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Exploring venlafaxine pharmacokinetic variability with a phenotyping approach, a multicentric french-swiss study (MARVEL study)

Célia Lloret-Linares 1, 2 Youssef Daali 3 Sylvie Chevret 4 Isabelle Nieto 5 Fanny Molière 6 Philippe Courtet 6 Florence Galtier 6 Raphaëlle-Marie Richieri 7 Sophie Morange 8 Pierre-Michel Llorca 8, 9 Wissam El-Hage 10, 11, 12 Thomas Desmidt 12, 10 Frédéric Haesebaert 13, 14 Philippe Vignaud 13 Jerôme Holtzmann 15 Jean-Luc Cracowski 16 Marion Leboyer 17, 18 Antoine Yrondi 19, 20 Fabienne Calvas 21 Liova Yon 22 Philippe Le Corvoisier 22 Olivier Doumy 23 Kyle Heron 24 Damien Montange 25 Siamak Davani 25 Julien Déglon 26, 3 Marie Besson 3 Jules Desmeules 3 Emmanuel Haffen 27 Frank Bellivier 28, 1
Abstract : Background: It is well known that the standard doses of a given drug may not have equivalent effects in all patients. To date, the management of depression remains mainly empirical and often poorly evaluated. The development of a personalized medicine in psychiatry may reduce treatment failure, intolerance or resistance, and hence the burden and costs of mood depressive disorders. The Geneva Cocktail Phenotypic approach presents several advantages including the "in vivo" measure of different cytochromes and transporter P-gp activities, their simultaneous determination in a single test, avoiding the influence of variability over time on phenotyping results, the administration of low dose substrates, a limited sampling strategy with an analytical method developed on DBS analysis. The goal of this project is to explore the relationship between the activity of drug-metabolizing enzymes (DME), assessed by a phenotypic approach, and the concentrations of Venlafaxine (VLX) + O-demethyl-venlafaxine (ODV), the efficacy and tolerance of VLX. Methods/design: This study is a multicentre prospective non-randomized open trial. Eligible patients present a major depressive episode, MADRS over or equal to 20, treatment with VLX regardless of the dose during at least 4 weeks. The Phenotype Visit includes VLX and ODV concentration measurement. Following the oral absorption of low doses of omeprazole, midazolam, dextromethorphan, and fexofenadine, drug metabolizing enzymes activity is assessed by specific metabolite/probe concentration ratios from a sample taken 2 h after cocktail administration for CYP2C19, CYP3A4, CYP2D6; and by the determination of the limited area under the curve from the capillary blood samples taken 2-3 and 6 h after cocktail administration for CYP2C19 and P-gp.
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Célia Lloret-Linares, Youssef Daali, Sylvie Chevret, Isabelle Nieto, Fanny Molière, et al.. Exploring venlafaxine pharmacokinetic variability with a phenotyping approach, a multicentric french-swiss study (MARVEL study). BMC Pharmacology and Toxicology, BioMed Central, 2017, 18 (1), pp.70. ⟨10.1186/s40360-017-0173-2⟩. ⟨hal-01696753⟩

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