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


Helena Heikkinen, Research Centre, Orion Corporation ORION PHARMA, Orionintie 1, PO Box 65, FIN-02101 Espoo, Finland. Tel.: + 358-10-4292862; Fax: + 358-10-4292111;

E-mail: helena.heikkinen@orionpharma.com


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 Cmax 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-dihydroxy-phenylacetic 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.