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The COMT Val158Met polymorphism affects the response to entacapone in Parkinson's disease: A randomized crossover clinical trial
Author(s) -
Corvol JeanChristophe,
Bonnet Cécilia,
CharbonnierBeaupel Fanny,
Bonnet AnneMarie,
Fiévet MarieHélène,
Bellanger Agnès,
Roze Emmanuel,
Meliksetyan Gayané,
Ben Djebara Mouna,
Hartmann Andreas,
Lacomblez Lucette,
Vrignaud Cédric,
Zahr Noël,
Agid Yves,
Costentin Jean,
Hulot JeanSébastien,
Vidailhet Marie
Publication year - 2011
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.22155
Subject(s) - entacapone , catechol o methyl transferase , parkinson's disease , crossover study , crossover , randomized controlled trial , medicine , disease , levodopa , psychology , oncology , genotype , genetics , biology , pathology , alternative medicine , gene , placebo , artificial intelligence , computer science
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, COMT HH ), intermediate (Val/Met, COMT HL ), or low (Met/Met, COMT LL ). The objective of this study was to determine the response to entacapone in COMT HH and COMT LL PD patients. Methods Thirty‐three PD patients, homozygous for the COMT alleles COMT HH (n = 17) and COMT LL (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 COMT HH than in COMT LL 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 COMT HH than in COMT LL patients (+62 ± 6% vs +34 ± 8%, p = 0.01). COMT inhibition by entacapone was higher in COMT HH than in COMT LL patients (−0.54 ± 0.07 vs −0.31 ± 0.06 pmol/min/mg protein, p = 0.02). Interpretation The COMT HH 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.