Objective: To evaluate the effect of once-daily administration of opicapone 50 mg on the pharmacokinetics (PK) of repaglinide.

Background: Opicapone, a highly selective catechol-O-methyltransferase (COMT) inhibitor, is approved in Europe and under development in the U.S. as an adjunct to levodopa in adults with PD and motor fluctuations. In vitro studies suggested a potential for opicapone and its primary circulating inactive metabolite, BIA 9-1103, to inhibit cytochrome P450 (CYP) 2C8 metabolism and organic anion transporter (OAT) P1B1 transport.  Repaglinide is a substrate of both CYP2C8 and OATP1B1 [1].

Method: Healthy men (N=9) and women (N=9) were enrolled in an open-label, single-sequence crossover study. Subjects received a single dose of 0.5 mg repaglinide on Days 1 and 15 and opicapone 50 mg once-daily on Days 2 through 15. Doses were administered following an overnight fast of at least 8 hours. Blood samples for determination of opicapone plasma PK were collected at intervals up to 120 hours after the last dose of opicapone. Blood samples for determination of repaglinide plasma PK were collected at intervals up to 24 hours post-dose on Days 1 and 15. Plasma opicapone and repaglinide concentrations were determined using validated analytical methods. PK parameters were determined using noncompartmental methods. The 90% confidence intervals (CI) about the geometric mean ratios of Cmax, AUClast, and AUCinf for repaglinide administered with opicapone (Test, T) versus repaglinide administered alone (Reference, R) were determined.

Results: Of the 18 enrolled subjects, 17 were included in the PK analysis.  Opicapone and repaglinide were well-tolerated. Mean plasma repaglinide concentration-time profiles were similar when administered alone or during a once-daily opicapone regimen. T/R ratios of repaglinide Cmax, AUClast, and AUCinf were 93% (90%CI: 82-105%), 97% (90%CI: 90-105%), and 100% (90%CI: 93-108%), respectively.

Conclusion: Once-daily administration with opicapone 50 mg did not affect the PK of repaglinide, a CYP2C8 and OATP1B1 substrate. Opicapone would also not be expected to affect the PK of other CYP2C8 or OATP1B1 substrates.

References: 1. Prandin US Prescribing Information, Feb 2017.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/effect-of-once-daily-opicapone-on-the-pharmacokinetics-of-repaglinide/