Effects of Maribavir on P‐Glycoprotein and CYP2D6 in Healthy Volunteers

Maribavir is an investigational drug being evaluated in transplant recipients with cytomegalovirus infection. To understand potential drug‐drug interactions, we examined the effects of multiple doses of maribavir on cytochrome P450 (CYP) 2D6 and P‐glycoprotein (P‐gp) activity using probe substrates in healthy volunteers. During this phase 1 open‐label study (NCT02775240), participants received the probe substrates digoxin (0.5 mg) and dextromethorphan (30 mg) before and after maribavir (400 mg twice daily for 8 days). Serial plasma samples were analyzed for digoxin, dextromethorpha, dextrorphan, and maribavir concentrations. Pharmacokinetic parameters were calculated (noncompartmental analysis) and analyzed with a linear mixed‐effects model for treatment comparison to estimate geometric mean ratios (GMRs) and 90% confidence intervals (CIs). CYP2D6 polymorphisms were genotyped using polymerase chain reaction. Overall, 17 of 18 participants (94.4%) completed the study. All participants were genotyped as CYP2D6 intermediate/extensive metabolizers. GMR (90%CI) of digoxin C(max), AUC(last), and AUC(0‐∞) with and without maribavir was 1.257 (1.139‐1.387), 1.187 (1.088‐1.296), and 1.217 (1.110‐1.335), respectively, outside the “no‐effect” window (0.8‐1.25). GMR (90%CI) of dextromethorphan AUC(last) and AUC(last) ratio of dextromethorphan/dextrorphan were 0.877 (0.692‐1.112) and 0.901 (0.717‐1.133), respectively, marginally outside the no‐effect window, although large variability was observed in these pharmacokinetic parameters. Pharmacokinetic parameters of dextrorphan were unaffected. Maribavir inhibited P‐gp activity but did not affect CYP2D6 activity. Maribavir's effect on the pharmacokinetics of P‐gp substrates should be evaluated individually, and caution should be exercised with P‐gp substrates with narrow therapeutic windows.