RESUMEN
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 24â¯h after the first and at 24â¯h after the last of 14 daily oral administrations of vehicle, 1, 10 and 100â¯mg/kg opicapone using a crossover design. In the second experiment, the effect of the maximally effective dose, 100â¯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 100â¯mg/kg. Maximal inhibition was 13.1%, 76.4% and 93.2% at 1, 10 and 100â¯mg/kg respectively, and COMT remained significantly inhibited at 24â¯h after 10 and 100â¯mg/kg (42.6% and 60.2% respectively). Following repeated administration of opicapone residual COMT inhibition at 24â¯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.