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The COMT Val158Met polymorphism affects the response to entacapone in Parkinson's disease: A randomized crossover clinical trial

Authors

  • Jean-Christophe Corvol MD, PhD,

    Corresponding author
    1. INSERM (French National Institute of Medical Research and Health), Clinical Investigation Center (CIC-9503), Pitié-Salpêtrière Hospital, Paris, France
    2. APHP (Assistance Publique Hôpitaux de Paris, Public Hospital of Paris), Department of Neurology, Pitié-Salpêtrière hospital, Paris, France
    3. Department of Pharmacology, Pitié-Salpêtrière hospital, Paris, France
    4. Department of Pharmacy, Assistance Publique Hôpitaux de Paris
    • Centre d'Investigation Clinique, Hôpital pitié-Salpêtrière, 47/83 Bd de l'Hôpital, 75013 Paris, France
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  • Cécilia Bonnet MD,

    1. INSERM (French National Institute of Medical Research and Health), Clinical Investigation Center (CIC-9503), Pitié-Salpêtrière Hospital, Paris, France
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  • Fanny Charbonnier-Beaupel PharmD,

    1. INSERM (French National Institute of Medical Research and Health), Clinical Investigation Center (CIC-9503), Pitié-Salpêtrière Hospital, Paris, France
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  • Anne-Marie Bonnet MD,

    1. APHP (Assistance Publique Hôpitaux de Paris, Public Hospital of Paris), Department of Neurology, Pitié-Salpêtrière hospital, Paris, France
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  • Marie-Hélène Fiévet PharmD,

    1. Department of Pharmacy, Assistance Publique Hôpitaux de Paris
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  • Agnès Bellanger PharmD,

    1. Department of Pharmacy, Assistance Publique Hôpitaux de Paris
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  • Emmanuel Roze MD, PhD,

    1. INSERM (French National Institute of Medical Research and Health), Clinical Investigation Center (CIC-9503), Pitié-Salpêtrière Hospital, Paris, France
    2. APHP (Assistance Publique Hôpitaux de Paris, Public Hospital of Paris), Department of Neurology, Pitié-Salpêtrière hospital, Paris, France
    3. INSERM (French National Institute of Medical Research and Health), UMRS_975 unit, CRICM (Research Center of the Brain and Spine Insitute), Paris, France
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  • Gayané Meliksetyan MD,

    1. INSERM (French National Institute of Medical Research and Health), Clinical Investigation Center (CIC-9503), Pitié-Salpêtrière Hospital, Paris, France
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  • Mouna Ben Djebara MD,

    1. INSERM (French National Institute of Medical Research and Health), Clinical Investigation Center (CIC-9503), Pitié-Salpêtrière Hospital, Paris, France
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  • Andreas Hartmann MD,

    1. INSERM (French National Institute of Medical Research and Health), Clinical Investigation Center (CIC-9503), Pitié-Salpêtrière Hospital, Paris, France
    2. APHP (Assistance Publique Hôpitaux de Paris, Public Hospital of Paris), Department of Neurology, Pitié-Salpêtrière hospital, Paris, France
    3. INSERM (French National Institute of Medical Research and Health), UMRS_975 unit, CRICM (Research Center of the Brain and Spine Insitute), Paris, France
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  • Lucette Lacomblez MD,

    1. Department of Pharmacology, Pitié-Salpêtrière hospital, Paris, France
    2. UPMC (Pierre and Marie Curie university), Paris, France
    3. INSERM (French National Institute of Medical Research and Health), UMRS_678 unit, Paris, France
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  • Cédric Vrignaud BSc,

    1. Department of Pharmacology, Pitié-Salpêtrière hospital, Paris, France
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  • Noël Zahr PhD,

    1. Department of Pharmacology, Pitié-Salpêtrière hospital, Paris, France
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  • Yves Agid MD, PhD,

    1. INSERM (French National Institute of Medical Research and Health), Clinical Investigation Center (CIC-9503), Pitié-Salpêtrière Hospital, Paris, France
    2. APHP (Assistance Publique Hôpitaux de Paris, Public Hospital of Paris), Department of Neurology, Pitié-Salpêtrière hospital, Paris, France
    3. UPMC (Pierre and Marie Curie university), Paris, France
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  • Jean Costentin MD,

    1. Neuropharmacology Laboratory, University of Rouen, Rouen, France
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  • Jean-Sébastien Hulot MD, PhD,

    1. Department of Pharmacology, Pitié-Salpêtrière hospital, Paris, France
    2. UPMC (Pierre and Marie Curie university), Paris, France
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  • Marie Vidailhet MD

    1. INSERM (French National Institute of Medical Research and Health), Clinical Investigation Center (CIC-9503), Pitié-Salpêtrière Hospital, Paris, France
    2. APHP (Assistance Publique Hôpitaux de Paris, Public Hospital of Paris), Department of Neurology, Pitié-Salpêtrière hospital, Paris, France
    3. UPMC (Pierre and Marie Curie university), Paris, France
    4. INSERM (French National Institute of Medical Research and Health), UMRS_975 unit, CRICM (Research Center of the Brain and Spine Insitute), Paris, France
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Abstract

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.

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