Vitamin D and Calcium Homeostasis
Conditions
Keywords
Vitamin D, CYP3A4, Calcium
Brief summary
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
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.
Interventions
DRUGRifampin
P450 inducer
DRUGClarithromycin
CYP3A4 and Pgp inhibitor in both intestine and liiver
OTHERGrapefruit Juice
CYP3A4 inhibitor in intestine
OTHERPlacebo
Sponsors
National Institute of General Medical Sciences (NIGMS)
University of Washington
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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). | Serum 1, 25(OH) D3 Vitamin D |
| 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). | Serum 25(OH) D3 Vitamin D |
| 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). | Blood Parathyroid Hormone |
| 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). | Serum Osteocalcin |
| Calcium, Ionized | 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). | Serum |
| 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). | Urine Calcium/Creatinine (mg/g) |
| 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). | Urine Phosphate/Creatinine(mg/g) |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Water 200 mL of water once a day for 14 days
Placebo | 14 |
| Rifampin Rifampin 600 mg once a day for 14 days
Rifampin: P450 inducer | 16 |
| Grapefruit Juice 200 mL of grapefruit juice once a day for 14 days
Grapefruit Juice: CYP3A4 inhibitor in intestine | 15 |
| 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
Rifampin: P450 inducer
Grapefruit Juice: CYP3A4 inhibitor in intestine | 14 |
| Clarithromycin Clarithromycin 250 mg twice a day for 14 days
Clarithromycin: CYP3A4 and Pgp inhibitor in both intestine and liiver | 15 |
| Clarithromycin Plus Rifampin Clarithromycin 250 mg twice a day for 14 days plus rifampin 600 mg once a day for 14 days
Rifampin: P450 inducer
Clarithromycin: CYP3A4 and Pgp inhibitor in both intestine and liiver | 11 |
| Total | 85 |
Baseline characteristics
| Characteristic | Water | Rifampin | Grapefruit Juice | Grapefruit Juice Plus Rifampin | Clarithromycin | Clarithromycin Plus Rifampin | Total |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 27.5 years STANDARD_DEVIATION 6.6 | 29.5 years STANDARD_DEVIATION 8.3 | 32.1 years STANDARD_DEVIATION 11.1 | 29.9 years STANDARD_DEVIATION 9.1 | 28.1 years STANDARD_DEVIATION 9.3 | 27.3 years STANDARD_DEVIATION 8 | 29.2 years STANDARD_DEVIATION 8.8 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 2 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 14 Participants | 15 Participants | 14 Participants | 14 Participants | 15 Participants | 9 Participants | 81 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 3 Participants | 4 Participants | 4 Participants | 4 Participants | 0 Participants | 17 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 2 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 10 Participants | 11 Participants | 11 Participants | 9 Participants | 10 Participants | 11 Participants | 62 Participants |
| Sex: Female, Male Female | 8 Participants | 6 Participants | 13 Participants | 10 Participants | 9 Participants | 5 Participants | 51 Participants |
| Sex: Female, Male Male | 6 Participants | 10 Participants | 2 Participants | 4 Participants | 6 Participants | 6 Participants | 34 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 16 | 0 / 18 | 0 / 15 | 0 / 15 | 0 / 16 | 0 / 12 |
| other Total, other adverse events | 1 / 16 | 1 / 18 | 0 / 15 | 1 / 15 | 0 / 16 | 1 / 12 |
| serious Total, serious adverse events | 0 / 16 | 0 / 18 | 0 / 15 | 0 / 15 | 0 / 16 | 0 / 12 |
Outcome results
Primary
1, 25(OH) D3 Vitamin D
Serum 1, 25(OH) D3 Vitamin D
Time frame: 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).
Population: Comparison of treatment effect (end of treatment - baseline) between treatment groups.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Water | 1, 25(OH) D3 Vitamin D | 3.2 pM |
| Rifampin | 1, 25(OH) D3 Vitamin D | 1.7 pM |
| Grapefruit Juice | 1, 25(OH) D3 Vitamin D | 3.7 pM |
| Grapefruit Juice Plus Rifampin | 1, 25(OH) D3 Vitamin D | -3.3 pM |
| Clarithromycin | 1, 25(OH) D3 Vitamin D | -4.7 pM |
| Clarithromycin Plus Rifampin | 1, 25(OH) D3 Vitamin D | 0.4 pM |
p-value: 0.88495% CI: [-21.2, 18.3]Mixed Models Analysis
p-value: 0.95595% CI: [-19.5, 20.7]Mixed Models Analysis
p-value: 0.5395% CI: [-26.5, 13.6]Mixed Models Analysis
p-value: 0.43495% CI: [-27.6, 11.9]Mixed Models Analysis
p-value: 0.79695% CI: [-24.2, 18.6]Mixed Models Analysis
Primary
25(OH) D3 Vitamin D
Serum 25(OH) D3 Vitamin D
Time frame: 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).
Population: Comparison of treatment effect (end of treatment - baseline) between treatment groups.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Water | 25(OH) D3 Vitamin D | -3.1 nM |
| Rifampin | 25(OH) D3 Vitamin D | -4.3 nM |
| Grapefruit Juice | 25(OH) D3 Vitamin D | -1.3 nM |
| Grapefruit Juice Plus Rifampin | 25(OH) D3 Vitamin D | -1.6 nM |
| Clarithromycin | 25(OH) D3 Vitamin D | 0.6 nM |
| Clarithromycin Plus Rifampin | 25(OH) D3 Vitamin D | -5.0 nM |
p-value: 0.6295% CI: [-6, 3.6]Mixed Models Analysis
p-value: 0.48295% CI: [-3.1, 6.7]Mixed Models Analysis
p-value: 0.55995% CI: [-3.4, 6.4]Mixed Models Analysis
p-value: 0.13895% CI: [-1.2, 8.5]Mixed Models Analysis
p-value: 0.47795% CI: [-7.1, 3.3]Mixed Models Analysis
Primary
Calcium/Creatinine (mg/g)
Urine Calcium/Creatinine (mg/g)
Time frame: 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).
Population: Comparison of treatment effect (end of treatment - baseline) between treatment groups.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Water | Calcium/Creatinine (mg/g) | 3.4 ratio (mg/g) |
| Rifampin | Calcium/Creatinine (mg/g) | -9.2 ratio (mg/g) |
| Grapefruit Juice | Calcium/Creatinine (mg/g) | -41.1 ratio (mg/g) |
| Grapefruit Juice Plus Rifampin | Calcium/Creatinine (mg/g) | -3.8 ratio (mg/g) |
| Clarithromycin | Calcium/Creatinine (mg/g) | 6.3 ratio (mg/g) |
| Clarithromycin Plus Rifampin | Calcium/Creatinine (mg/g) | 41.4 ratio (mg/g) |
p-value: 0.5395% CI: [-52, 26.7]Mixed Models Analysis
p-value: 0.0395% CI: [-84.5, -4.5]Mixed Models Analysis
p-value: 0.7295% CI: [-47.3, 32.8]Mixed Models Analysis
p-value: 0.8995% CI: [-36.6, 42.2]Mixed Models Analysis
p-value: 0.0895% CI: [-4.7, 80.6]Mixed Models Analysis
Primary
Calcium, Ionized
Serum
Time frame: 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).
Population: Comparison of treatment effect (end of treatment - baseline) between treatment groups.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Water | Calcium, Ionized | 0.0 mM |
| Rifampin | Calcium, Ionized | -0.008 mM |
| Grapefruit Juice | Calcium, Ionized | -0.017 mM |
| Grapefruit Juice Plus Rifampin | Calcium, Ionized | -0.011 mM |
| Clarithromycin | Calcium, Ionized | -0.005 mM |
| Clarithromycin Plus Rifampin | Calcium, Ionized | -0.009 mM |
p-value: 0.4395% CI: [-0.027, 0.012]Mixed Models Analysis
p-value: 0.0995% CI: [-0.037, 0.003]Mixed Models Analysis
p-value: 0.2995% CI: [-0.031, 0.009]Mixed Models Analysis
p-value: 0.6195% CI: [-0.025, 0.015]Mixed Models Analysis
p-value: 0.4695% CI: [-0.03, 0.014]Mixed Models Analysis
Primary
Osteocalcin
Serum Osteocalcin
Time frame: 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).
Population: Comparison of treatment effect (end of treatment - baseline) between treatment groups.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Water | Osteocalcin | 0.0 ng/mL |
| Rifampin | Osteocalcin | -1.1 ng/mL |
| Grapefruit Juice | Osteocalcin | 0.7 ng/mL |
| Grapefruit Juice Plus Rifampin | Osteocalcin | 0.0 ng/mL |
| Clarithromycin | Osteocalcin | 3.7 ng/mL |
| Clarithromycin Plus Rifampin | Osteocalcin | 4.0 ng/mL |
p-value: 0.1795% CI: [-2.7, 0.5]Mixed Models Analysis
p-value: 0.4495% CI: [-1, 2.2]Mixed Models Analysis
p-value: 0.9495% CI: [-1.7, 1.6]Mixed Models Analysis
p-value: <0.000195% CI: [2.1, 5.2]Mixed Models Analysis
p-value: <0.000195% CI: [2.2, 5.6]Mixed Models Analysis
Primary
Parathyroid Hormone
Blood Parathyroid Hormone
Time frame: 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).
Population: Comparison of treatment effect (end of treatment - baseline) between treatment groups.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Water | Parathyroid Hormone | 0.3 pg/mL |
| Rifampin | Parathyroid Hormone | 0.4 pg/mL |
| Grapefruit Juice | Parathyroid Hormone | 1.6 pg/mL |
| Grapefruit Juice Plus Rifampin | Parathyroid Hormone | 1.0 pg/mL |
| Clarithromycin | Parathyroid Hormone | 2.7 pg/mL |
| Clarithromycin Plus Rifampin | Parathyroid Hormone | 0.6 pg/mL |
p-value: 0.9895% CI: [-11, 11.3]Mixed Models Analysis
p-value: 0.8195% CI: [-10, 12.7]Mixed Models Analysis
p-value: 0.9195% CI: [-10.8, 12.2]Mixed Models Analysis
p-value: 0.6895% CI: [-8.9, 13.8]Mixed Models Analysis
p-value: 0.9695% CI: [-11.9, 12.6]Mixed Models Analysis
Primary
Phosphate/Creatinine (mg/g)
Urine Phosphate/Creatinine(mg/g)
Time frame: 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).
Population: Comparison of treatment effect (end of treatment - baseline) between treatment groups.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Water | Phosphate/Creatinine (mg/g) | 8.3 ratio (mg/g) |
| Rifampin | Phosphate/Creatinine (mg/g) | 11.1 ratio (mg/g) |
| Grapefruit Juice | Phosphate/Creatinine (mg/g) | 23.3 ratio (mg/g) |
| Grapefruit Juice Plus Rifampin | Phosphate/Creatinine (mg/g) | 79.6 ratio (mg/g) |
| Clarithromycin | Phosphate/Creatinine (mg/g) | 5.5 ratio (mg/g) |
| Clarithromycin Plus Rifampin | Phosphate/Creatinine (mg/g) | 60.0 ratio (mg/g) |
p-value: 0.9695% CI: [-104.5, 110.2]Mixed Models Analysis
p-value: 0.7995% CI: [-94.2, 124.2]Mixed Models Analysis
p-value: 0.295% CI: [-37.9, 180.5]Mixed Models Analysis
p-value: 0.9695% CI: [-110.1, 104.7]Mixed Models Analysis
p-value: 0.3895% CI: [-64.7, 168.2]Mixed Models Analysis