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BMC Pharmacol Toxicol. 2017 Nov 7;18(1):70. doi: 10.1186/s40360-017-0173-2.

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

Author information

1
Inserm, U1144, F-75006, Paris, France. celialloret@yahoo.fr.
2
Université Paris Diderot, UMR-S 1144, F-75013, Paris, France. celialloret@yahoo.fr.
3
Department of Internal Medicine, Assistance Publique-Hôpitaux de Paris, Hôpital Lariboisière, Therapeutic Research Unit, F-75010, Paris, France. celialloret@yahoo.fr.
4
Division of Clinical Pharmacology and Toxicology, Geneva University Hospitals, Geneva, Switzerland.
5
Service de Biostatistiques et Information Médicale, Hôpital Saint-Louis, AP-HP, ECSTRA Team, Inserm UMR-1153, Université Paris Diderot, 1 rue Claude Vellefaux, 75010, Paris, France.
6
Department of Psychiatry and Addiction Medicine, Assistance Publique-Hôpitaux de Paris, Hôpital F. Widal, F-75010, Paris, France.
7
CHRU Montpellier, Mont-Saint-Éloi, France.
8
Pôle psychiatrie, addictologie, pédopsychiatrie, Assistance Publique des hôpitaux de Marseille, Marseille, France.
9
APHM, Aix Marseille Univ, Institut Paoli-Calmettes, INSERM, CIC Hôpital Conception, Marseille, France.
10
Service Psychiatrie et Addictologie de l'Adulte CMP B, Centre Hospitalier Universitaire, Rue Montalembert, Clermont-Ferrand, France.
11
Inserm U930, Université François Rabelais de Tours, Tours, France.
12
Inserm CIC 1415, Tours, France.
13
Clinique Psychiatrique Universitaire, CHRU de Tours, Tours, France.
14
PsyR2 Team, U 1028, INSERM and UMR 5292, CNRS, Center for Neuroscience Research of Lyon (CRNL), CH Le Vinatier, Lyon-1 University, Bron, France.
15
Centre Interdisciplinaire de Recherche en Réadaptation et en Intégration Sociale (CIRRIS), Centre de Recherche de l'Institut Universitaire en Santé Mentale (CRIUSM), Université Laval, QC, Québec, Canada.
16
Service Hospitalo-Universitaire de Psychiatrie. CHU Grenoble-Alpes, La Tronche, France.
17
Unité de Pharmacologie Clinique, Centre d'Investigation Clinique de Grenoble, INSERM CIC1406, CHU de Grenoble, Grenoble, France.
18
AP-HP, pole de psychiatrie des HU Henri Mondor, Equipe psychiatrie translationnelle, Créteil, France.
19
Inserm U955 and foundation FondaMental, Créteil, France.
20
Service de psychiatrie et psychologie médicale CHU Toulouse-Purpan, Toulouse, France.
21
Toulouse NeuroImaging Center, ToNIC, University of Toulouse, Inserm, UPS, Toulouse, France.
22
Inserm CIC 1436, CHU Toulouse, Université Toulouse III Paul Sabatier, Toulouse, France.
23
Inserm, Clinical Investigation Center 1430 and Henri Mondor University Hospital, AP-HP, Créteil, France.
24
Centre Expert Dépression Résistante, Centre Référence Pathologies Anxieuses et Dépression (CERPAD), Centre Hospitalier Charles Perrens, Bordeaux, France.
25
Department of Experimental Psychology, University of Bristol, UK and Somerset Partnership NHS Foundation Trust, Bristol, UK.
26
Department of Pharmacology, CHRU Besançon, Univ. Bourgogne-Franche-Comté, EA3920, Besançon, France.
27
Unit of Toxicology, CURML, University Hospitals of Lausanne, Lausanne, Switzerland.
28
Unit of Toxicology, CURML, University Hospitals of Geneva, Geneva, Switzerland.
29
Department of Clinical Psychiatry, University Hospital of Besançon, Besançon, France.
30
Inserm, U1144, F-75006, Paris, France.
31
Université Paris Diderot, UMR-S 1144, F-75013, Paris, France.

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. Two follow-up visits will take place between 25 and 40 days and 50-70 days after inclusion. They include assessment of efficacy, tolerance and observance. Eleven french centres are involved in recruitment, expected to be completed within approximately 2 years with 205 patients. Metabolic ratios are determined in Geneva, Switzerland.

DISCUSSION:

By showing an association between drug metabolism and VLX concentrations, efficacy and tolerance, there is a hope that testing drug metabolism pathways with a phenotypical approach would help physicians in selecting and dosing antidepressants. The MARVEL study will provide an important contribution to increasing the knowledge of VLX variability and in optimizing the use of methods of personalized therapy in psychiatric settings.

TRIAL REGISTRATION:

ClinicalTrials.gov NCT02590185 (10/27/2015). This study is currently recruiting participants.

PMID:
29115994
PMCID:
PMC5678760
DOI:
10.1186/s40360-017-0173-2
[Indexed for MEDLINE]
Free PMC Article

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