Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, PO Box 30 001, 9700 RB, Groningen, The Netherlands.
Clinical Pharmacy, Martini Hospital, Groningen, The Netherlands.
Clin Pharmacokinet. 2021 Apr;60(4):517-525. doi: 10.1007/s40262-020-00956-1. Epub 2021 Feb 15.
Dapagliflozin, a sodium-glucose co-transporter inhibitor, was originally developed as an oral glucose-lowering drug for the treatment of type 2 diabetes mellitus. Emerging data suggest that cardiovascular and kidney benefits extend to patients without diabetes. Limited pharmacological data are, however, available in patients without diabetes. We aimed to characterise the pharmacokinetic profile of dapagliflozin in patients with chronic kidney disease without type 2 diabetes.
Plasma samples were collected in a randomised, placebo-controlled, double-blind, cross-over trial (DIAMOND, NCT03190694, n = 53) that assessed the effects of 10 mg of dapagliflozin in patients with a glomerular filtration rate ≥ 25 mL/min/1.73 m and proteinuria > 500 mg/day. Mixed-effects models were used to develop a pharmacokinetic model and to evaluate the association between plasma exposure and response.
Plasma concentrations (n = 430 observations) from 48 patients (mean age 50.8 years, mean glomerular filtration rate 57.9 mL/min/1.73 m, median proteinuria 1115 mg/24 h) were best described using a two-compartment model with first-order elimination. Apparent clearance and volume of distribution were 11.7 (95% confidence interval 10.7-12.7) L/h and 44.9 (95% confidence interval 39.0-50.9) L, respectively. Median dapagliflozin plasma exposure was 740.9 ng h/mL (2.5th-97.5th percentiles: 434.0-1615.3). Plasma exposure increased with decreasing kidney function. Every 100-ng h/mL increment in dapagliflozin plasma exposure was associated with a decrease in the urinary albumin:creatinine ratio (β = - 2.8%, p = 0.01), glomerular filtration rate (β = - 0.5 mL/min/1.73 m, p < 0.01) and systolic blood pressure (β = - 0.4 mmHg, p = 0.03).
The dapagliflozin plasma concentration-time profile in patients with non-diabetic kidney disease appears similar to the profile of patients with diabetic kidney disease described in the literature. Furthermore, the plasma exposure was associated with changes in risk markers for kidney disease.
达格列净是一种钠-葡萄糖协同转运蛋白抑制剂，最初被开发为治疗 2 型糖尿病的口服降糖药物。新出现的数据表明，心血管和肾脏益处可扩展至无糖尿病的患者。然而，在无糖尿病的患者中，达格列净的药理学数据有限。我们旨在描述慢性肾脏病且无 2 型糖尿病患者的达格列净药代动力学特征。
在一项随机、安慰剂对照、双盲、交叉试验（DIAMOND，NCT03190694，n=53）中采集了血浆样本，该试验评估了 10 mg 达格列净对肾小球滤过率≥25 mL/min/1.73 m 和蛋白尿>500 mg/天的患者的影响。使用混合效应模型来建立药代动力学模型，并评估血浆暴露与反应之间的关系。
来自 48 名患者（平均年龄 50.8 岁，平均肾小球滤过率 57.9 mL/min/1.73 m，中位数蛋白尿 1115 mg/24 h）的 430 次观测的血浆浓度（n=430）最好用具有一级消除的两室模型来描述。表观清除率和分布容积分别为 11.7（95%置信区间 10.7-12.7）L/h 和 44.9（95%置信区间 39.0-50.9）L。达格列净的中位血浆暴露量为 740.9 ng·h/mL（2.5 至 97.5 百分位数：434.0-1615.3）。随着肾功能的降低，血浆暴露量增加。达格列净的血浆暴露量每增加 100-ng·h/mL，尿白蛋白/肌酐比值（β=-2.8%，p=0.01）、肾小球滤过率（β=-0.5 mL/min/1.73 m，p<0.01）和收缩压（β=-0.4 mmHg，p=0.03）均降低。
非糖尿病肾病患者的达格列净血浆浓度-时间曲线与文献中描述的糖尿病肾病患者的曲线相似。此外，血浆暴露与肾脏疾病风险标志物的变化相关。
