Drug Metabolizing Enzyme and Transporter Function in Chronic Kidney Disease

Not Applicable

Completed

• Conditions: Deficiency, Vitamin D; Chronic Kidney Diseases
• Interventions: Dietary Supplement: Cholecalciferol

• Registration Number: NCT02360644
• Lead Sponsor: 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.

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.

Study Timeline

• Study Start: 2014-10
• Study First Submitted: 2014-12-19
• Study First Submitted QC: 2015-02-05
• Study First Posted: 2015-02-10
• Primary Completion: 2019-02-01
• Study Completion: 2019-02-01
• Status Verified: 2021-06
• Last Update Submitted: 2021-06-29
• Last Update Posted: 2021-06-30

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 23

Inclusion Criteria

Not provided

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Exclusion Criteria

Not provided

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Arm 2: Vitamin D Pharmacokinetics	Cholecalciferol	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.
Arm 1: Drug Metabolism and Transport	Cholecalciferol	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.

Primary Outcome Measures

Name	Time	Method
Change in area under the plasma concentration time curves for probe drugs (bupropion, midazolam, olmesartan and fexofenadine) from baseline to 12 weeks.	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

Name	Time	Method
Change in area under the plasma concentration time curves for cholecalciferol from baseline to 12 weeks.	12 weeks	Change in area under the plasma concentration time curves for cholecalciferol at 12 weeks.

Trial Locations

Locations (2)

University of Colorado; 🇺🇸 Aurora, Colorado, United States

University of Pittsburgh; 🇺🇸 Pittsburgh, Pennsylvania, United States