Drug Metabolizing Enzyme and Transporter Function in Chronic Kidney Disease

NCT02360644 | Completed DMC

• 3 other identifiers: 14-1150UL1TR0010821R01GM107122-01A1
• Study Type: interventional
• Target: 23
• Locations: 1 country
• Sites: 2

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.

Conditions

Chronic Kidney Diseases; Deficiency, Vitamin D

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (1)

• Change in area under the plasma concentration time curves for cholecalciferol from baseline to 12 weeks.

  12 weeks

Study Arms (2)

Arm 1: Drug Metabolism and Transport

EXPERIMENTAL

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

Arm 2: Vitamin D Pharmacokinetics

EXPERIMENTAL

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

Interventions

Cholecalciferol DIETARY_SUPPLEMENT

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

Also known as: Vitamin D

Arm 1: Drug Metabolism and Transport; Arm 2: Vitamin D Pharmacokinetics

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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)

Sponsors & Collaborators

• University of Colorado, Denver: lead
• University of Pittsburgh: collaborator
• National Institute of General Medical Sciences (NIGMS): collaborator

Study Sites (2)

University of Colorado

Aurora, Colorado, 80045, United States

Location

University of Pittsburgh

Pittsburgh, Pennsylvania, 15261, United States

Location

MeSH Terms

Conditions

Renal Insufficiency, Chronic; Vitamin D Deficiency

Interventions

Cholecalciferol; Vitamin D

Condition Hierarchy (Ancestors)

Renal Insufficiency; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Avitaminosis; Deficiency Diseases; Malnutrition; Nutrition Disorders; Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

Cholestenes; Cholestanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Sterols; Secosteroids; Membrane Lipids; Lipids

Study Officials

• Melanie Joy, PharmD, PhD

  University of Colorado, Denver

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: OTHER
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 19, 2014
• First Posted: February 10, 2015
• Study Start: October 1, 2014
• Primary Completion: February 1, 2019
• Study Completion: February 1, 2019
• Last Updated: June 30, 2021

Record last verified: 2021-06

Data Sharing

• IPD Sharing: Will not share

Locations

US (2)