The COMT Val158Met Polymorphism Affects the Response to Entacapone in Parkinson's Disease: A Randomized Crossover Clinical Trial

Objective: In Parkinson disease (PD), the selective C-O-methyltransferase (COMT) inhibitor entacapone prolongs the effect of levodopa on motor symptoms (ON time) by increasing its bioavailability. The COMT Val158Met polymorphism is equally distributed in PD patients and modulates COMT activity, which can be high (Val/Val, COMTHH), intermediate (Val/Met, COMTHL), or low (Met/Met, COMTLL). The objective of this study was to determine the response to entacapone in COMTHH and COMTLL PD patients. Methods: Thirty-three PD patients, homozygous for the COMT alleles COMTHH (n = 17) and COMTLL (n = 16), were randomized in a double-blind crossover trial consisting of 2 successive acute levodopa challenges associated with 200mg entacapone or placebo. The primary endpoint was the gain in the best ON time. Secondary endpoints were levodopa pharmacokinetics and COMT activity in red blood cells. Results: The gain in the best ON time was higher in COMTHH than in COMTLL patients (39 +/- 10 vs 9 +/- 9 minutes, p = 0.04, interaction between treatment and genotype). Area under the concentration over time curve of levodopa increased more after entacapone in COMTHH than in COMTLL patients (+62 +/- 6% vs +34 +/- 8%, p = 0.01). COMT inhibition by entacapone was higher in COMTHH than in COMTLL patients (-0.54 +/- 0.07 vs -0.31 +/- 0.06 pmol/min/mg protein, p = 0.02). Interpretation: The COMTHH genotype in PD patients enhances the effect of entacapone on the pharmacodynamics and pharmacokinetics of levodopa. The response to entacapone after repeated administrations and in heterozygous patients remains to be determined. ANN NEUROL 2011;69:111-118