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

Jules Desmeules

Status and phase: Completed; Phase 1

Conditions: Healthy Volunteers

Treatments: Drug: Cocktail probe drugs

Study type: Interventional

Funder types: Other

Identifiers

NCT01731067

Coktail DBS

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.

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.

Enrollment: 10 estimated patients

Sex: Male

Ages: 18 to 65 years old

Volunteers: Accepts Healthy Volunteers

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

Trial design

Primary purpose: Diagnostic

Allocation: Non-Randomized

Interventional model: Crossover Assignment

Masking: None (Open label)

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10 participants in 4 patient groups

CYP1A2, 2B6, 2C9, 2C19, 3A4 inhibitors

Active Comparator group

Description:

Oral intake of fluvoxamine (50 mg per day during 2 days) and voriconazole (400 mg) before oral intake of the cocktail probe drugs

Treatment:

Drug: Cocktail probe drugs

CYP2D6 and P-gp inhibitor

Active Comparator group

Description:

Oral intake of quinidine (200 mg) before oral intake of the cocktail probe drugs

Treatment:

Drug: Cocktail probe drugs

CYPs and P-gp inducer

Active Comparator group

Description:

Oral intake of rifampicin (600 mg per day during 7 days) before oral intake of the cocktail probe drugs

Treatment:

Drug: Cocktail probe drugs

Probe cocktail alone

Experimental group

Description:

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)

Treatment:

Drug: Cocktail probe drugs