Faculty of Pharmacy, Université de Montréal, Montreal, Quebec, Canada.
Montreal Heart Institute, Montreal, Quebec, Canada.
Clin Transl Sci. 2021 Jan;14(1):194-203. doi: 10.1111/cts.12842. Epub 2020 Aug 28.
Heart failure (HF) causes pathological changes in multiple organs, thus affecting the pharmacokinetics (PK) of drugs. The aim of this study was to investigate the PK of candesartan in patients with HF while examining significant covariates and their related impact on estimated clearance using a population PK (Pop-PK) modeling approach. Data from a prospective, multicenter study were used. Modeling and simulations were conducted using Nonlinear Mixed-Effects Modeling (NONMEM) and R software. A total of 281 white patients were included to develop the Pop-PK model. The final model developed for apparent oral clearance (CL/F) included weight, estimated glomerular filtration rate (eGFR), and diabetes, which partly explained its interindividual variability. The mean CL/F value estimated was 7.6 L/h (1.7-22.6 L/h). Simulations revealed that an important decrease in CL/F (> 25%) is obtained with the combination of the factors retained in the final model. Considering these factors, a more individualized approach of candesartan dosing should be investigated in patients with HF.
心力衰竭（HF）会引起多个器官的病理变化，从而影响药物的药代动力学（PK）。本研究旨在通过群体 PK（Pop-PK）建模方法研究心力衰竭患者坎地沙坦的 PK，同时考察重要的协变量及其对估计清除率的相关影响。研究使用了一项前瞻性、多中心研究的数据。使用非线性混合效应建模（NONMEM）和 R 软件进行建模和模拟。共纳入 281 名白人患者来建立 Pop-PK 模型。最终建立的表观口服清除率（CL/F）模型包括体重、估算肾小球滤过率（eGFR）和糖尿病，这些因素部分解释了其个体间的变异性。估计的平均 CL/F 值为 7.6 L/h（1.7-22.6 L/h）。模拟结果表明，保留在最终模型中的因素的组合会导致 CL/F 显著下降（>25%）。考虑到这些因素，应该在心力衰竭患者中研究更个体化的坎地沙坦给药方法。
