Clinical trial NCT02391688: Evaluation of the Potential Pharmacokinetic Interactions Between Probe Drugs in the Geneva Phenotyping Cocktail
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Drug Interaction
Lead sponsor: University Hospital, Geneva
Sponsor class: OTHER
First posted: 2015-03-18
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: DIAGNOSTIC

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.


Eligibility criteria: 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

Primary outcomes:
measure: Area under the capillary blood concentration-time curve (AUC) of caffeine
timeFrame: 0, 0.5, 1, 2, 3, 4, 6, 8 hours post treatment A or D
measure: Area under the capillary blood concentration-time curve (AUC) of dextromethorphan
timeFrame: 0, 0.5, 1, 2, 3, 4, 6, 8 hours post treatment A or D
measure: Area under the capillary blood concentration-time curve (AUC) of flurbiprofen
timeFrame: 0, 0.5, 1, 2, 3, 4, 6, 8 hours post treatment A or D
measure: Area under the capillary blood concentration-time curve (AUC) of midazolam
timeFrame: 0, 0.5, 1, 2, 3, 4, 6, 8 hours post treatment A or D
measure: Area under the capillary blood concentration-time curve (AUC) of omeprazole
timeFrame: 0, 0.5, 1, 2, 3, 4, 6, 8 hours post treatment A or D
measure: Area under the capillary blood concentration-time curve (AUC) of fexofenadine
timeFrame: 0, 0.5, 1, 2, 3, 4, 6, 8 hours post treatment B or D
measure: Area under the capillary blood concentration-time curve (AUC) of bupropion
timeFrame: 0, 0.5, 1, 2, 3, 4, 6, 8, 12, 24 hours post treatment C or D
Secondary outcomes:
measure: Metabolic ratio (MR) of paraxanthine blood concentration /caffeine blood concentration
timeFrame: 0.5, 1, 2, 3, 4, 6, 8 hours post treatment A or D
measure: Metabolic ratio (MR) of dextrorphan blood concentration /dextromethorphan blood concentration
timeFrame: 0.5, 1, 2, 3, 4, 6, 8 hours post treatment A or D
measure: Metabolic ratio (MR) of 4-hydroxyflurbiprofen blood concentration /flurbiprofen blood concentration
timeFrame: 0.5, 1, 2, 3, 4, 6, 8 hours post treatment A or D
measure: Metabolic ratio (MR) of 1-hydroxymidazolam blood concentration /midazolam blood concentration
timeFrame: 0.5, 1, 2, 3, 4, 6, 8 hours post treatment A or D
measure: Metabolic ratio (MR) of 5-hydroxyomeprazole blood concentration /omeprazole blood concentration
timeFrame: 0.5, 1, 2, 3, 4, 6, 8 hours post treatment A or D
measure: Metabolic ratio (MR) of 4-hydroxybupropion blood concentration /bupropion blood concentration
timeFrame: 0.5, 1, 2, 3, 4, 6, 8, 12, 24 hours post treatment C or D
measure: Number of adverse events
timeFrame: at each drug administration day
Other outcomes:
measure: Correlation of drug concentrations (ng/ml) in DBS obtained with two sampling techniques for all administered drugs
timeFrame: 0.5, 1, 2, 3, 4, 6, 8 hours post treatment A, B, C and D
Locations:
city: Genève
country: Switzerland
facility: Centre de Recherche Clinique, HUG, Rue Gabrielle Perret-Gentil 4
Study officials:
References: