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

Jules Desmeules

Status and phase: Completed; Phase 1

Conditions: Drug Interaction

Treatments: Drug: Fexofenadine; Drug: Caffeine, omeprazole, flurbiprofen, dextromethorphan, midazolam; Drug: Bupropion

Study type: Interventional

Funder types: Other

Identifiers

NCT02391688

14-061

Details and patient eligibility

About

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.

Enrollment: 30 patients

Sex: All

Ages: 18 to 60 years old

Volunteers: Accepts Healthy Volunteers

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

Trial design

Primary purpose: Diagnostic

Allocation: Randomized

Interventional model: Crossover Assignment

Masking: None (Open label)

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30 participants in 4 patient groups

Treatment A

Experimental group

Description:

Oral intake of: caffeine 50 mg dextromethorphan 10 mg omeprazole 10 mg flurbiprofen 10 mg midazolam 1 mg

Treatment:

Drug: Caffeine, omeprazole, flurbiprofen, dextromethorphan, midazolam

Treatment B

Experimental group

Description:

Oral intake of: fexofenadine 25 mg

Treatment:

Drug: Fexofenadine

Treatment C

Experimental group

Description:

Oral intake of: bupropion 20 mg

Treatment:

Drug: Bupropion

Treatment D

Experimental group

Description:

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

Treatment:

Drug: Bupropion

Drug: Caffeine, omeprazole, flurbiprofen, dextromethorphan, midazolam

Drug: Fexofenadine