INTEGRATED PHARMACOKINETICS AND PHARMACODYNAMICS OF THE NOVEL CATECHOL-O-METHYLTRANSFERASE INHIBITOR TOLCAPONE DURING FIRST ADMINISTRATION TO HUMANS

Objectives: To assess the tolerability, pharmacokinetics and pharmacod ynamics of single oral doses of the novel catechol-O-methyltransferase (COMT) inhibitor tolcapone in healthy volunteers. Methods: In this do uble-blind, placebo-controlled, ascending-single-dose study, doses of 5 to 800 mg tolcapone were administered orally to eight sequential gro ups of six young healthy male volunteers. Adverse events, vital signs, and clinical laboratory variables were recorded. Pharmacokinetic para meters of tolcapone and its 3-O-methylmetabolite were determined. Phar macodynamics were assessed by determination of COMT activity in erythr ocytes. Results: Tolcapone was well tolerated at all dose levels and d id not exert a detectable influence on vital sign measurements. The dr ug was rapidly absorbed and showed dose-proportional pharmacokinetics. Its mean elimination half-life was 2.0 +/- 0.8 hours (n = 42). Plasma levels of the 3-O-methylmetabolite of tolcapone were not Proportional to dose, and its formation was delayed at higher doses. Its eliminati on half-life was 32 +/- 7 hours (n = 29). Tolcapone caused a rapid and reversible inhibition of COMT activity in erythrocytes. At doses of 2 00 mg and higher, COMT activity was inhibited by more than 80%. The ph armacokinetic-pharmacodynamic relationship could be described by an in hibitory E(max) model and suggested that metabolites of tolcapone did not substantially contribute to its inhibitory activity. Conclusions: The novel COMT inhibitor tolcapone was well tolerated at oral doses of 5 to 800 mg. Tolcapone concentration-dependently inhibited COMT activ ity in erythrocytes and exhibited dose-proportional kinetics. Further investigations into its applicability in the treatment of Parkinson's disease are warranted.