Entacapone improves the availability of l‐dopa in plasma by decreasing its peripheral metabolism independent of l‐dopa/carbidopa dose
Authors: Heikkinen Helena , Varhe Anu , Laine Tarmo , Puttonen Jaakko , Kela Marjo , Kaakkola Seppo , Reinikainen Kari 
Published: March 2003

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.