Cocktail Approach for Cytochrome P450 and P-glycoprotein Activity Assessment Using Dried Blood Spot

Phenotyping is an approach largely used for the evaluation of the activity of cytochromes and transporters in vivo. It consists of the administration of probe substances metabolised by a specific cytochrome or transported by P-glycoprotein (P-gp) for example, followed by the determination of a metabolic ratio or the evaluation of the plasmatic or urinary concentrations of the probe substances. The administration of a cocktail containing several probe substances allows the simultaneous evaluation of the activity of several cytochromes and P-gp in a single test.

The aim of this project is the validation of a phenotyping cocktail of low dose probe drugs for the assessment of cytochrome P450 and P-gp activities by simple capillary blood sampling and dried blood spot (DBS) analysis. The cocktail consists of caffeine, bupropion, flurbiprofen, omeprazole, dextromethorphan, midazolam and fexofenadine for the simultaneous phenotyping of CYP1A2, CYP2B6, CYP2C9, CAP2C19, CYP2D6, CYP3A4 and P-gp, respectively.

The modulation of the activity of cytochromes or P-gp will be evaluated by the administration of inhibitors (fluvoxamine, voriconazole, quinidine) or inducer (rifampicin) of the metabolic pathways or the P-gp mediated transport.

Study Overview

• Status: Completed
• Conditions: Healthy Volunteers
• Intervention / Treatment: Drug: Cocktail probe drugs

• Study Type: Interventional
• Enrollment (Anticipated): 10
• Phase: Phase 1

Contacts and Locations

Study Locations

• Switzerland
  • Geneva 14, Switzerland
    • University Hospitals

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

• Healthy male volunteers aged from 18 to 60 years
• BMI between 18 and 25
• Understanding of French language and able to give a written inform consent.

Exclusion Criteria:

• Smoker
• Taking drugs which alter CYPs activity
• Renal or hepatic impairment
• Medical history of porphyria
• Medical history of chronic alcoholism or abuse of psychoactive drugs
• Liver transplantation
• Sensitivity to any of the drugs used
• Wearing contact lenses (risk of coloration with rifampicin)
• ECG showing long QT interval (>0.46sec)
• Alteration of hepatic tests
• Presenting genetic polymorphism of poor CYP 2B6, 2C9, 2C19, 2D6 metabolisers

Study Plan

How is the study designed?

Design Details

• Primary Purpose: DIAGNOSTIC
• Allocation: NON_RANDOMIZED
• Interventional Model: CROSSOVER
• Masking: NONE

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: CYP1A2, 2B6, 2C9, 2C19, 3A4 inhibitors; Oral intake of fluvoxamine (50 mg per day during 2 days) and voriconazole (400 mg) before oral intake of the cocktail probe drugs	Drug: Cocktail probe drugs; Other Names: Oral intake of the cocktail probe drugs :; bupropion 25 mg; flurbiprofen 25 mg; omeprazole 5 mg; dextromethorphan 5 mg; midazolam 1 mg; fexofenadine 25mg; Caffeine (a cup of coffee)
ACTIVE_COMPARATOR: CYP2D6 and P-gp inhibitor; Oral intake of quinidine (200 mg) before oral intake of the cocktail probe drugs	Drug: Cocktail probe drugs; Other Names: Oral intake of the cocktail probe drugs :; bupropion 25 mg; flurbiprofen 25 mg; omeprazole 5 mg; dextromethorphan 5 mg; midazolam 1 mg; fexofenadine 25mg; Caffeine (a cup of coffee)
ACTIVE_COMPARATOR: CYPs and P-gp inducer; Oral intake of rifampicin (600 mg per day during 7 days) before oral intake of the cocktail probe drugs	Drug: Cocktail probe drugs; Other Names: Oral intake of the cocktail probe drugs :; bupropion 25 mg; flurbiprofen 25 mg; omeprazole 5 mg; dextromethorphan 5 mg; midazolam 1 mg; fexofenadine 25mg; Caffeine (a cup of coffee)
EXPERIMENTAL: Probe cocktail alone; Oral intake of the cocktail probe drugs : bupropion 25 mg; flurbiprofen 25 mg; omeprazole 5 mg; dextromethorphan 5 mg; midazolam 1 mg; fexofenadine 25mg; Caffeine (a cup of coffee)	Drug: Cocktail probe drugs; Other Names: Oral intake of the cocktail probe drugs :; bupropion 25 mg; flurbiprofen 25 mg; omeprazole 5 mg; dextromethorphan 5 mg; midazolam 1 mg; fexofenadine 25mg; Caffeine (a cup of coffee)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Probe cocktail drugs plasma and capillary concentrations in presence/absence of CYP1A2,2B6, 2C9, 2C19, 2D6, 3A4 and P-gp inhibitor or inducer	4 singles days spaced out with one week wash-out periods

Secondary Outcome Measures

Outcome Measure	Time Frame
correlation between plasma or urine and capillary concentrations for each probe cocktail drug	4 singles days spaced out with one week wash-out periods
comparison. between genotype and phenotype for each enzyme	one day

Collaborators and Investigators

• Sponsor: Jules Desmeules

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.

Study record dates

Study Major Dates

• Study Start: November 1, 2012
• Primary Completion (ACTUAL): May 1, 2013
• Study Completion (ACTUAL): January 1, 2014

Study Registration Dates

• First Submitted: November 14, 2012
• First Submitted That Met QC Criteria: November 20, 2012
• First Posted (ESTIMATE): November 21, 2012

Study Record Updates

• Last Update Posted (ESTIMATE): September 16, 2014
• Last Update Submitted That Met QC Criteria: September 15, 2014
• Last Verified: September 1, 2014

More Information

Terms related to this study

• Additional Relevant MeSH Terms: 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: Coktail DBS