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Clinical Trial Details — Status: Completed

Administrative data

NCT number NCT02360644
Other study ID # 14-1150
Secondary ID UL1TR0010821R01G
Status Completed
Phase N/A
First received
Last updated
Start date October 2014
Est. completion date February 1, 2019

Study information

Verified date June 2021
Source University of Colorado, Denver
Contact n/a
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial Summary

This study investigates the effect of vitamin D deficiency on drug metabolism and transport in patients with chronic kidney disease (CKD) and in healthy controls. The central hypothesis is that vitamin D concentrations independently affect metabolism and transport function in CKD patients. An over-arching goal of this proposal is to make drug therapies safer and more effective to reduce the significant morbidity and mortality in patients with CKD.


Description:

Specific Aim 1: Determine the effect of vitamin D deficiency and repletion on xenobiotic clearance in vivo. The study will mechanistically evaluate the function of major pathways of metabolism and transport by prospectively studying clearance phenotypes utilizing "probe" drugs commonly used for this purpose in CKD patients and healthy volunteers under vitamin D deficient and replete states. Bupropion, midazolam, olmesartan, fexofenadine, in addition to an endogenous probe (N-methylnicotinamide), will be used to phenotype major phase I drug metabolizing enzymes [cytochrome P450 2B6 (CYP2B6), cytochrome P450 3A4/5 (CYP3A4/5)], and transporters [multidrug resistance associated protein 2 (MRP2), P-glycoprotein (P-gp), and multidrug and toxin extrusion protein 1/2K (MATE1/2K)], respectively. Hypothesis: The in vivo function of individual pathways of xenobiotic metabolism and transport are affected by vitamin D status (and CKD). Specific Aim 2: Determine the effect of CKD on the in vivo function of individual CYPs responsible for vitamin D metabolism and the pharmacokinetics of cholecalciferol (vitamin D3). The research will prospectively measure the activity of CYP450s responsible for cholecalciferol metabolism, and simultaneously evaluate the pharmacokinetics (PK) of cholecalciferol after single- and multiple-dose administration to CKD patients (stages 1-5) and healthy volunteers. Hypothesis: CKD alters the activity of individual CYPs responsible for vitamin D metabolism, leading to modified clearance of cholecalciferol.


Recruitment information / eligibility

Status Completed
Enrollment 23
Est. completion date February 1, 2019
Est. primary completion date February 1, 2019
Accepts healthy volunteers Accepts Healthy Volunteers
Gender All
Age group 18 Years to 70 Years
Eligibility Inclusion criteria for CKD patients: - vitamin D deficient (<30 ng/mL) - hemoglobin >10 g/dL - willing to abstain from fruit juices or alcohol within 7 days of PK assessments - no changes in prescription or nonprescription medications within 4 wks of study start - age 18-70 yrs - If a diagnosis of CKD, must be due to diabetes mellitus or hypertension - Signed informed consent Inclusion Criteria for Healthy Controls: - vitamin D deficient (<30 ng/mL) - hemoglobin >10 g/dL - willing to abstain from fruit juices or alcohol within 7 days of PK assessments - no changes in prescription or nonprescription medications within 4 wks of study start - age 18-70 yrs - Signed informed consent Exclusion criteria for CKD patients: - History of >14 alcoholic drinks/wk - Not likely to be compliant with study visits - Pregnant or lactating - Predisposition to or history of hypercalcemia - History of allergy, sensitivity, or contraindication to probe drugs (seizures, drug metabolism interactions, etc) - Use of prescribed or nonprescribed therapies that could interact with probe drugs (including prototypical inhibitors or inducers) - Active autoimmune disease or active/recent infections requiring antimicrobial treatment within the previous 4 wks will be excluded to minimize inflammatory-mediated changes in vitamin D status and patient heterogeneity. - Presence of clinically significant hepatic insufficiency (total bilirubin greater than 1.5 times the upper limit of normal or transaminase (ALT, AST) elevations greater than 2 times the upper limit of the laboratory reference range or liver disease - Active seizure disorder or those patients receiving large doses of medications that are known to reduce seizure threshold - Currently receiving cholecalciferol or a vitamin D analogue Exclusion Criteria for Healthy Controls: - History of >14 alcoholic drinks/wk - Not likely to be compliant with study visits - Pregnant or lactating - Predisposition to or history of hypercalcemia - History of allergy, sensitivity, or contraindication to probe drugs (seizures, drug metabolism interactions, etc) - Use of prescribed or nonprescribed therapies that could interact with probe drugs (including prototypical inhibitors or inducers) - Active autoimmune disease or active/recent infections requiring antimicrobial treatment within the previous 4 wks will be excluded to minimize inflammatory-mediated changes in vitamin D status and patient heterogeneity. - Presence of clinically significant hepatic insufficiency (total bilirubin greater than 1.5 times the upper limit of normal or transaminase (ALT, AST) elevations greater than 2 times the upper limit of the laboratory reference range or liver disease - Active seizure disorder or those patients receiving large doses of medications that are known to reduce seizure threshold - Currently receiving cholecalciferol or a vitamin D analogue - Any clinical evidence of chronic kidney disease as defined by the National Kidney Foundation Dialysis Outcomes Quality Initiative (NKF DOQI) guidelines

Study Design


Intervention

Dietary Supplement:
Cholecalciferol
Vitamin D deficient patients, in both Arms, will be administered Cholecalciferol 5,000 IU daily.

Locations

Country Name City State
United States University of Colorado Aurora Colorado
United States University of Pittsburgh Pittsburgh Pennsylvania

Sponsors (3)

Lead Sponsor Collaborator
University of Colorado, Denver National Institute of General Medical Sciences (NIGMS), University of Pittsburgh

Country where clinical trial is conducted

United States, 

Outcome

Type Measure Description Time frame Safety issue
Primary Change in area under the plasma concentration time curves for probe drugs (bupropion, midazolam, olmesartan and fexofenadine) from baseline to 12 weeks. Change in area under the plasma concentration time curves for probe drugs (bupropion, midazolam, olmesartan, and fexofenadine) at 12 weeks. 12 weeks
Secondary Change in area under the plasma concentration time curves for cholecalciferol from baseline to 12 weeks. Change in area under the plasma concentration time curves for cholecalciferol at 12 weeks. 12 weeks
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