Drug Metabolism and Antidepressant (METADEP)

Cocktail Phenotypic Approach to Explore Antidepressant Pharmacokinetic Variability: a Pilot Study

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.

Study Overview

• Status: Unknown
• Conditions: Depression
• Intervention / Treatment: Drug: Omeprazole (10 mg, A02BC01)

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

• Study Type: Interventional
• Enrollment (Anticipated): 100
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Switzerland
  • Genève, Switzerland, 1205
    • Recruiting
    • Hôpitaux Universitaires de Genève
    • Contact: celia Lloret-Linares, MD, PhD; Phone Number: 0041 79 55 36 389; Email: celia.LloretLinares@hcuge.ch

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
OTHER: Overall population	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; Other Names: Flurbiprofen (10 mg, M01AE09); Dextromethorphan (10 mg, R05DA09); Midazolam (1 mg, N05CD08); Fexofenadine (25mg, R06AX26 ); Bupropion (20 mg, N06AX12); Caffeine (50 mg, N06BC01)

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

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

Collaborators and Investigators

• Sponsor: University Hospital, Geneva
• Investigators: Principal Investigator: Celia Lloret-Linares, MD, PhD, Hôpitaux Universitaires de Genève

Publications and helpful links

General Publications

• 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.
• 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.
• Lloret-Linares C, Bosilkovska M, Daali Y, Gex-Fabry M, Heron K, Bancila V, Michalopoulos G, Perroud N, Richard-Lepouriel H, Aubry JM, Desmeules J, Besson M. Phenotypic Assessment of Drug Metabolic Pathways and P-Glycoprotein in Patients Treated With Antidepressants in an Ambulatory Setting. J Clin Psychiatry. 2018 Mar/Apr;79(2):16m11387. doi: 10.4088/JCP.16m11387.

Study record dates

Study Major Dates

• Study Start: December 1, 2014
• Primary Completion (ANTICIPATED): December 1, 2015
• Study Completion (ANTICIPATED): December 1, 2015

Study Registration Dates

• First Submitted: April 30, 2015
• First Submitted That Met QC Criteria: May 5, 2015
• First Posted (ESTIMATE): May 8, 2015

Study Record Updates

• Last Update Posted (ESTIMATE): May 8, 2015
• Last Update Submitted That Met QC Criteria: May 5, 2015
• Last Verified: May 1, 2015

More Information

Terms related to this study

• Keywords: drug metabolism; P-glycoprotein; CYP450; antidepressive agent; Phenotypic study
• Additional Relevant MeSH Terms: Behavioral Symptoms; Depression; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Excitatory Amino Acid Antagonists; Excitatory Amino Acid Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Cyclooxygenase Inhibitors; Purinergic Antagonists; Purinergic Agents; Gastrointestinal Agents; Tranquilizing Agents; Psychotropic Drugs; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Antidepressive Agents; Dopamine Agents; Hypnotics and Sedatives; Adjuvants, Anesthesia; Anti-Anxiety Agents; GABA Modulators; GABA Agents; Cytochrome P-450 Enzyme Inhibitors; Antidepressive Agents, Second-Generation; Cytochrome P-450 CYP2D6 Inhibitors; Respiratory System Agents; Anti-Ulcer Agents; Proton Pump Inhibitors; Dopamine Uptake Inhibitors; Anti-Allergic Agents; Phosphodiesterase Inhibitors; Purinergic P1 Receptor Antagonists; Histamine H1 Antagonists; Histamine Antagonists; Histamine Agents; Central Nervous System Stimulants; Antitussive Agents; Histamine H1 Antagonists, Non-Sedating; Midazolam; Bupropion; Dextromethorphan; Caffeine; Omeprazole; Flurbiprofen; Fexofenadine
• Other Study ID Numbers: CER-14051