Drug Metabolism and Antidepressant

Overview

We propose here to explore systematically the association between drug-metabolizing enzymes activity assessed by a phenotypical approach and antidepressant plasma concentration, efficacy and tolerance in the clinical setting. During one year, patients receiving antidepressant will be included in tis prospective clinical, naturalistic and descriptive pilot study.

Full Title of Study: “Cocktail Phenotypic Approach to Explore Antidepressant Pharmacokinetic Variability: a Pilot Study”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: N/A
    • Intervention Model: Single Group Assignment
    • Masking: None (Open Label)
  • Study Primary Completion Date: December 2015

Detailed Description

– Objectives To describe drug metabolism variability in depressive patients using a phenotypic approach – Study design Prospective, clinical, naturalistic, descriptive study During a consultation with their clinician, depressive patients will receive information. During the visit V0 with an investigator: patients will be included: – Verification of inclusion and non inclusion criteria – Reminder participation conditions – Inclusion, signature of consent – Collection of clinical and demographic features Between V0 and V1, for patients with change in antidepressant therapy, will take place telephone interviews every two weeks, conducted by the clinician to evaluate treatment depression response (tolerance and efficacy) During the visit V1, will take place: – Phenotypic study – Genetic study – Dosage of current antidepressant drug – Clinical evaluation: efficacy and tolerance – Number of patients During one year, the protocol will be proposed to all patients with depression and decision of change in antidepressant therapy, and all patients with stability od prescription since almost 6 weeks. The inclusion of approximately 100 patients is expected. – Name of the finished product Zyban®, Froben®, Antra®, Bexine®, Dormicum® Telfast® – Name of the active substance Omeprazole (10 mg, A02BC01) Caffeine (50 mg, N06BC01) Flurbiprofen (10 mg, M01AE09) Dextromethorphan (10 mg, R05DA09) Midazolam (1 mg, N05CD08) Fexofenadine (25mg, R06AX26 ) Bupropion (20 mg, N06AX12) – Duration of treatment One time during the study, one day (Visit 1) – Time plan of research -Duration for the patient: The study will stop when the patient has performed the V1 study Minimal delay between V0 and V1: 6 weeks (5-7 weeks) : for patient with decision to change the treatment, 5 days for patients with stability of treatment since almost 6 weeks. Maximal delay of participation for the patient: 4 months even when V1 was not performed -Overall duration of inclusion: one year Maximal overall duration of the study: 12 months+4 months= 16 months Maximal duration for the analytical study since the beginning of the study= 16 months+6 months: 22 months. Maximal delay for communication of the results: 2 years after the beginning of the study

Interventions

  • Drug: Omeprazole (10 mg, A02BC01)
    • The cocktail of drug substrates will be given one time, one day during the study, to explore the activity of CYP 1A2, 2B6, 2C9, 2C19, 3A4, 2D6, and the P-gp

Arms, Groups and Cohorts

  • Other: Overall population

Clinical Trial Outcome Measures

Primary Measures

  • CYP1A2 activity
    • Time Frame: >two hours after an oral intake of the cocktail probe drugs
    • paraxanthine/caffeine
  • CYP2B6 activity
    • Time Frame: >two hours after an oral intake of the cocktail probe drugs
    • 4-hydroxybupropion/ bupropion
  • CYP2D6 activity
    • Time Frame: >two hours after an oral intake of the cocktail probe drugs
    • dextrorphan / dextromethorphan
  • CYP2C9 activity
    • Time Frame: >two hours after an oral intake of the cocktail probe drugs
    • 4-hydroxyflurbiprofen/ flurbiprofen
  • CYP2C19 activity
    • Time Frame: >two, three and six hours after an oral intake of the cocktail probe drugs
    • 5-hydroxyomeprazole/ omeprazole
  • CYP3A4 activity
    • Time Frame: >two hours after an oral intake of the cocktail probe drugs
    • 1-hydroxymidazolam/ midazolam
  • P-gp activity
    • Time Frame: >two, three and six hours after an oral intake of the cocktail probe drugs
    • Limited sampling fexofenadine AUC

Secondary Measures

  • Antidepressant Concentration
    • Time Frame: almost 6 weeks after the last treatment change
  • Antidepressant tolerance
    • Time Frame: almost 6 weeks after the last treatment change
    • FISBER test
  • Antidepressant efficacy
    • Time Frame: almost 6 weeks after the last treatment change
    • Tests: MADRS, Hamilton, QIDS-16

Participating in This Clinical Trial

Inclusion Criteria

1. Patients with clinical diagnosis of depression and decision to change antidepressant therapy (augmentation or switch) OR Patients with clinical diagnosis of depression and stability of prescription since almost 6 weeks 2. Male and female aged from 18 to 70 years 3. Volunteers to participate to the study 4. Understanding of French language and able to give a written inform consent. Exclusion Criteria:

Renal or hepatic impairment (Clearance below 60mL/min, AST or ALT over 3N) Sensitivity to any of the substrate drugs used ECG showing long QT interval (>0.46sec) No antidepressant dosage available Current pregnancy or desire to get pregnant Criteria to perform V1 Sufficient compliance between V0 and V1 Six weeks period without change in antidepressant therapy

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: 70 Years

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • University Hospital, Geneva
  • Provider of Information About this Clinical Study
    • Principal Investigator: Celia Lloret-Linares, Doctor – University Hospital, Geneva
  • Overall Official(s)
    • Celia Lloret-Linares, MD, PhD, Principal Investigator, Hôpitaux universitaires de Genève
  • Overall Contact(s)
    • Celia Lloret-Linares, MD, PhD, 0041 79 55 36 389, Celia.LloretLinares@hcuge.ch

References

Bosilkovska M, Samer CF, Deglon J, Rebsamen M, Staub C, Dayer P, Walder B, Desmeules JA, Daali Y. Geneva cocktail for cytochrome p450 and P-glycoprotein activity assessment using dried blood spots. Clin Pharmacol Ther. 2014 Sep;96(3):349-59. doi: 10.1038/clpt.2014.83. Epub 2014 Apr 10.

Citations Reporting on Results

Hall-Flavin DK, Winner JG, Allen JD, Carhart JM, Proctor B, Snyder KA, Drews MS, Eisterhold LL, Geske J, Mrazek DA. Utility of integrated pharmacogenomic testing to support the treatment of major depressive disorder in a psychiatric outpatient setting. Pharmacogenet Genomics. 2013 Oct;23(10):535-48. doi: 10.1097/FPC.0b013e3283649b9a.

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