Modulation of P-glycoprotein Expression and Function under Disease States in Rats and Humans

Murakami, Teruo; Ishiguro, Masashi; Oda, Keisuke

doi:10.15344/2456-3501/2017/130

Cited by 1 publication

(1 citation statement)

References 24 publications

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“…C max by 51% and 38%, respectively. 33 The mechanism of the greater than expected increase in tacrolimus exposure following maribavir coadministration in kidney transplant recipients is currently unknown, but may be related to study design, the high variability in tacrolimus PK variability, 34 differences in CYP3A/Ppg activity between healthy subjects and transplant recipients, 35,36 variability in CYP3A/P-gp activity over time posttransplant, 37 and involvement of other transporters that may be affected by maribavir such as BCRP. Given the significant increase in tacrolimus exposure by maribavir, close therapeutic drug monitoring of immunosuppressants on initiation and discontinuation of maribavir treatment is required in ongoing phase 3 clinical trials with maribavir for the treatment of CMV infections in transplant recipients.…”

Section: Discussionmentioning

confidence: 99%

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

Song

Ilic

Murphy

et al. 2019

The Journal of Clinical Pharma

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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-Ý 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.

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