EFFECT OF TOLCAPONE ON PLASMA LEVODOPA CONCENTRATIONS AFTER COADMINISTRATION WITH LEVODOPA CARBIDOPA TO HEALTHY-VOLUNTEERS/

Tolcapone (Ro 40-7592) is a novel inhibitor of catechol-O-methyltransf erase that is being developed for clinical use in the treatment of Par kinson's disease as add-on therapy to a combination of levodopa and a peripheral amino acid decarboxylase inhibitor (benserazide or carbidop a). The current single-blind, randomized study was designed to evaluat e the effect of tolcapone compared with placebo on plasma levodopa con centrations in healthy volunteers concomitantly receiving 25 mg of car bidopa and 100 mg of levodopa (Sinemet 25-100) and to assess the toler ability and safety of this combination. Placebo or tolcapone at doses of 5, 10, 25, 50, 100, 200, 400, and 800 mg was coadministered orally with Sinemet 25-100. Each dose was tested in a crossover fashion in a new group of six participants who each received active drug on one occ asion and placebo on the other. Tolcapone increased the area under the plasma concentration-time curve and half-life of levodopa approximate ly twofold, without appreciably increasing the peak concentration. The maximum effect on levodopa half-life was observed with the 200-mg dos e. Adverse effects were minor at all doses.