Objective: To examine the inhibitory effect of COMT on the plasma pharmacokinetics of levodopa resulting from repeated, once daily, oral administration of an Opicapone (OPC) tablet.

Background: OPC is a peripheral, long-acting COMT inhibitor. OPC inhibits the metabolic pathway by which peripheral COMT mediates the metabolization of levodopa into 3-OMD, which increases the plasma concentration of levodopa. The capsule form of OPC has previously been approved by the European Commission for adjuvant treatment to levodopa preparations of Parkinson’s disease and end-of-dose motor fluctuations.

Method: OPC tablets were orally administered at doses of 5, 10, 25, or 50 mg once daily at bedtime under a fasted condition for 11 days to 80 healthy Japanese adult males (20 in each group). In addition, levodopa/carbidopa (100/10 mg) were orally administered three times a day under a fasted condition before the first dose of OPC on day 1 and day 12 (the following day after the last dose of OPC tablets) in an open-label, 3-period crossover design.

Results: The geometric mean ratios of the AUC24h of levodopa in the plasma (90% CIs) between post- and pre-administration in the groups that received 5, 10, 25, and 50 mg of OPC were 1.16 (1.10 to 1.21), 1.26 (1.23 to 1.30), 1.51 (1.44 to 1.57), and 1.60 (1.54 to 1.66), respectively. Thus, the use of OPC concomitantly with levodopa/carbidopa leads to an increase in plasma exposure to levodopa. Adverse events including nausea, vomiting, and dizziness were reported in 2 or more subjects. Since nausea, vomiting, and dizziness are all known adverse reactions to levodopa, the increased frequencies of these adverse events could be attributable to an increased levodopa exposure following administration of OPC.

Conclusion: When OPC tablets were repeatedly administered via the oral route to healthy Japanese adult males, OPC exerted a long-lasting inhibitory effect on soluble cytoplasmatic COMT activity. In addition, as the dose of OPC increased after the administration of OPC, the plasma exposure to levodopa was higher than that before OPC administration. No major safety issues were noted, and the safety of OPC tablets in the dosage regimen was clinically acceptable.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/impact-of-repeated-oral-administration-of-opicapone-on-the-plasma-pharmacokinetics-of-levodopa/