Poster Abstract #7: Pharmacokinetic-Pharmacodynamic Interaction Between Nebicapone (BIA 3-202) and Controlled-release Levodopa/Benserazide (Madopar HBS 125)

Abstract

Background and Objective Nebicapone (formerly known as BIA 3-202) is a new catechol-O-methyltransferase (COMT) inhibitor in development as a levodopa-sparing agent to be used in levodopa-treated Parkinson disease patients. The objective of this study was to investigate the effect of single oral doses of nebicapone (50 mg, 100 mg and 200 mg) on the levodopa and 3-O-methyldopa (3-OMD) systemic exposure and erythrocyte soluble COMT (S-COMT) activity when coadministered with a single-dose of controlled-release levodopa/benserazide 100/25 mg (Madopar HBS 125). Methods Double-blind, randomized, placebo-controlled, four-way crossover study in 16 healthy subjects, with a washout of 5 or more days between periods. Results Taking placebo as reference, levodopa AUC0-t geometric mean ratios (GMR) and 90% confidence intervals (90%CI) were 1.14 (0.83;1.65), 1.37 (0.91;1.80), and 1.42 (0.97;1.92) for nebicapone 50 mg, 100 mg and 200 mg, respectively. Regarding 3-OMD, AUC0-t GMR and 90%CI were 0.67 (0.53;0.80), 0.63 (0.51;0.77), and 0.55 (0.49;0.75), respectively. Maximum S-COMT inhibition occurred at 1.5 h after the dose and ranged from 57% with nebicapone 50 mg to 74% with nebicapone 200 mg. There was an inverse correlation between plasma concentrations of nebicapone and S-COMT activity, and nebicapone tmax correlated well with tEmax of S-COMT inhibition. Treatments were well tolerated. Conclusions Single doses of 50 mg, 100 mg, and 200 mg of the novel COMT inhibitor nebicapone dose-dependently and significantly inhibited S-COMT activity, increased the bioavailability of levodopa, and reduced the formation of 3-OMD, when administered concomitantly with controlled-release levodopa/benserazide 100/25 mg (Madopar HBS 125). Supported by BIAL-Portela & Ca SA.