Pharmacokinetics of Opicapone and Effect on Comt and Levodopa Pharmacokinetics in Patients with Parkinson's Disease
Loewen G, LeWitt P, Olanow CW, Kieburtz KD, Liang GS, Jimenez R, Olson K, and Roberts E. Pharmacokinetics of Opicapone and Effect on Comt and Levodopa Pharmacokinetics in Patients with Parkinson's Disease. J Mov Disord 2019; 34:S7.
J Mov Disord
Objective: To evaluate the pharmacokinetics and pharmacodynamics of opicapone in Parkinson's disease (PD). Background: Opicapone is a novel, peripherally-acting, highly-selective catechol-O-methyltransferase (COMT) inhibitor being developed in the U.S. for PD as an adjunct to levodopa-related motor fluctuations. Methods: Patients with stable PD were administered once-daily opicapone (50mg) 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 (25/100mg) 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 Day1 (prior to opicapone dosing), Day2 and Day15. The effect of opicapone on levodopa pharmacokinetics and S-COMT activity was assessed. Mean values (±standard errors) are presented. Results: The study enrolled 16 participants (men=10, women=6). Day 14 opicapone Cmax and AUC0-last were 459±63 ng/mL and 2022±196 ng∗hr/mL, respectively. At steady-state (Day14), COMT activity was inhibited on average by 76.3±1.4%, compared to baseline. After opicapone administration, total levodopa AUC (ng∗hr/mL) increased from Day1 (Q3H, 7339±949; Q4H, 7570±946) to Day15 (Q3H, 11714±1674; Q4H, 13159±1509). Peak-to-trough fluctuation in levodopa concentrations for the third daily levodopa dose were reduced from 88.3±15.2% and 173±18.3% for the Q3H and Q4H regimens on Day1 to 58.1±8.7% and 94.3±9.2%, respectively, on Day15. Trough levodopa concentrations for the third daily levodopa dose increased from 547±51 and 227±28 ng/mL for the Q3H and Q4H regimens on Day1 to 1142±201 and 749±125 ng/mL, respectively, on Day15. Conclusions: Once-daily opicapone 50mg 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.