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

Abstract

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 Cmax , AUClast , and AUC0-∞ 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 AUClast and AUClast 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.

Keywords: P-glycoprotein; cytochrome P450 2D6; dextromethorphan; digoxin; maribavir; pharmacokinetics.

Conflict of interest statement

Ivy H. Song, Katarina Ilic, Joseph Murphy, and Patrick Martin are employees of Shire, a Takeda company, and Takeda stock owners. Kenneth Lasseter is an employee of Clinical Pharmacology of Miami Inc., which was funded by Shire Development LLC, Lexington, Massahusetts, a Takeda company, to perform the study. Under the direction of the authors, Amy Horne, MSc, and Yelena Lyustikman, MSc, of Caudex Health, Oxford, UK, provided writing assistance for this publication, funded by Shire International GmbH, a Takeda company. I.H.S., K.I., J.M., and P.M. have received salary and ownership of stocks from Takeda. K.L. has received study funding from Takeda. I.H.S., K.I., J.M., P.M., and K.L. have signed authorship agreements with Shire, a Takeda company. These authorship agreements are in accordance with ICMJE and GPP3 guidelines.

© 2019 Shire Plc. The Journal of Clinical Pharmacology published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.

Figures

Figure 1

Mean plasma concentration‐time profile for digoxin by treatment period: log scale (pharmacokinetic set, n = 18). Treatment 1: digoxin 0.5 mg and dextromethorphan 30 mg administered on day 1. Treatment 2: maribavir 400 mg (2 × 200 mg) twice daily from days 8 to 15. On day 13, digoxin 0.5 mg and dextromethorphan 30 mg were administered with the morning dose of maribavir 400 mg (2 × 200 mg). Error bars represent the standard deviation.

Figure 2

Mean plasma concentration‐time profile for dextromethorphan and dextrorphan by treatment, with log scale (pharmacokinetic set, n = 18).a Treatment 1: digoxin 0.5 mg and dextromethorphan 30 mg administered on day 1. Treatment 2: maribavir 400 mg (2 × 200 mg) twice daily from days 8 to 15. On day 13, digoxin 0.5 mg and dextromethorphan 30 mg was administered with the morning dose of maribavir 400 mg (2 × 200 mg). Error bars represent the standard deviation. aSamples with concentrations of less than the LLOQ (0.2 ng/mL for dextromethorphan and 2.5 ng/mL for dextrorphan) were treated as zero when calculating mean concentration.