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

Study Overview
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Brief Summary
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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.

Conditions
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Drug Interaction

Intervention / Treatment
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* Drug: Caffeine, omeprazole, flurbiprofen, dextromethorphan, midazolam
* Drug: Bupropion
* Drug: Fexofenadine


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment A<br>Oral intake of: caffeine 50 mg dextromethorphan 10 mg omeprazole 10 mg flurbiprofen 10 mg midazolam 1 mg | Drug: Caffeine, omeprazole, flurbiprofen, dextromethorphan, midazolam<br> <br> |
| Experimental: Treatment B<br>Oral intake of: fexofenadine 25 mg | Drug: Fexofenadine<br> <br> |
| Experimental: Treatment C<br>Oral intake of: bupropion 20 mg | Drug: Bupropion<br> <br> |
| Experimental: Treatment D<br>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: Caffeine, omeprazole, flurbiprofen, dextromethorphan, midazolam<br> <br> Drug: Bupropion<br> <br> Drug: Fexofenadine<br> <br> |

What is the study measuring?
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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 |