THE EFFECT OF COMT INHIBITION BY TOLCAPONE ON TOLERABILITY AND PHARMACOKINETICS OF DIFFERENT LEVODOPA BENSERAZIDE FORMULATIONS/

This double-blind, placebo-controlled, randomized, crossover study was designed to evaluate the effects of catechol-O-methyltransferase (COM T) inhibition by tolcapone on the pharmacokinetics of levodopa given a s four different formulations of levodopa/benserazide: 50/12.5 mg, 100 /25 mg, 200/50 mg (all standard release), or 100/25 mg (controlled rel ease). Sixteen healthy volunteers, in two groups of 8, were given two different levodopa/benserazide formulations with and without tolcapone in random order on 4 days, each separated by a 7-day washout period. On each treatment day, 200 mg tolcapone or placebo (blinded) was taken orally 1 h before and 3 and 7 h after a single (unblinded) dose of le vodopa/benserazide. All treatment combinations were well tolerated. Co ntinuous inhibition of erythrocyte COMT activity by approximately 75% was observed over 13 h with tolcapone; this was unaffected by levodopa /benserazide formulation. Tolcapone had similar effects on plasma levo dopa concentrations with the standard-release formulations: half-life and bioavailability increased approximately 2-fold compared with place bo, and maximum plasma concentration (C-max) and time to C-max (t(max) ) were unaffected, except for a slight increase in C-max with the levo dopa/benserazide 200/50 mg formulation. With the controlled-release fo rmulation, tolcapone increased the levodopa area under the plasma conc entration/time curve approximately 2-fold. Although levodopa t(max) ap peared delayed, the absorption phase was unaffected. Onset of levodopa effect is therefore not likely to be delayed when tolcapone is coadmi nistered with this formulation. Regardless of levodopa/benserazide for mulation, 3-O-methyldopa formation was reduced by 90% with tolcapone c ompared with placebo. These results show that tolcapone could potentia te the antiparkinsonian effects of levodopa independently of levodopa/ benserazide formulation.