Evaluation of the Potential Pharmacokinetic Interactions Between Probe Drugs in the Geneva Phenotyping Cocktail

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.

When a cocktail approach is used it is important to make sure that no drug-drug interactions occur between the probes within the cocktail. The validation of the lack of interactions, which is the aim of the study, consists of demonstrating that there is no difference in the pharmacokinetic parameters and/or metabolic ratios when a probe is administered alone or as part of the cocktail. The Geneva 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.

Probe and metabolite concentrations will be measured in capillary blood using a dried blood spot (DBS) analysis. To further facilitate sampling, a new simple device will be used to ensure the precision of capillary blood collection.

Study Overview

• Status: Completed
• Conditions: Drug Interaction
• Intervention / Treatment: Drug: Bupropion; Drug: Fexofenadine; Drug: Caffeine, omeprazole, flurbiprofen, dextromethorphan, midazolam

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Phase 1

Contacts and Locations

Study Locations

• Switzerland
  • Genève, Switzerland, 1211
    • Centre de Recherche Clinique, HUG, Rue Gabrielle Perret-Gentil 4

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 58 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Healthy volunteers aged from 18 to 60 years
• BMI between 18 and 27
• Understanding of French language and able to give a written inform consent.

Exclusion Criteria:

• smoker
• pregnant women
• taking drugs which alter cytochrome P450 (CYP) activity
• renal or hepatic impairment
• medical history of chronic alcoholism or abuse of psychoactive drugs
• liver transplantation
• sensitivity to any of the drugs used
• Alteration of hepatic tests, more than 2x normal (aspartate transaminase >100U/L ; alanine transaminase >100 units/L ; gamma-glutamyl transferase >80 units/L ; bilirubin >50µmol/L)
• Presenting genetic polymorphism of poor CYP2C9, CYP2C19, CYP2D6 metabolizer

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment A; Oral intake of: caffeine 50 mg dextromethorphan 10 mg omeprazole 10 mg flurbiprofen 10 mg midazolam 1 mg	Drug: Caffeine, omeprazole, flurbiprofen, dextromethorphan, midazolam
Experimental: Treatment B; Oral intake of: fexofenadine 25 mg	Drug: Fexofenadine
Experimental: Treatment C; Oral intake of: bupropion 20 mg	Drug: Bupropion
Experimental: Treatment D; Oral Intake of Geneva cocktail (A+B+C): caffeine 50 mg dextromethorphan 10 mg omeprazole 10 mg flurbiprofen 10 mg midazolam 1 mg fexofenadine 25 mg bupropion 20 mg	Drug: Bupropion; Drug: Fexofenadine; Drug: Caffeine, omeprazole, flurbiprofen, dextromethorphan, midazolam

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area under the capillary blood concentration-time curve (AUC) of caffeine	Comparison of caffeine AUC when treatment A or D is administered	0, 0.5, 1, 2, 3, 4, 6, 8 hours post treatment A or D
Area under the capillary blood concentration-time curve (AUC) of dextromethorphan	Comparison of dextromethorphan AUC when treatment A or D is administered	0, 0.5, 1, 2, 3, 4, 6, 8 hours post treatment A or D
Area under the capillary blood concentration-time curve (AUC) of flurbiprofen	Comparison of flurbiprofen AUC when treatment A or D is administered	0, 0.5, 1, 2, 3, 4, 6, 8 hours post treatment A or D
Area under the capillary blood concentration-time curve (AUC) of midazolam	Comparison of midazolam AUC when treatment A or D is administered	0, 0.5, 1, 2, 3, 4, 6, 8 hours post treatment A or D
Area under the capillary blood concentration-time curve (AUC) of omeprazole	Comparison of omeprazole AUC when treatment A or D is administered	0, 0.5, 1, 2, 3, 4, 6, 8 hours post treatment A or D
Area under the capillary blood concentration-time curve (AUC) of fexofenadine	Comparison of fexofenadine AUC when treatment B or D is administered	0, 0.5, 1, 2, 3, 4, 6, 8 hours post treatment B or D
Area under the capillary blood concentration-time curve (AUC) of bupropion	Comparison of bupropion AUC when treatment C or D is administered	0, 0.5, 1, 2, 3, 4, 6, 8, 12, 24 hours post treatment C or D

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Metabolic ratio (MR) of paraxanthine blood concentration /caffeine blood concentration	Comparison of paraxanthine/caffeine MRs between treatment A and D	0.5, 1, 2, 3, 4, 6, 8 hours post treatment A or D
Metabolic ratio (MR) of dextrorphan blood concentration /dextromethorphan blood concentration	Comparison of dextrorphan/dextromethorphan MRs between treatment A and D	0.5, 1, 2, 3, 4, 6, 8 hours post treatment A or D
Metabolic ratio (MR) of 4-hydroxyflurbiprofen blood concentration /flurbiprofen blood concentration	Comparison of 4-hydroxyflurbiprofen/flurbiprofen MRs between treatment A and D	0.5, 1, 2, 3, 4, 6, 8 hours post treatment A or D
Metabolic ratio (MR) of 1-hydroxymidazolam blood concentration /midazolam blood concentration	Comparison of 1-hydroxymidazolam/midazolam MRs between treatment A and D	0.5, 1, 2, 3, 4, 6, 8 hours post treatment A or D
Metabolic ratio (MR) of 5-hydroxyomeprazole blood concentration /omeprazole blood concentration	Comparison of 5-hydroxyomeprazole/omeprazole MRs between treatment A and D	0.5, 1, 2, 3, 4, 6, 8 hours post treatment A or D
Metabolic ratio (MR) of 4-hydroxybupropion blood concentration /bupropion blood concentration	Comparison of 4-hydroxybupropion/bupropion MRs between treatment C and D	0.5, 1, 2, 3, 4, 6, 8, 12, 24 hours post treatment C or D
Number of adverse events		at each drug administration day

Other Outcome Measures

Outcome Measure	Time Frame
Correlation of drug concentrations (ng/ml) in DBS obtained with two sampling techniques for all administered drugs	0.5, 1, 2, 3, 4, 6, 8 hours post treatment A, B, C and D

Collaborators and Investigators

• Sponsor: Jules Desmeules

Study record dates

Study Major Dates

• Study Start: November 1, 2014
• Primary Completion (Actual): April 1, 2015
• Study Completion (Actual): April 1, 2015

Study Registration Dates

• First Submitted: February 19, 2015
• First Submitted That Met QC Criteria: March 12, 2015
• First Posted (Estimate): March 18, 2015

Study Record Updates

• Last Update Posted (Estimate): February 7, 2017
• Last Update Submitted That Met QC Criteria: February 6, 2017
• Last Verified: February 1, 2017

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: 14-061