its estimated maximal unbound plasma concentration (Cmax,u) of 0.74 μM in transplant patients with CMV infection.