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

NCT02391688 | Completed Phase 1

• 1 other identifier: 14-061
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

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.

Conditions

Drug Interaction

Outcome Measures

Primary Outcomes (7)

• 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 Outcomes (7)

• Metabolic ratio (MR) of paraxanthine blood concentration /caffeine blood concentration

  0.5, 1, 2, 3, 4, 6, 8 hours post treatment A or 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

• 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

• 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

• 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

Other Outcomes (1)

• 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

Study Arms (4)

Treatment A

EXPERIMENTAL

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

Drug: Caffeine, omeprazole, flurbiprofen, dextromethorphan, midazolam

Treatment B

EXPERIMENTAL

Oral intake of: fexofenadine 25 mg

Drug: Fexofenadine

Treatment C

EXPERIMENTAL

Oral intake of: bupropion 20 mg

Drug: Bupropion

Treatment D

EXPERIMENTAL

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; Drug: Bupropion; Drug: Fexofenadine

Interventions

Caffeine, omeprazole, flurbiprofen, dextromethorphan, midazolam DRUG

Treatment A; Treatment D

Bupropion DRUG

Treatment C; Treatment D

Fexofenadine DRUG

Treatment B; Treatment D

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Jules Desmeules: lead

Study Sites (1)

Centre de Recherche Clinique, HUG, Rue Gabrielle Perret-Gentil 4

Geneva, 1211, Switzerland

Location

MeSH Terms

Interventions

Caffeine; Omeprazole; Flurbiprofen; Dextromethorphan; Midazolam; Bupropion; fexofenadine

Intervention Hierarchy (Ancestors)

Xanthines; Alkaloids; Heterocyclic Compounds; Purinones; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; 2-Pyridinylmethylsulfinylbenzimidazoles; Sulfoxides; Sulfur Compounds; Organic Chemicals; Pyridines; Heterocyclic Compounds, 1-Ring; Benzimidazoles; Propionates; Acids, Acyclic; Carboxylic Acids; Biphenyl Compounds; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Morphinans; Opiate Alkaloids; Heterocyclic Compounds, Bridged-Ring; Heterocyclic Compounds, 4 or More Rings; Phenanthrenes; Polycyclic Aromatic Hydrocarbons; Polycyclic Compounds; Benzodiazepines; Benzazepines; Propiophenones; Ketones

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: DIAGNOSTIC
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: February 19, 2015
• First Posted: March 18, 2015
• Study Start: November 1, 2014
• Primary Completion: April 1, 2015
• Study Completion: April 1, 2015
• Last Updated: February 7, 2017

Record last verified: 2017-02

Locations

CH (1)