人群药代动力学模型研究慢性肾脏病对替诺福韦艾拉酚胺给药后替诺福韦暴露的影响。
Population pharmacokinetic modelling to characterize the effect of chronic kidney disease on tenofovir exposure after tenofovir alafenamide administration.
机构信息
Service and Laboratory of Clinical Pharmacology, Department of Laboratory Medicine and Pathology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, Zurich, Switzerland.
出版信息
J Antimicrob Chemother. 2023 Jun 1;78(6):1433-1443. doi: 10.1093/jac/dkad103.
BACKGROUND
Tenofovir alafenamide is gradually replacing tenofovir disoproxil fumarate, both prodrugs of tenofovir, in HIV prevention and treatment. There is thus an interest in describing tenofovir pharmacokinetics (PK) and its variability in people living with HIV (PLWH) under tenofovir alafenamide in a real-life setting.
OBJECTIVES
To characterize the usual range of tenofovir exposure in PLWH receiving tenofovir alafenamide, while assessing the impact of chronic kidney disease (CKD).
METHODS
We conducted a population PK analysis (NONMEM®) on 877 tenofovir and 100 tenofovir alafenamide concentrations measured in 569 PLWH. Model-based simulations allowed prediction of tenofovir trough concentrations (Cmin) in patients having various levels of renal function.
RESULTS
Tenofovir PK was best described using a one-compartment model with linear absorption and elimination. Creatinine clearance (CLCR, estimated according to Cockcroft and Gault), age, ethnicity and potent P-glycoprotein inhibitors were statistically significantly associated with tenofovir clearance. However, only CLCR appeared clinically relevant. Model-based simulations revealed 294% and 515% increases of median tenofovir Cmin in patients with CLCR of 15-29 mL/min (CKD stage 3), and less than 15 mL/min (stage 4), respectively, compared with normal renal function (CLCR = 90-149 mL/min). Conversely, patients with augmented renal function (CLCR > 149 mL/min) had a 36% decrease of median tenofovir Cmin.
CONCLUSIONS
Kidney function markedly affects circulating tenofovir exposure after tenofovir alafenamide administration in PLWH. However, considering its rapid uptake into target cells, we suggest only a cautious increase of tenofovir alafenamide dosage intervals to 2 or 3 days only in case of moderate or severe CKD, respectively.
背景
替诺福韦艾拉酚胺（tenofovir alafenamide）逐渐取代了富马酸替诺福韦二吡呋酯（tenofovir disoproxil fumarate），这两种都是替诺福韦的前体药物，用于 HIV 的预防和治疗。因此，人们对替诺福韦艾拉酚胺在 HIV 感染者（PLWH）中的药代动力学（PK）及其变异性很感兴趣。
目的
描述替诺福韦艾拉酚胺治疗下 PLWH 的替诺福韦暴露的常见范围，并评估慢性肾脏病（CKD）的影响。
方法
我们对 569 例 PLWH 中的 877 个替诺福韦和 100 个替诺福韦艾拉酚胺浓度进行了群体 PK 分析（NONMEM®）。基于模型的模拟允许预测具有不同肾功能水平的患者的替诺福韦谷浓度（Cmin）。
结果
替诺福韦 PK 最好使用具有线性吸收和消除的单室模型来描述。根据 Cockcroft 和 Gault 估计的肌酐清除率（CLCR）、年龄、种族和强效 P-糖蛋白抑制剂与替诺福韦清除率呈统计学显著相关。然而，只有 CLCR 具有临床相关性。基于模型的模拟显示，与正常肾功能（CLCR = 90-149 mL/min）相比，CLCR 为 15-29 mL/min（CKD 第 3 期）和小于 15 mL/min（第 4 期）的患者的替诺福韦 Cmin 中位数分别增加了 294%和 515%。相反，肾功能增强（CLCR > 149 mL/min）的患者替诺福韦 Cmin 中位数降低了 36%。
结论
在 PLWH 中，肾功能显著影响替诺福韦艾拉酚胺给药后的循环替诺福韦暴露。然而，考虑到其快速被靶细胞摄取，我们建议仅在中度或重度 CKD 时，谨慎地将替诺福韦艾拉酚胺的给药间隔增加至 2 天或 3 天。
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