search
Back to results

Drug Metabolizing Enzyme and Transporter Function in Chronic Kidney Disease

Primary Purpose

Chronic Kidney Diseases, Deficiency, Vitamin D

Status
Completed
Phase
Not Applicable
Locations
United States
Study Type
Interventional
Intervention
Cholecalciferol
Sponsored by
University of Colorado, Denver
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional other trial for Chronic Kidney Diseases

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)All SexesAccepts Healthy Volunteers

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

Sites / Locations

  • University of Colorado
  • University of Pittsburgh

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Arm 1: Drug Metabolism and Transport

Arm 2: Vitamin D Pharmacokinetics

Arm Description

The aim of Arm 1 is to determine the effect of vitamin D deficiency and repletion on xenobiotic clearance in vivo. The study will evaluate the in vivo function of targeted metabolism and transport pathways in 40 CKD and 18 healthy volunteer subjects (controls) under the influence of a vitamin D depleted state and repeated under a vitamin D replete state with cholecalciferol. The function of two major phase I drug metabolizing enzymes (CYP2B6, CYP3A), and three transporters [P-gp, MRP2, and MATE1/2K] will be assessed by administering oral bupropion, midazolam, olmesartan, and fexofenadine.

The aim of Arm 2 is to determine the effect of CKD on the in vivo function of individual CYP450s responsible for vitamin D metabolism and their functional relevance on the pharmacokinetics of cholecalciferol. A total of 90 CKD subjects will be enrolled [30 per group: group I (CKD stage 1/2), group II (CKD stage 3), and group III (CKD stage 4/5, pre-ESRD)], as well as 30 healthy controls.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.

Full Information

First Posted
December 19, 2014
Last Updated
June 29, 2021
Sponsor
University of Colorado, Denver
Collaborators
University of Pittsburgh, National Institute of General Medical Sciences (NIGMS)
search

1. Study Identification

Unique Protocol Identification Number
NCT02360644
Brief Title
Drug Metabolizing Enzyme and Transporter Function in Chronic Kidney Disease
Official Title
Drug Metabolizing Enzyme and Transporter Function in Chronic Kidney Disease
Study Type
Interventional

2. Study Status

Record Verification Date
June 2021
Overall Recruitment Status
Completed
Study Start Date
October 2014 (undefined)
Primary Completion Date
February 1, 2019 (Actual)
Study Completion Date
February 1, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of Colorado, Denver
Collaborators
University of Pittsburgh, National Institute of General Medical Sciences (NIGMS)

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief 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.
Detailed 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Chronic Kidney Diseases, Deficiency, Vitamin D

7. Study Design

Primary Purpose
Other
Study Phase
Not Applicable
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
23 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Arm 1: Drug Metabolism and Transport
Arm Type
Experimental
Arm Description
The aim of Arm 1 is to determine the effect of vitamin D deficiency and repletion on xenobiotic clearance in vivo. The study will evaluate the in vivo function of targeted metabolism and transport pathways in 40 CKD and 18 healthy volunteer subjects (controls) under the influence of a vitamin D depleted state and repeated under a vitamin D replete state with cholecalciferol. The function of two major phase I drug metabolizing enzymes (CYP2B6, CYP3A), and three transporters [P-gp, MRP2, and MATE1/2K] will be assessed by administering oral bupropion, midazolam, olmesartan, and fexofenadine.
Arm Title
Arm 2: Vitamin D Pharmacokinetics
Arm Type
Experimental
Arm Description
The aim of Arm 2 is to determine the effect of CKD on the in vivo function of individual CYP450s responsible for vitamin D metabolism and their functional relevance on the pharmacokinetics of cholecalciferol. A total of 90 CKD subjects will be enrolled [30 per group: group I (CKD stage 1/2), group II (CKD stage 3), and group III (CKD stage 4/5, pre-ESRD)], as well as 30 healthy controls.
Intervention Type
Dietary Supplement
Intervention Name(s)
Cholecalciferol
Other Intervention Name(s)
Vitamin D
Intervention Description
Vitamin D deficient patients, in both Arms, will be administered Cholecalciferol 5,000 IU daily.
Primary Outcome Measure Information:
Title
Change in area under the plasma concentration time curves for probe drugs (bupropion, midazolam, olmesartan and fexofenadine) from baseline to 12 weeks.
Description
Change in area under the plasma concentration time curves for probe drugs (bupropion, midazolam, olmesartan, and fexofenadine) at 12 weeks.
Time Frame
12 weeks
Secondary Outcome Measure Information:
Title
Change in area under the plasma concentration time curves for cholecalciferol from baseline to 12 weeks.
Description
Change in area under the plasma concentration time curves for cholecalciferol at 12 weeks.
Time Frame
12 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Melanie Joy, PharmD, PhD
Organizational Affiliation
University of Colorado, Denver
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Colorado
City
Aurora
State/Province
Colorado
ZIP/Postal Code
80045
Country
United States
Facility Name
University of Pittsburgh
City
Pittsburgh
State/Province
Pennsylvania
ZIP/Postal Code
15261
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No

Learn more about this trial

Drug Metabolizing Enzyme and Transporter Function in Chronic Kidney Disease

We'll reach out to this number within 24 hrs