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Cocktail Approach for Cytochrome P450 and P-glycoprotein Activity Assessment Using Dried Blood Spot

This study has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT01731067
First Posted: November 21, 2012
Last Update Posted: September 16, 2014
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Information provided by (Responsible Party):
Jules Desmeules, University Hospital, Geneva
  Purpose

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.

The aim of this project is the validation of a phenotyping cocktail of low dose probe drugs for the assessment of cytochrome P450 and P-gp activities by simple capillary blood sampling and dried blood spot (DBS) analysis. The 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.

The modulation of the activity of cytochromes or P-gp will be evaluated by the administration of inhibitors (fluvoxamine, voriconazole, quinidine) or inducer (rifampicin) of the metabolic pathways or the P-gp mediated transport.


Condition Intervention Phase
Healthy Volunteers Drug: Cocktail probe drugs Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)
Primary Purpose: Diagnostic

Further study details as provided by Jules Desmeules, University Hospital, Geneva:

Primary Outcome Measures:
  • Probe cocktail drugs plasma and capillary concentrations in presence/absence of CYP1A2,2B6, 2C9, 2C19, 2D6, 3A4 and P-gp inhibitor or inducer [ Time Frame: 4 singles days spaced out with one week wash-out periods ]

Secondary Outcome Measures:
  • correlation between plasma or urine and capillary concentrations for each probe cocktail drug [ Time Frame: 4 singles days spaced out with one week wash-out periods ]
  • comparison. between genotype and phenotype for each enzyme [ Time Frame: one day ]

Estimated Enrollment: 10
Study Start Date: November 2012
Study Completion Date: January 2014
Primary Completion Date: May 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: CYP1A2, 2B6, 2C9, 2C19, 3A4 inhibitors
Oral intake of fluvoxamine (50 mg per day during 2 days) and voriconazole (400 mg) before oral intake of the cocktail probe drugs
Drug: Cocktail probe drugs
Other Names:
  • Oral intake of the cocktail probe drugs :
  • bupropion 25 mg
  • flurbiprofen 25 mg
  • omeprazole 5 mg
  • dextromethorphan 5 mg
  • midazolam 1 mg
  • fexofenadine 25mg
  • Caffeine (a cup of coffee)
Active Comparator: CYP2D6 and P-gp inhibitor
Oral intake of quinidine (200 mg) before oral intake of the cocktail probe drugs
Drug: Cocktail probe drugs
Other Names:
  • Oral intake of the cocktail probe drugs :
  • bupropion 25 mg
  • flurbiprofen 25 mg
  • omeprazole 5 mg
  • dextromethorphan 5 mg
  • midazolam 1 mg
  • fexofenadine 25mg
  • Caffeine (a cup of coffee)
Active Comparator: CYPs and P-gp inducer
Oral intake of rifampicin (600 mg per day during 7 days) before oral intake of the cocktail probe drugs
Drug: Cocktail probe drugs
Other Names:
  • Oral intake of the cocktail probe drugs :
  • bupropion 25 mg
  • flurbiprofen 25 mg
  • omeprazole 5 mg
  • dextromethorphan 5 mg
  • midazolam 1 mg
  • fexofenadine 25mg
  • Caffeine (a cup of coffee)
Experimental: Probe cocktail alone

Oral intake of the cocktail probe drugs :

  • bupropion 25 mg
  • flurbiprofen 25 mg
  • omeprazole 5 mg
  • dextromethorphan 5 mg
  • midazolam 1 mg
  • fexofenadine 25mg
  • Caffeine (a cup of coffee)
Drug: Cocktail probe drugs
Other Names:
  • Oral intake of the cocktail probe drugs :
  • bupropion 25 mg
  • flurbiprofen 25 mg
  • omeprazole 5 mg
  • dextromethorphan 5 mg
  • midazolam 1 mg
  • fexofenadine 25mg
  • Caffeine (a cup of coffee)

  Eligibility

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 65 Years   (Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Healthy male volunteers aged from 18 to 60 years
  • BMI between 18 and 25
  • Understanding of French language and able to give a written inform consent.

Exclusion Criteria:

  • Smoker
  • Taking drugs which alter CYPs activity
  • Renal or hepatic impairment
  • Medical history of porphyria
  • Medical history of chronic alcoholism or abuse of psychoactive drugs
  • Liver transplantation
  • Sensitivity to any of the drugs used
  • Wearing contact lenses (risk of coloration with rifampicin)
  • ECG showing long QT interval (>0.46sec)
  • Alteration of hepatic tests
  • Presenting genetic polymorphism of poor CYP 2B6, 2C9, 2C19, 2D6 metabolisers
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01731067


Locations
Switzerland
University Hospitals
Geneva 14, Switzerland
Sponsors and Collaborators
Jules Desmeules
Investigators
Principal Investigator: Jules A Desmeules, Pr University Hospital, Geneva
  More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Jules Desmeules, Pr, University Hospital, Geneva
ClinicalTrials.gov Identifier: NCT01731067     History of Changes
Other Study ID Numbers: Coktail DBS
First Submitted: November 14, 2012
First Posted: November 21, 2012
Last Update Posted: September 16, 2014
Last Verified: September 2014

Additional relevant MeSH terms:
Midazolam
Caffeine
Bupropion
Dextromethorphan
Fexofenadine
Omeprazole
Flurbiprofen
Adjuvants, Anesthesia
Hypnotics and Sedatives
Central Nervous System Depressants
Physiological Effects of Drugs
Anti-Anxiety Agents
Tranquilizing Agents
Psychotropic Drugs
Anesthetics, Intravenous
Anesthetics, General
Anesthetics
GABA Modulators
GABA Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Central Nervous System Stimulants
Phosphodiesterase Inhibitors
Enzyme Inhibitors
Purinergic P1 Receptor Antagonists
Purinergic Antagonists
Purinergic Agents
Antidepressive Agents, Second-Generation
Antidepressive Agents
Dopamine Uptake Inhibitors