Drug Interaction
Conditions
Brief summary
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.
Interventions
DRUGCaffeine, omeprazole, flurbiprofen, dextromethorphan, midazolam
DRUGBupropion
DRUGFexofenadine
Sponsors
Jules Desmeules
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
DIAGNOSTIC
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area under the capillary blood concentration-time curve (AUC) of bupropion | 0, 0.5, 1, 2, 3, 4, 6, 8, 12, 24 hours post treatment C or D | Comparison of bupropion AUC when treatment C or D is administered |
| Area under the capillary blood concentration-time curve (AUC) of caffeine | 0, 0.5, 1, 2, 3, 4, 6, 8 hours post treatment A or D | Comparison of caffeine AUC when treatment A or D is administered |
| Area under the capillary blood concentration-time curve (AUC) of dextromethorphan | 0, 0.5, 1, 2, 3, 4, 6, 8 hours post treatment A or D | Comparison of dextromethorphan AUC when treatment A or D is administered |
| Area under the capillary blood concentration-time curve (AUC) of flurbiprofen | 0, 0.5, 1, 2, 3, 4, 6, 8 hours post treatment A or D | Comparison of flurbiprofen AUC when treatment A or D is administered |
| Area under the capillary blood concentration-time curve (AUC) of midazolam | 0, 0.5, 1, 2, 3, 4, 6, 8 hours post treatment A or D | Comparison of midazolam AUC when treatment A or D is administered |
| Area under the capillary blood concentration-time curve (AUC) of omeprazole | 0, 0.5, 1, 2, 3, 4, 6, 8 hours post treatment A or D | Comparison of omeprazole AUC when treatment A or D is administered |
| Area under the capillary blood concentration-time curve (AUC) of fexofenadine | 0, 0.5, 1, 2, 3, 4, 6, 8 hours post treatment B or D | Comparison of fexofenadine AUC when treatment B or D is administered |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of adverse events | at each drug administration day | — |
| Metabolic ratio (MR) of paraxanthine blood concentration /caffeine blood concentration | 0.5, 1, 2, 3, 4, 6, 8 hours post treatment A or D | Comparison of paraxanthine/caffeine MRs between treatment A and D |
| Metabolic ratio (MR) of dextrorphan blood concentration /dextromethorphan blood concentration | 0.5, 1, 2, 3, 4, 6, 8 hours post treatment A or D | Comparison of dextrorphan/dextromethorphan MRs between treatment A and D |
| Metabolic ratio (MR) of 4-hydroxyflurbiprofen blood concentration /flurbiprofen blood concentration | 0.5, 1, 2, 3, 4, 6, 8 hours post treatment A or D | Comparison of 4-hydroxyflurbiprofen/flurbiprofen MRs between treatment A and D |
| Metabolic ratio (MR) of 1-hydroxymidazolam blood concentration /midazolam blood concentration | 0.5, 1, 2, 3, 4, 6, 8 hours post treatment A or D | Comparison of 1-hydroxymidazolam/midazolam MRs between treatment A and D |
| Metabolic ratio (MR) of 5-hydroxyomeprazole blood concentration /omeprazole blood concentration | 0.5, 1, 2, 3, 4, 6, 8 hours post treatment A or D | Comparison of 5-hydroxyomeprazole/omeprazole MRs between treatment A and D |
| Metabolic ratio (MR) of 4-hydroxybupropion blood concentration /bupropion blood concentration | 0.5, 1, 2, 3, 4, 6, 8, 12, 24 hours post treatment C or D | Comparison of 4-hydroxybupropion/bupropion MRs between treatment C and D |
Other
| 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 |
Countries
Switzerland
Outcome results
None listed