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Intérêt clinique de la pharmacogénétique : anticiper les toxicités et mieux prédire l’efficacité des médicaments

Clinical utility of pharmacogenetics for predicting drug efficacy and toxicity

  • Enseignement Supérieur en Réanimation
  • Médecin
  • Published:
Réanimation

Résumé

La réponse aux médicaments est souvent variable d’un individu à l’autre, ce qui rend parfois leur maniement délicat. La prédiction de la réponse devient un problème crucial en cas de fenêtre thérapeutique étroite de ces médicaments ou de l’existence d’alternatives thérapeutiques. Des facteurs génétiques affectant le métabolisme et le transport des médicaments expliquent en partie la variabilité interindividuelle dans la réponse. La pharmacogénétique étudie les mécanismes d’origine génétique intervenant dans la réponse aux médicaments dans le but d’optimiser les traitements médicamenteux, tant en termes d’efficacité que de sécurité d’emploi. L’existence de polymorphismes génétiques affectant les gènes codant pour les enzymes du métabolisme des médicaments aboutit à distinguer, dans la population générale, différentes classes d’individus en fonction de leur capacité métabolique vis-à-vis d’une enzyme donnée, à savoir des métaboliseurs lents, rapides et même parfois ultrarapides. Des méthodes de phénotypage et de génotypage permettent de déterminer ou de prédire le statut métabolique d’un individu et de savoir ainsi s’il présente un risque particulier d’inefficacité ou de toxicité vis-à-vis de certains médicaments. Plusieurs exemples d’applications cliniques (thiopurines, antivitamine K, codéine et tramadol) permettent d’illustrer l’intérêt de la pharmacogénétique pour la prise en charge des malades. La validation clinique d’un grand nombre d’analyses pharmacogénétiques et la mise au point de nouvelles technologies très performantes et peu coûteuses de génotypage vont contribuer au développement rapide de cette discipline dans la pratique médicale courante, avec la perspective d’une individualisation des traitements médicamenteux associée à l’amélioration du taux de réponse et la diminution des accidents iatrogènes.

Abstract

The narrow therapeutic index of most pharmaceutical agents and the severe consequences of undertreatment or overdosing have led to search for molecular predictive factors of toxicity and efficacy. Genetic factors involved in drug metabolism and transport partly explain inter-individual variability in drug response. Pharmacogenetics focuses on the molecular mechanisms involved in drug response. Its ultimate goal is to optimize the treatments, combining the better efficacy with the minimal risk of severe side-effects. Polymorphisms in genes encoding specific drugmetabolising enzymes may be encountered in some individuals and allow characterizing different groups in the general population as low, rapid and even ultra-rapid metabolisers. Phenotyping and genotyping tests are now available to determine or predict the metabolic status of an individual and, thus, enabling to evaluate the risk of drug failure or toxicity. Several clinical applications of pharmacogenetics (thiopurines, antivitamine K, codeine, and tramadol) have already been developed in the routine medical practice resulting in significant improvement in patient treatment. The clinical validation of an increasing number of pharmacogenetic tests as well as the development of new highly efficient technologies for genotyping should further promote pharmacogenetics in clinical practice and lead to the development of a patient-tailored drug therapy.

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Authors and Affiliations

  1. Inserm UMR-S 775, université Paris-Descartes, centre universitaire des Saints-Pères, 45, rue des Saints-Pères, F-75015, Paris, France

    C. Narjoz, C. Moreau, P. Beaune & M. -A. Loriot

  2. UF pharmacogénétique et oncologie moléculaire, service de biochimie, pôle biologie et produits de la santé, Hôpital Européen Georges-Pompidou, 20, rue Leblanc, F-75015, Paris, France

    C. Narjoz, C. Moreau, P. Beaune & M. -A. Loriot

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  1. C. Narjoz
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  2. C. Moreau
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  3. P. Beaune
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  4. M. -A. Loriot
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Correspondence to M. -A. Loriot.

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Cet article correspond à la conférence faite par l’auteur au congrès de la SRLF 2012 dans la session : Des traitements du futur.

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Narjoz, C., Moreau, C., Beaune, P. et al. Intérêt clinique de la pharmacogénétique : anticiper les toxicités et mieux prédire l’efficacité des médicaments. Réanimation 21 (Suppl 2), 354–362 (2012). https://doi.org/10.1007/s13546-011-0336-x

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