Cholesterol Metabolites as Markers for CYP3A Induction

Sponsor

Karolinska University Hospital (Other)

Overall Status

Completed

CT.gov ID

NCT01340456

Collaborator

AstraZeneca (Industry)

Enrollment

Location

Arms

Duration (Months)

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
CYP3A4 Induction	Drug: Rifampicin treatment	N/A

Study Design

Study Type:

Interventional

Actual Enrollment :

24 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Diagnostic

Official Title:

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

Study Start Date :

May 1, 2011

Actual Primary Completion Date :

Jul 1, 2011

Actual Study Completion Date :

Jul 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Rifampicin 10 mg QD	Drug: Rifampicin treatment induction of CYP3A4 with one of three rifampicin doses (10, 20, 100 mg QD) Other Names: Rifadin
Experimental: Rifampicin 20 mg QD	Drug: Rifampicin treatment induction of CYP3A4 with one of three rifampicin doses (10, 20, 100 mg QD) Other Names: Rifadin
Experimental: Rifampicin 100 mg QD	Drug: Rifampicin treatment induction of CYP3A4 with one of three rifampicin doses (10, 20, 100 mg QD) Other Names: Rifadin

Arm

Intervention/Treatment

Experimental: Rifampicin 10 mg QD

Drug: Rifampicin treatment

induction of CYP3A4 with one of three rifampicin doses (10, 20, 100 mg QD)

Other Names:

Rifadin

Experimental: Rifampicin 20 mg QD

Drug: Rifampicin treatment

induction of CYP3A4 with one of three rifampicin doses (10, 20, 100 mg QD)

Other Names:

Rifadin

Experimental: Rifampicin 100 mg QD

Drug: Rifampicin treatment

induction of CYP3A4 with one of three rifampicin doses (10, 20, 100 mg QD)

Other Names:

Rifadin

Outcome Measures

Primary Outcome Measures

Change in 4beta-OHcholesterol [Directly before treatment with rifampicin and 14 days after the end of treatment with rifampicin]
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.

Secondary Outcome Measures

Ratio between midazolam AUC induced and midazolam AUC uninduced [Before treatment with rifampicin and after 14 days of treatment with rifampicin]
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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

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.