Entacapone improves the availability of L-dopa in plasma by decreasing its peripheral metabolism independent of L-dopa/carbidopa dose

Aims Entacapone is a peripherally acting catechol-O-methyltransferase (COMT) inhibitor. To improve the benefits of oral L-dopa in the treatment of Parkinson's disease (PD), entacapone is administered as a 200 mg dose with each daily dose of L-dopa. This study evaluated the effects of entacapone 200 mg on the pharmacokinetics and metabolism of L-dopa given as standard release L-dopa/carbidopa. Methods Six different doses of L-dopa/carbidopa were investigated in this placebo-controlled, double-blind (regarding entacapone), randomized, single-dose study in 46 young healthy males. The subjects were divided into three groups (n = 14-16). Two different L-dopa/carbidopa doses were administered to each subject (50/12.5 mg and 150/37.5 mg, or 100/10 mg and 100/25 mg, or 200/50 mg and 250/25 mg). Each dose was given on two occasions; simultaneously with entacapone or with placebo, in random order, on two consecutive study visits, separated by a washout period of at least 3 weeks (four-way crossover design). Serial blood samples were drawn before dosing and up to 24 h after the dose and pharmacokinetic parameters of L-dopa, its metabolites, carbidopa, and entacapone were determined. Results Entacapone increased the AUC(0,12 h) of L-dopa to a similar extent at all doses of L-dopa/carbidopa, that is by about 30-40% compared with placebo (P < 0.001, 95% CI 0.15, 0.40). When evaluated as the ratio of geometric means, entacapone slightly decreased the mean C-max values for L-dopa at all L-dopa/ carbidopa doses compared with placebo. When given with entacapone, higher plasma concentrations of L-dopa were maintained for a longer period at all doses of L-dopa/ carbidopa. Entacapone also decreased the peripheral formation of 3-O-methyldopa(3-OMD) to about 55-60% of the placebo treatment level (P < 0.001, 95% CI - 0.72, - 0.35) and increased the mean AUC( 0,12 h) of 3,4-dihydroxyphenylacetic acid (DOPAC) 2-2.6-fold compared with placebo (P < 0.001, 95% CI 0.60, 1.10). The mean AUC( 0,12 h) of 3-methoxy-4-hydroxy- phenylacetic acid (HVA) following entacapone was approximately 65-75% of that observed with placebo (P < 0.001-0.05, 95% CI -0.76, - 0.01) at each L-dopa/ carbidopa dose except the 50/12.5 mg dose (P > 0.05, 95% CI -0.59, 0.05). The metabolic ratios (MR, AUC metabolite/AUC L-dopa) also confirmed that entacapone significantly decreased the proportion of 3-OMD (P < 0.001, 95% CI - 0.85, - 0.68) and HVA (P < 0.001, 95% CI - 1.01, - 0.18) in plasma at each L-dopa/ carbidopa dose, whereas the AUC DOPAC/AUC L-dopa ratio was increased again at all doses (P < 0.001, 95% CI 0.26, 0.90). Entacapone did not significantly affect the pharmacokinetics of carbidopa at any of the doses, nor did L-dopa/ carbidopa affect the pharmacokinetics of entacapone. Conclusions The 200 mg dose of entacapone similarly and significantly increases the AUC of L-dopa by changing the metabolic balance of L-dopa independent of the L-dopa/carbidopa dose and therefore entacapone is likely to have a similar L-dopa potentiating effect independent of L-dopa dose.