CYP3A4 Activity and Mineral Homeostasis

Effect of Modulating CYP3A4 Activity on Mineral Homeostasis

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.

Study Overview

• Status: Completed
• Conditions: Vitamin D and Calcium Homeostasis
• Intervention / Treatment: Other: Placebo; Drug: Rifampin; Other: Grapefruit Juice; Drug: Clarithromycin

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 92
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• United States
  • Washington
    • Seattle, Washington, United States, 98195
      • University of Washington

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

6

Arms and Interventions

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

What is the study measuring?

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).

Collaborators and Investigators

• Sponsor: University of Washington
• Collaborators: National Institute of General Medical Sciences (NIGMS)

Study record dates

Study Major Dates

• Study Start: June 1, 2014
• Primary Completion (Actual): December 1, 2020
• Study Completion (Actual): December 1, 2020

Study Registration Dates

• First Submitted: December 18, 2013
• First Submitted That Met QC Criteria: December 18, 2013
• First Posted (Estimate): December 24, 2013

Study Record Updates

• Last Update Posted (Actual): April 19, 2023
• Last Update Submitted That Met QC Criteria: March 27, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Keywords: Vitamin D; Calcium; CYP3A4
• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-Bacterial Agents; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Leprostatic Agents; Protein Synthesis Inhibitors; 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; Clarithromycin
• Other Study ID Numbers: STUDY00001894; R01GM063666 (U.S. NIH Grant/Contract)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No