Drug Metabolizing Enzyme and Transporter Function in Chronic Kidney Disease

NCT ID: NCT02360644

Last Updated: 2021-06-30

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 23 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-10-31
• Study Completion Date: 2019-02-01

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.

Conditions

Chronic Kidney Diseases; Deficiency, Vitamin D

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: OTHER
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

Cholecalciferol

Intervention Type: DIETARY_SUPPLEMENT

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

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.

Group Type: EXPERIMENTAL

Cholecalciferol

Intervention Type: DIETARY_SUPPLEMENT

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

Interventions

Cholecalciferol

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

Intervention Type: DIETARY_SUPPLEMENT

Other Intervention Names

Vitamin D

Eligibility Criteria

Inclusion Criteria

• 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

• 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

• 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

• 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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 70 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

University of Pittsburgh

OTHER

Sponsor Role: collaborator

National Institute of General Medical Sciences (NIGMS)

NIH

Sponsor Role: collaborator

University of Colorado, Denver

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Melanie Joy, PharmD, PhD

Role: PRINCIPAL_INVESTIGATOR

University of Colorado, Denver

Locations

University of Colorado

Aurora, Colorado, United States

University of Pittsburgh

Pittsburgh, Pennsylvania, United States

Countries

United States

Other Identifiers

UL1TR001082

Identifier Type: NIH

Identifier Source: secondary_id

View Link

1R01GM107122-01A1

Identifier Type: NIH

Identifier Source: secondary_id

View Link

14-1150

Identifier Type: -

Identifier Source: org_study_id