Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands.
Department of Psychiatric and Mental Healthcare, West Noord Brabant, The Netherlands.
Diabetes Obes Metab. 2020 Jun;22(6):916-921. doi: 10.1111/dom.13976. Epub 2020 Feb 17.
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.
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.
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).
An individual's exposure to dapagliflozin is consistent upon re-exposure and correlates with pharmacodynamic response in renal risk markers.
定量评估个体再次暴露于达格列净时其血浆暴露的一致性，并探讨个体对达格列净的系统暴露是否可以解释达格列净对多种肾脏风险标志物的反应存在个体间差异。
本研究数据来自一项交叉随机临床试验，该试验评估了达格列净对 33 名 2 型糖尿病合并白蛋白尿升高患者的降低白蛋白尿作用。其中 15 名参与者接受了两次达格列净暴露。在稳态时，为每位参与者测量达格列净的谷血浆浓度。通过液相色谱串联质谱法测量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。使用线性混合效应模型来量化暴露-反应关系。
首次和第二次暴露于达格列净后的血浆浓度中位数分别为 5.3ng/mL 和 4.6ng/mL（P=0.78）。两次之间的 Lin 一致性相关系数为 0.73（P<0.0021）。达格列净血浆浓度曲线下面积每增加 100ng·h/mL，尿白蛋白/肌酐比值的对数值（β=-5.9，P<0.01）、体重（β=-0.3，P<0.01）和估算肾小球滤过率（β=-0.7，P=0.01）降低，尿葡萄糖排泄增加（β=17.0，P<0.001）。
个体再次暴露于达格列净时的暴露情况是一致的，并与肾脏风险标志物的药效反应相关。
