Pharmacokinetics of oral entacapone after frequent multiple dosing and effects on levodopa disposition

Objective: Entacapone is a peripherally acting catechol O-methyltransferase (COMT) inhibitor used as an adjunct to each daily levodopa/dopa decarboxyl ase (DDC) inhibitor dose in the treatment of Parkinson's disease. Parkinson ian patients with advanced disease and motor fluctuations take several dose s of levodopa daily, due to the short action of levodopa in this patient po pulation. The present study was conducted in order to evaluate the pharmaco kinetics of entacapone after multiple dosing and the pattern of COMT inhibi tion in erythrocytes during the first day of dosing as well as during stead y state. Furthermore, the disposition of plasma levodopa and carbidopa was studied after a single dose of levodopa/carbidopa during the same condition s. Methods: Twelve healthy male volunteers received 200 mg entacapone eight ti mes daily during study day 1 and day 6 at 2-h intervals from 0800 hours to 2200 hours. During days 3, 4 and 5, 200 mg of entacapone was taken ten time s daily, from 0800 hours to 0200 hours on the following day. One levodopa/c arbidopa tablet (100/25 mg) was taken on study day 1 and day 6 at 1000 hour s. Plasma entacapone concentrations and erythrocyte COMT activities were me asured frequently on study days 1-2 and 6-7, and twice daily on study days 3-5. Pharmacokinetic parameters calculated from plasma drug concentrations on days 1-2 and 6-7 were compared with each other. Results: There were no differences in maximal plasma concentration (C-max), time to maximal drug concentration in plasma (t(max)), elimination half-li fe (t(1/2)) and area under the plasma concentration-time curve (AUC) of ent acapone between day 1 and day 6. The mean t(1/2) values of entacapone were 1.3 h and 1.8 h during the first and sixth days, respectively; the differen ce was not significant. No signs of accumulation of entacapone were noted a fter the first day. Entacapone reduced erythrocyte COMT activity after the first dose, and this effect was quite stable during frequent dosing. There were no indications of accumulation of COMT inhibition during frequent dosi ng of entacapone. There were no between-day differences in C-max, t(1/2) (2 .4 h on days 1-2 and 2.3 h on days 6-7) or AUC of levodopa, whereas t(max) occurred at 0.8 h on day 1 and at 1.2 h on day 6 (P = 0.03). There were no between-day differences in the pharmacokinetic parameters (C-max, t(max) an d AUG) of carbidopa. Conclusion: Even when dosed frequently, there are neither indications of ac cumulation of entacapone nor of its COMT inhibiting activity.