CYP3A4 Activity and Mineral Homeostasis

Study Overview
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Brief Summary
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The purpose of this study is to determine whether changes in the activity of the enzyme CYP3A4 can change the Vitamin D and bone mineral homeostasis.

Detailed Description
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Healthy volunteers will receive one of six interventions for 14 days (determined by randomization):a). 200 mL of water once a day; b) rifampin 600 mg once a day; c) 200 mL of grapefruit juice once a day for 8 days plus rifampin 600 mg once a day for 14 days; d) clarithromycin 250 mg twice a day; f) clarithromycin 250 mg twice a day plus rifampin 600 mg once a day.

Official Title
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Effect of Modulating CYP3A4 Activity on Mineral Homeostasis

Conditions
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Vitamin D and Calcium Homeostasis

Intervention / Treatment
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* Drug: Rifampin
* Drug: Clarithromycin
* Other: Grapefruit Juice
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects with no history of significant medical conditions including cardiac, pulmonary, gastrointestinal, or renal disease, HIV, diabetes mellitus or Hepatitis B or C Subjects will be males or females 18-60 years of age Subjects must read and understand English Subjects must be able to provide informed consent Subjects must be willing to avoid prescription medications, OTC drugs, dietary supplements and foods that are known to modulate CYP3A4 expression or activity Subjects must be willing to maintain a consistent consumption of calcium and Vitamin D during the study and maintain a daily logbook of their dietary consumption Women not currently pregnant or lactating. In addition, women participants of childbearing age must be willing to utilize a barrier method of birth control (sterilization will be acceptable) Subjects will have no known allergies to the study drugs to be used Subject's corrected QTc interval obtained by electrocardiogram will be ≤ 430 ms in men or ≤ 450 ms in women Exclusion Criteria: Subjects with any significant chronic medical condition, including cardiac, pulmonary, gastrointestinal, or renal disease, HIV, diabetes mellitus or Hepatitis B or C Subjects less than 18 or greater than 60 years of age Subjects unable to read and understand English Subjects unable to provide informed consent Subjects unable to avoid prescription medications, OTC drugs, dietary supplements and foods that are known to modulate CYP3A4 expression or activity Subjects not willing to maintain a consistent consumption of calcium and Vitamin D during the study and maintain a daily logbook of their dietary consumption Women who are pregnant or lactating and women participants of childbearing age not willing to utilize a barrier method of birth control (sterilization will be acceptable) Subjects with allergies to rifampin, clarithromycin or grapefruit juice Potential participants will be excluded if they are concurrently participating in another research study Subjects with corrected QTc interval > 430 ms in men or > 450 ms in women on electrocardiogram

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 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: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Water<br>200 mL of water once a day for 14 days | Other: Placebo<br> <br> |
| Active Comparator: Rifampin<br>Rifampin 600 mg once a day for 14 days | Drug: Rifampin<br>* P450 inducer<br>* Other names: Rifadin;|
| Active Comparator: Grapefruit Juice<br>200 mL of grapefruit juice once a day for 14 days | Other: Grapefruit Juice<br>* CYP3A4 inhibitor in intestine<br>|
| Active Comparator: Grapefruit Juice Plus Rifampin<br>200 mL of grapefruit juice once a day for 8 days plus rifampin 600 mg once a day for 14 days | Drug: Rifampin<br>* P450 inducer<br>* Other names: Rifadin;Other: Grapefruit Juice<br>* CYP3A4 inhibitor in intestine<br>|
| Active Comparator: Clarithromycin<br>Clarithromycin 250 mg twice a day for 14 days | Drug: Clarithromycin<br>* CYP3A4 and Pgp inhibitor in both intestine and liiver<br>* Other names: Biaxin;|
| Active Comparator: Clarithromycin Plus Rifampin<br>Clarithromycin 250 mg twice a day for 14 days plus rifampin 600 mg once a day for 14 days | Drug: Rifampin<br>* P450 inducer<br>* Other names: Rifadin;Drug: Clarithromycin<br>* CYP3A4 and Pgp inhibitor in both intestine and liiver<br>* Other names: Biaxin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 1, 25(OH) D3 Vitamin D | Serum 1, 25(OH) D3 Vitamin D | Samples will be collected on days 1, 4 and 7, and day 22 (last day of intervention). Treatment began on day 8. Data presented is day 22 concentration - Baseline (the average of day 1, day 4 and day 7 concentrations). | 
| 25(OH) D3 Vitamin D | Serum 25(OH) D3 Vitamin D | Samples will be collected on days 1, 4 and 7, and day 22 (last day of intervention). Treatment began on day 8. Data presented is day 22 concentration - Baseline (the average of day 1, day 4 and day 7 concentrations). | 
| Parathyroid Hormone | Blood Parathyroid Hormone | Samples will be collected on days 1, 4 and 7, and day 22 (last day of intervention). Treatment began on day 8. Data presented is day 22 concentration - Baseline (the average of day 1, day 4 and day 7 concentrations). | 
| Osteocalcin | Serum Osteocalcin | Samples will be collected on days 1, 4 and 7, and day 22 (last day of intervention). Treatment began on day 8. Data presented is day 22 concentration - Baseline (the average of day 1, day 4 and day 7 concentrations). | 
| Calcium, Ionized | Serum | Samples will be collected on days 1, 4 and 7, and day 22 (last day of intervention). Treatment began on day 8. Data presented is day 22 concentration - Baseline (the average of day 1, day 4 and day 7 concentrations). | 
| Calcium/Creatinine (mg/g) | Urine Calcium/Creatinine (mg/g) | Samples will be collected on days 1, 4 and 7, and day 22 (last day of intervention). Treatment began on day 8. Data presented is day 22 concentration - Baseline (the average of day 1, day 4 and day 7 concentrations). | 
| Phosphate/Creatinine (mg/g) | Urine Phosphate/Creatinine(mg/g) | Samples will be collected on days 1, 4 and 7, and day 22 (last day of intervention). Treatment began on day 8. Data presented is day 22 concentration - Baseline (the average of day 1, day 4 and day 7 concentrations). | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Vitamin D, CYP3A4, Calcium