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Exposure-response relationships for the sodium-glucose co-transporter-2 inhibitor dapagliflozin with regard to renal risk markers.
Diabetes, Obesity and Metabolism ( IF 5.4 ) Pub Date : 2020-02-17 , DOI: 10.1111/dom.13976
Marjolein Y A M Kroonen 1 , Jeroen V Koomen 1 , Sergei I Petrykiv 2 , Gozewijn D Laverman 3 , Hiddo J L Heerspink 1 , Jasper Stevens
Affiliation  

AIMS To quantitate the consistency of an individual's plasma exposure to dapagliflozin upon re-exposure, and to investigate whether the individual's systemic exposure to dapagliflozin explains inter-individual variation in response to dapagliflozin with regard to multiple renal risk markers. METHODS Data were used from a crossover randomized clinical trial that assessed the albuminuria-lowering effect of dapagliflozin in 33 people with type 2 diabetes and elevated albuminuria. Fifteen participants were exposed twice to dapagliflozin. Trough plasma concentrations of dapagliflozin were measured for each participant at steady state. Dapagliflozin plasma concentrations were measured by liquid chromatography tandem mass spectrometry, and pharmacokinetic characteristics were simulated based on a population pharmacokinetic model. Linear mixed-effects models were used to quantify the exposure-response relationships. RESULTS The median plasma concentration after first and second exposure to dapagliflozin was 5.3 ng/mL vs 4.6 ng/mL, respectively (P = 0.78). Lin's concordance correlation coefficient between occasions was 0.73 (P < 0.0021). Every 100 ng.h/mL increment in area under the dapagliflozin plasma concentration curve was associated with a decrease in log-transformed urinary albumin:creatinine ratio (β = -5.9, P < 0.01), body weight (β = -0.3, P < 0.01) and estimated glomerular filtration rate (β = -0.7, P = 0.01) and an increase in urinary glucose excretion (β = 17.0, P < 0.001). CONCLUSION An individual's exposure to dapagliflozin is consistent upon re-exposure and correlates with pharmacodynamic response in renal risk markers.

中文翻译:

钠-葡萄糖共转运蛋白2抑制剂dapagliflozin与肾脏风险标志物的暴露-反应关系。

目的定量重新暴露后个体血浆对达格列净的血浆暴露量的一致性,并调查该个体对达格列净的全身暴露量是否解释了针对多种肾脏风险标志物对达格列净的个体间差异。方法采用交叉随机临床试验的数据,该试验评估了达格列净对33例2型糖尿病和高蛋白尿症患者的降低蛋白尿的作用。15名参与者两次接受达格列净治疗。在稳定状态下,对每个参与者测量了达格列净的低谷血浆浓度。通过液相色谱串联质谱法测定达格列净的血浆浓度,并基于群体药代动力学模型模拟药代动力学特征。线性混合效应模型用于量化暴露-反应关系。结果首次和第二次达格列净暴露后的血浆中位数浓度分别为5.3 ng / mL和4.6 ng / mL(P = 0.78)。林之间的一致性相关系数为0.73(P <0.0021)。达格列净血浆浓度曲线下每增加100 ng.h / mL面积,对数转换的尿白蛋白:肌酐比值(β= -5.9,P <0.01),体重(β= -0.3,P <0.01)和估计的肾小球滤过率(β= -0.7,P = 0.01)和尿葡萄糖排泄增加(β= 17.0,P <0.001)。结论个人再次暴露于达格列净后的暴露是一致的,并且与肾脏危险标志物中的药效学反应相关。
更新日期:2020-02-17
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