MetAbolism vaRiability of VEnLafaxine (MARVEL)

Xploring Venlafaxine Pharmacokinetic Variability by a Phenotyping Approach

Regarding the direct costs and the social value of depression, the decision of an antidepressant treatment prescription must be optimized as much as possible. The development of a personalized medicine in psychiatry may reduce treatment failure, intolerance or resistance, and hence burden and costs of affective disorders.

There is hope that biomarkers will be found to guide treatment selection. It might be of decisive interest to be able to assess an individual's metabolism activity. We propose here to explore the relationship between the activity of drug-metabolizing enzymes (DME) and transporters- assessed by a phenotypic approach and the efficacy of antidepressants. We will focus on venlafaxine (V) that provides a reasonable second-step choice for patients with depression and is used extensively in psychiatric practice, and the metabolism of which involves several cytochromes (CYP) P450 enzymes and the transporter P-gp.

Thus, the primary objective of this study is to study the correlation between the concentration of V and its metabolite ODesmethylV (V+ODV) and drug metabolism variability assessed by a phenotypic approach, in patients with major depressive disorder and MADRS ≥ 20 despite 4 weeks of V at 150mg or less

Study Overview

• Status: Unknown
• Conditions: Major Depressive Disorders
• Intervention / Treatment: Drug: cocktail probe drugs

• Study Type: Interventional
• Enrollment (Anticipated): 205
• Phase: Not Applicable

Contacts and Locations

Study Locations

• France
  • Paris, France, 75010
    • Recruiting
    • Lariboisiere Hospital
    • Contact: celia Lloret-Linares, MD; Email: celia.lloret-linares@aphp.fr
  • Paris, France, 75010
    • Recruiting
    • Fernand Widal Hospital
    • Contact: Frank Bellivier, MD PhD; Email: frank.bellivier@inserm.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patient (Hospitalized or outpatient) with major depressive disorder and MADRS ≥ 20 at visit of selection
• Patients non responders to V after 4 weeks of V at 150mg or less
• Decision of the psychiatrist to increase the dose of V at visit of selection
• Understanding of French language and able to give a written inform consent.
• Informed consent signed to participate to the study
• Individuals covered by social security regimen

Exclusion Criteria:

• Patients treated by more than one antidepressant
• Patients currently treated with one of the drug substrate of the cocktail
• Sensitivity or contra-indication to any of the substrate drugs used
• Current pregnancy, desire to get pregnant, or breastfeeding
• Bipolar disorder and schizophrenia

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: cocktail probe drugs; A capsule of omeprazole ABBOTT® 10mg; 10 mg of an oral liquid formulation of Dextrométhorphane bromhydrate (Drill Pierre FABRE MEDICAMENT® 5mg/5mL, syrup); 1 mg of an injectable solution of Midazolam for oral administration (Midazolam Panpharma® 1mg/mL, injectable solution); A tablet of fexofenadine Zentiva® 120mg

Drug: cocktail probe drugs; For the assessment of drug-metabolizing enzyme activity, the patients will be given the cocktail probe drugs, by oral route, one time during the study: A capsule of omeprazole ABBOTT® 10mg; 10 mg of an oral liquid formulation of Dextrométhorphane bromhydrate (Drill Pierre FABRE MEDICAMENT® 5mg/5mL, syrup); 1 mg of an injectable solution of Midazolam for oral administration (Midazolam Panpharma® 1mg/mL, injectable solution); A tablet of fexofenadine Zentiva® 120mg

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The CYP2C19 activity	5-hydroxyomeprazole/omeprazole	2 hours
The CYP2D6 activity	dextrorphan/dextromethorphan ratio	2 hours
The CYP3A4 activity	1-hydroxymidazolam/ midazolam ratio	2 hours
The P-gp activity	Fexofenadine AUC based on fexofenadine concentrations	2, 3 and 6 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Tobacco use	Fagerstrom test	20, 40, 70 days
Mood disorder		20, 40, 70 days
Anxiety scale Tyrer		20, 40, 70 days
QIDS-SR16		20, 40, 70 days
Criteria for rating medication trials for antidepressant failure and level of resistance		20, 40, 70 days
MARS Score		20, 40, 70 days
PRISE-M score		20, 40, 70 days
FISBER score		20, 40, 70 days

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Investigators: Principal Investigator: Celia Lloret-Linares, MD, APHP

Publications and helpful links

General Publications

• Lloret-Linares C, Daali Y, Chevret S, Nieto I, Moliere F, Courtet P, Galtier F, Richieri RM, Morange S, Llorca PM, El-Hage W, Desmidt T, Haesebaert F, Vignaud P, Holtzmann J, Cracowski JL, Leboyer M, Yrondi A, Calvas F, Yon L, Le Corvoisier P, Doumy O, Heron K, Montange D, Davani S, Deglon J, Besson M, Desmeules J, Haffen E, Bellivier F. Exploring venlafaxine pharmacokinetic variability with a phenotyping approach, a multicentric french-swiss study (MARVEL study). BMC Pharmacol Toxicol. 2017 Nov 7;18(1):70. doi: 10.1186/s40360-017-0173-2.

Study record dates

Study Major Dates

• Study Start: December 1, 2015
• Primary Completion (Anticipated): December 1, 2019
• Study Completion (Anticipated): April 1, 2020

Study Registration Dates

• First Submitted: October 27, 2015
• First Submitted That Met QC Criteria: October 27, 2015
• First Posted (Estimate): October 28, 2015

Study Record Updates

• Last Update Posted (Actual): February 19, 2019
• Last Update Submitted That Met QC Criteria: February 18, 2019
• Last Verified: February 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Mood Disorders; Depressive Disorder; Depressive Disorder, Major
• Other Study ID Numbers: AOM14562