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

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.

Conflict of interest statement

Ethics approval and consent to participate

Ethical approval was obtained by an Independent Ethics Committee (CPP Ile de France I, Paris) and by the Agence Française de Sécurité Sanitaire des Produits de Santé (ANSM, French Health Products Safety Agency). The study was registered at the All subjects give their written informed consent for the study and for the use of its individual publication for analysis and publication.

Consent for publication

All subjects give their written informed consent for the study and for the use of its individual publication for analysis and publication.

Competing interests

The authors declare that they have no competing interests. J Déglon is founder of the DBS System Company.

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Figures

Fig. 1

Venlafaxine metabolism

Fig. 2

Summary of MARVEL design. V (Venlafaxine), ODV (O-demethyl-Venlafaxine). MADRS (Montgomery and Asberg Depression Rating Scale); HAM-D (Hamilton Rating Scale for Depression). V0 (Inclusion Visit), V1 (Phenotypic visit)