Cholesterol Metabolites as Markers for CYP3A Induction

Study Overview
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Brief Summary
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The objectives of this study are: To investigate if the endogenous cholesterol metabolite, 4beta-OHcholesterol could be used as a marker for induction of cytochrome P450 (CYP) 3A4. To compare 4beta-OHcholesterol with midazolam as a marker for induction of CYP3A4.

Official Title
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Induction of Drug Metabolism by Rifampicin to Compare the Endogenous Biomarker 4beta-OHcholesterol With the Probe Drug Midazolam as Quantitative Markers for Cytochrome P450 3A4 Induction

Conditions
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CYP3A4 Induction

Intervention / Treatment
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* Drug: Rifampicin treatment


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Females and males. Age of 18 and above. Caucasians. Healthy as assessed by medical history and examination by principal investigator or delegated personnel. Accept to refrain from herbal drugs, natural preparations, and grapefruit juice 48 hours before and during the study period. Accept to completely refrain from alcohol during day -1 to 1 and R14-R16. During the rest of the study moderate alcohol use is permitted (equal to 1 glass of wine or 1 beer per day). Women of childbearing age should accept using a reliable barrier contraceptive method throughout the study. Women of childbearing age should have a negative pregnancy test at the screening visit. Capable of following given instructions. Has given written informed consent after receiving both oral and written study information. Exclusion Criteria: Predisposal to allergic drug reactions. Anamnestic and/or visual signs of infection. Women are not allowed to use oral hormone-based contraceptives 2 weeks before start of study and during the study. Participation in another study within one month before entering the present study. Intake of any other drug that can influence the enzyme activity of CYP3A4. Pregnancy. Breast-feeding. A history of liver disease.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Rifampicin 10 mg QD<br> | Drug: Rifampicin treatment<br>* induction of CYP3A4 with one of three rifampicin doses (10, 20, 100 mg QD)<br>* Other names: Rifadin;|
| Experimental: Rifampicin 20 mg QD<br> | Drug: Rifampicin treatment<br>* induction of CYP3A4 with one of three rifampicin doses (10, 20, 100 mg QD)<br>* Other names: Rifadin;|
| Experimental: Rifampicin 100 mg QD<br> | Drug: Rifampicin treatment<br>* induction of CYP3A4 with one of three rifampicin doses (10, 20, 100 mg QD)<br>* Other names: Rifadin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in 4beta-OHcholesterol | The primary objective of the study is to investigate whether the endogenous cholesterol metabolite 4β-hydroxycholesterol could be used as a marker for induction of CYP3A4. For this purpose the induction of 4β-hydroxycholesterol formation will be compared to the induction of quinine and midazolam metabolism. | Directly before treatment with rifampicin and 14 days after the end of treatment with rifampicin | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ratio between midazolam AUC induced and midazolam AUC uninduced | Secondary aim of the study is to compare 4β-hydroxycholesterol as a biomarker for CYP3A4 compared to 6β-hydroxycortisol/cortisol ratio, which sometimes is used as a marker for CYP3A4 induction. Another secondary aim is to relate our estimations of CYP3A4-expression to measured levels of 25-OH-vitamin D. | Before treatment with rifampicin and after 14 days of treatment with rifampicin | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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4beta-OHcholesterol, Midazolam, CYP3A4, Enzyme induction, Drug metabolism