Development of Cocktail for Measuring the Activity of Important Cytochrome P450 Enzymes

University of Southern Denmark (SDU)

Status: Terminated

Conditions: Cytochrome P450 Phenotype and Genotype Metrics

Treatments: Drug: Tramadol; Drug: Omeprazole, losartan, caffeine; Drug: Tramadol, omeprazole, losartan, caffeine

Study type: Interventional

Funder types: Other

Identifiers

NCT00981929

AKF-375

Details and patient eligibility

About

The Cytochrome P450 enzymes are responsible for the metabolism of a wide range of drugs and other xenobiotics. Genetic variants of the encoding P450 genes have shown to influence the rate of metabolism of many clinically used drugs.

The drugs tramadol, omeprazole, losartan, quinidine and caffeine reflect the activity of CYP2D6 (tramadol), CYP2C19 (omeprazole), CYP2C9 (losartan), CYP1A2 (caffeine) and CYP3A4/5 (quinidine).

The aim of the study is to investigate if the cocktail of tramadol, omeprazole, losartan and caffeine can be used to simultaneously determine the activity of CYP2D6, CYP2C19, CYP2C9 and CYP1A2. Furthermore, will the natural occurring 4-beta-hydroxy-cholesterol in the blood be measured as a metric for CYP3A4/5.

The study is divided in two. First part will include 12 healthy volunteers and consists of three arms separated by at least one week. In the first arm 50 mg of tramadol will be ingested and urine will be collected for 8 hours. In the second arm 20 mg omeprazole, 25 mg losartan and 200 mg caffeine will be ingested followed by 8 hours urine collection and a blood sample 4 hours after administration of the drugs. In the last arm 50 mg of tramadol, 20 mg omeprazole, 25 mg losartan and 200 mg caffeine will be ingested followed by 8 hours urine collection and a blood sample 4 hours after administration of the drugs.

Metabolic ratios will be calculated based on urine and plasma concentrations of the drugs and the relevant metabolites. Relevant genetic variants of the cytochrome P450 encoding genes will be determined.

If the metabolic ratios of the drugs are not significantly different between the arms, Second part of the study will be conducted.

This part is identical with the last arm and will include a maximum of 400 healthy volunteers: 50 mg of tramadol, 20 mg omeprazole, 25 mg losartan and 200 mg caffeine will be ingested followed by 8 hours urine collection and a blood sample 4 hours after administration of the drugs.

Enrollment: 412 estimated patients

Sex: All

Ages: 18 to 65 years old

Volunteers: Accepts Healthy Volunteers

Inclusion criteria

• Healthy volunteers,
• Written consent, AND
• Age 18-65 years old.

Exclusion criteria

• Daily medication,
• Alcohol abuse,
• Pregnancy, OR
• Breastfeeding.

Trial design

Primary purpose: Screening

Allocation: Non-Randomized

Interventional model: Crossover Assignment

Masking: None (Open label)

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412 participants in 3 patient groups

Tramadol

Active Comparator group

Description:

CYP2D6 metric

Treatment:

Drug: Tramadol

Omeprazole, losartan, caffeine

Active Comparator group

Description:

CYP2C19, CYP2C9 and CYP1A2 metrics

Treatment:

Drug: Omeprazole, losartan, caffeine

Tramadol, omeprazole, losartan and caffeine

Active Comparator group

Description:

CYP2D6, CYP2C19, CYP2C9 and CYP1A2 metrics

Treatment:

Drug: Tramadol, omeprazole, losartan, caffeine