Objective: To evaluate the pharmacokinetics and pharmacodynamics of opicapone in Parkinson’s disease (PD).

Background: Opicapone, a highly selective COMT inhibitor, is approved in Europe and under development in the U.S. as an adjunct to levodopa in adults with PD and motor fluctuation.

Method: Patients with stable PD were administered once-daily opicapone (50 mg) in the evening on Days 1-14. Serial blood samples for determination of plasma opicapone concentrations and erythrocyte soluble COMT (S-COMT) activity were collected after the first and last opicapone dose. Participants were randomized to receive carbidopa/levodopa (25/100 mg) every 3 or 4 hours (Q3H or Q4H) on pharmacokinetic sampling days, and their usual carbidopa/levodopa regimen on other days. Serial plasma samples for determination of levodopa and 3-O-methyldopa concentrations were collected after the first three levodopa doses on Day 1 (prior to opicapone dosing), Day 2 and Day 15. The effect of opicapone on levodopa pharmacokinetics and S-COMT activity was assessed. Mean values (±standard deviations) are presented.

Results: The study enrolled 16 participants (men=10, women=6). Day 14 opicapone Cmax and AUC0-last were 459±252 ng/mL and 2022±783 ng/mL*hr, respectively. At steady-state (Day 14), COMT activity was inhibited on average by 76.3±5.4%, compared to baseline. After opicapone administration, total levodopa AUC (ng/mL*hr) increased from Day 1 (Q3H, 7339±2512; Q4H, 7570±2675) to Day 15 (Q3H, 11714±4429; Q4H, 13159±4528). Peak-to-trough fluctuation in levodopa concentrations for the third daily levodopa dose were reduced from 88.3±40.3% and 173±51.9% for the Q3H and Q4H regimens on Day 1 to 58.1±23.0% and 94.3±25.9%, respectively, on Day 15. Trough levodopa concentrations for the third daily levodopa dose increased from 547±134 and 227±80 ng/mL for the Q3H and Q4H regimens on Day 1 to 1142±532 and 749±354 ng/mL, respectively, on Day 15.

Conclusion: Once-daily opicapone 50 mg resulted in substantial and prolonged COMT inhibition, which increased systemic exposure to levodopa and led to both decreased peak-to-trough fluctuations in levodopa concentrations and to higher trough levodopa concentrations.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/pharmacokinetics-of-opicapone-and-effect-on-comt-and-levodopa-pharmacokinetics-in-patients-with-parkinsons-disease/