Clinical, pharmacokinetic, and pharmacodynamic effects of tolcapone withdrawal in levodopa-treated patients with parkinsonism

The effect and clinical significance of tolcapone withdrawal on erythrocyte catechol-O-methyltransferase (COMT) activity, Levodopa pharmacokinetics, and levodopa requirements were investigated in 59 patients with fluctuating parkinsonism who were randomized to receive placebo or tolcapone 100 or 200 mg three times daily for 6 weeks. Tolcapone withdrawal caused a transient elevation in COMT activity by Glib in patients receiving 100 mg three limes daily and by 128% in those receiving 200 mg three times daily at approximately 1-2 weeks after discontinuation of drug. Thereafter, COMT activity was declining but did not reach baseline values by the 12-week study endpoint. However, this had no effect on plasma levodopa and 3-O-methyldopa (3-OMD) concentrations or on levodopa requirements. During treatment, tolcapone: increased "on" time and decreased "off" time: after discontinuation of study medication and levodopa dose adjustment, on and off times were similar to baseline. Withdrawal was generally well tolerated; no patients withdrew from the trial during the posttreatment period, and no serious adverse events were observed. In conclusion, the transient increase in erythrocyte COMT activity observed after discontinuation of tolcapone is not associated with changes in peripheral levodopa metabolism and therefore has no significant clinical consequences in terms of levodopa requirements, clinical symptoms, or adverse events.