The effects of different repeated doses of entacapone on the pharmacokinetics of L-Dopa and on the clinical response to L-Dopa in Parkinson's disease

We performed a double-blind, placebo-controlled, randomized, crossover, mul tiple-dose study on entacapone in 25 patients with Parkinson's disease with levodopa (L-Dopa) treatment-related fluctuations. A run-in period was foll owed by four 2-week treatment periods during which the patients took 4 to 6 daily doses of L-Dopa concomitantly with 100, 200, or 400 mg of entacapone or with placebo. The effects were assessed at the end of each period: the inhibition of soluble catechol-O-methyltransferase (S-COMT) activity in red blood cells and the plasma concentrations of entacapone, L-Dopa, and 3-O-m ethyldopa (3-OMD) were measured and clinical effects assessed on an 18-hour home diary. Twenty-one patients completed the study. Entacapone decreased the COMT activity from predose level: 100 mg by 25%, 200 mg by 33%, and 400 mg by 32% (p < 0.001 vs. placebo for each dose). Correspondingly, the 3-OM D concentrations decreased by 39%, 54%, and 66% with 100-, 200-, and 400-mg doses, respectively. The elimination half-life of L-Dopa was prolonged by 23% (p < 0.05), 26% (p < 0.001), and 48% (p < 0.001), and the area under th e curve of L-Dopa increased by 17% (p < 0.05), 27% (p < 0.001), and 37% (p < 0.001) with the increasing doses. Despite a significant decrease in the d aily dose of L-Dopa, entacapone decreased the proportion of daily "off" tim e: 100 mg by 11%, 200 mg by 18%, and 400 mg by 20% compared with placebo. H owever, this decrease was not statistically significant for any of the dose s in this small patient population. The dyskinetic "on" time did not increa se with different doses of entacapone. All doses were well tolerated, and n o severe adverse events were reported. The study showed that repeated dosin g of entacapone inhibits the COMT activity in a dose-dependent manner and t hereby reduces the loss of L-Dopa to 3-OMD. Therefore, the area under the c urve of L-Dopa is increased and the patient's clinical condition improved.