Pharmacokinetics, pharmacodynamics, and tolerability of tolcapone: a review of early studies in volunteers.

Tolcapone is a potent, reversible inhibitor of catechol O-methyltransferase (COMT) intended for use as an adjunct to levodopa therapy for Parkinson's disease (PD). Findings from the first pharmacokinetics/pharmacodynamics and tolerability studies of tolcapone in volunteers are reviewed. Following linear and dose-proportional pharmacokinetics, tolcapone is rapidly absorbed and eliminated after single- or multiple-dose (i.e., tid) administration. Onset of COMT inhibition is rapid, substantial, and reversible, and is not affected by the co-administration of levodopa/decarboxylase inhibitor (levodopa/DCI). When given together with levodopa/DCI, tolcapone increases the relative bioavailability and plasma elimination half-life of levodopa, without affecting its peak plasma concentration. This leads to more stable plasma levels of levodopa, and the formation of 3-O-methyldopa is effectively reduced. Tolcapone was well tolerated alone or in combination with levodopa/DCI, and the results indicated that the effective dose in patients with PD would be in the range of 50-400 mg tid.