Inhibition of catechol-O-methyltransferase in the cynomolgus monkey by opicapone after acute and repeated administration. (December 2018)

• Record Type: Journal Article
• Authors: Kitajima, Takashi; Mizote, Shintaro; Bonifácio, Maria João; Umemura, Takeo; Yoneda, Kazuhiro; Moser, Paul; Soares-da-Silva, Patrício; Tanaka, Makoto
• Is Part Of: Neuropharmacology. Volume 143(2018)
• Page Start: 282
• Page End: 288
• Publication Date: 2018-12
• Subjects: Neuropsychopharmacology -- Periodicals; Autonomic Agents -- Periodicals; Neuropsychopharmacologie -- Périodiques; Neuropsychopharmacology; Periodicals; Electronic journals; 615.78
• DOI: 10.1016/j.neuropharm.2018.10.001
• Languages: English
• ISSNs: 0028-3908

Abstract

Abstract: Introduction: The aim of the study was to clarify the dose response for inhibition of catechol- O -methyltransferase (COMT) by opicapone, a third generation COMT inhibitor, after acute and repeated administration to the cynomolgus monkey with pharmacokinetic evaluation at the higher dose. Methods: Three cynomolgus monkeys were used in the study. In the first experiment, COMT inhibition was evaluated over 24 h after the first and at 24 h after the last of 14 daily oral administrations of vehicle, 1, 10 and 100 mg/kg opicapone using a crossover design. In the second experiment, the effect of the maximally effective dose, 100 mg/kg, was retested under the same conditions with additional monitoring of plasma opicapone levels to explore the relationship between pharmacokinetics and pharmacodynamics. Results: Opicapone dose-dependently inhibited COMT activity, significantly so at 10 and 100 mg/kg. Maximal inhibition was 13.1%, 76.4% and 93.2% at 1, 10 and 100 mg/kg respectively, and COMT remained significantly inhibited at 24 h after 10 and 100 mg/kg (42.6% and 60.2% respectively). Following repeated administration of opicapone residual COMT inhibition at 24 h was 15–25% greater at all doses. In contrast to its pharmacodynamic effect, opicapone was rapidly absorbed and eliminated, with no accumulation in plasma following repeated administration. Conclusion: Opicapone showed sustained and dose-dependent COMT inhibition despite being rapidly eliminated from plasma and with no evidence for accumulation in plasma after 14 days administration. Opicapone fills the unmet need for a compound with sustained COMT inhibition which will improve levodopa bioavailability in patients with Parkinson's disease. Highlights: Confirmed strong and sustained COMT inhibition by opicapone in a dose dependent manner. Opicapone was rapidly absorbed and eliminated after oral administration in monkeys. No accumulation of plasma opicapone occurred after multiple dosing. Opicapone may fit the unmet need for a sustained COMT inhibitor.