Cholesterol Metabolites as Markers for CYP3A Induction

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

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.

Study Overview

• Status: Completed
• Conditions: CYP3A4 Induction
• Intervention / Treatment: Drug: Rifampicin treatment

• Study Type: Interventional
• Enrollment (Actual): 24
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Sweden
  • Stockholm, Sweden, SE-14186
    • Clinical Pharmacology Trial Unit (CPTU), Karolinska University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Females and males.
2. Age of 18 and above.
3. Caucasians.
4. Healthy as assessed by medical history and examination by principal investigator or delegated personnel.
5. Accept to refrain from herbal drugs, natural preparations, and grapefruit juice 48 hours before and during the study period.
6. 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).
7. Women of childbearing age should accept using a reliable barrier contraceptive method throughout the study.
8. Women of childbearing age should have a negative pregnancy test at the screening visit.
9. Capable of following given instructions.
10. Has given written informed consent after receiving both oral and written study information.

Exclusion Criteria:

1. Predisposal to allergic drug reactions.
2. Anamnestic and/or visual signs of infection.
3. Women are not allowed to use oral hormone-based contraceptives 2 weeks before start of study and during the study.
4. Participation in another study within one month before entering the present study.
5. Intake of any other drug that can influence the enzyme activity of CYP3A4.
6. Pregnancy.
7. Breast-feeding.
8. A history of liver disease.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: DIAGNOSTIC
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

3

Arms and Interventions

Participant Group / 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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Karolinska University Hospital
• Collaborators: AstraZeneca
• Investigators: Principal Investigator: Tobias Bäckström, MD PhD, Department of Clinical Pharmacology, Karolinska University Hospital

Study record dates

Study Major Dates

• Study Start: May 1, 2011
• Primary Completion (ACTUAL): July 1, 2011
• Study Completion (ACTUAL): July 1, 2011

Study Registration Dates

• First Submitted: April 15, 2011
• First Submitted That Met QC Criteria: April 20, 2011
• First Posted (ESTIMATE): April 22, 2011

Study Record Updates

• Last Update Posted (ESTIMATE): July 11, 2011
• Last Update Submitted That Met QC Criteria: July 8, 2011
• Last Verified: May 1, 2011

More Information

Terms related to this study

• Keywords: Midazolam; CYP3A4; Drug metabolism; Enzyme induction; 4beta-OHcholesterol
• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-Bacterial Agents; Leprostatic Agents; Cytochrome P-450 Enzyme Inducers; Cytochrome P-450 CYP3A Inducers; Antitubercular Agents; Antibiotics, Antitubercular; Cytochrome P-450 CYP2B6 Inducers; Cytochrome P-450 CYP2C8 Inducers; Cytochrome P-450 CYP2C19 Inducers; Cytochrome P-450 CYP2C9 Inducers; Rifampin
• Other Study ID Numbers: 1001-01