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Drug Metabolizing Enzyme and Transporter Function in Chronic Kidney Disease

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ClinicalTrials.gov Identifier: NCT02360644
Recruitment Status : Recruiting
First Posted : February 10, 2015
Last Update Posted : September 18, 2018
Sponsor:
Collaborators:
University of Pittsburgh
National Institute of General Medical Sciences (NIGMS)
Information provided by (Responsible Party):
University of Colorado, Denver

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.


Condition or disease Intervention/treatment Phase
Chronic Kidney Diseases Deficiency, Vitamin D Dietary Supplement: Cholecalciferol Not Applicable

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 120 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Other
Official Title: Drug Metabolizing Enzyme and Transporter Function in Chronic Kidney Disease
Study Start Date : October 2014
Estimated Primary Completion Date : March 2019
Estimated Study Completion Date : August 2019

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Arm 1: Drug Metabolism and Transport

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.

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

Experimental: Arm 2: Vitamin D Pharmacokinetics
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.
Dietary Supplement: Cholecalciferol
Vitamin D deficient patients, in both Arms, will be administered Cholecalciferol 5,000 IU daily.
Other Name: Vitamin D




Primary Outcome Measures :
  1. Change in area under the plasma concentration time curves for probe drugs (bupropion, midazolam, olmesartan and fexofenadine) from baseline to 12 weeks. [ Time Frame: 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 :
  1. Change in area under the plasma concentration time curves for cholecalciferol from baseline to 12 weeks. [ Time Frame: 12 weeks ]
    Change in area under the plasma concentration time curves for cholecalciferol at 12 weeks.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02360644


Contacts
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Contact: Melanie Joy, PharmD, PhD 303-724-7416 melanie.joy@ucdenver.edu
Contact: Thomas Nolin, PharmD, PhD 412-624-4683 Nolin@pitt.edu

Locations
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United States, Colorado
University of Colorado Not yet recruiting
Aurora, Colorado, United States, 80045
Contact: Melanie Joy, Pharm D, PhD    303-724-7416    melanie.joy@ucdenver.edu   
United States, Pennsylvania
University of Pittsburgh Recruiting
Pittsburgh, Pennsylvania, United States, 15261
Contact: Thomas Nolin, PharmD, PhD    412-624-4683    nolin@pitt.edu   
Sponsors and Collaborators
University of Colorado, Denver
University of Pittsburgh
National Institute of General Medical Sciences (NIGMS)
Investigators
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Principal Investigator: Melanie Joy, PharmD, PhD University of Colorado, Denver

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Responsible Party: University of Colorado, Denver
ClinicalTrials.gov Identifier: NCT02360644     History of Changes
Other Study ID Numbers: 14-1150
UL1TR001082 ( U.S. NIH Grant/Contract )
1R01GM107122-01A1 ( U.S. NIH Grant/Contract )
First Posted: February 10, 2015    Key Record Dates
Last Update Posted: September 18, 2018
Last Verified: September 2018

Additional relevant MeSH terms:
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Kidney Diseases
Renal Insufficiency, Chronic
Avitaminosis
Vitamin D Deficiency
Urologic Diseases
Renal Insufficiency
Deficiency Diseases
Malnutrition
Nutrition Disorders
Vitamins
Vitamin D
Ergocalciferols
Cholecalciferol
Micronutrients
Nutrients
Growth Substances
Physiological Effects of Drugs
Bone Density Conservation Agents
Calcium-Regulating Hormones and Agents