Drug Metabolizing Enzyme and Transporter Function in Chronic Kidney Disease
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 入组人数
- 23
- 试验地点
- 2
- 主要终点
- Change in area under the plasma concentration time curves for probe drugs (bupropion, midazolam, olmesartan and fexofenadine) from baseline to 12 weeks.
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Single Group
- 主要目的
- Other
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
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.
干预措施: Cholecalciferol (Dietary Supplement)
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.
干预措施: Cholecalciferol (Dietary Supplement)
结局指标
主要结局
Change in area under the plasma concentration time curves for probe drugs (bupropion, midazolam, olmesartan and fexofenadine) from baseline to 12 weeks.
时间窗: 12 weeks
Change in area under the plasma concentration time curves for probe drugs (bupropion, midazolam, olmesartan, and fexofenadine) at 12 weeks.
次要结局
- Change in area under the plasma concentration time curves for cholecalciferol from baseline to 12 weeks.(12 weeks)