Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
Institute of Clinical Pharmacology, Santa Maria della Misericordia University, ASUIUD, Udine, Italy.
Clin Pharmacokinet. 2018 Nov;57(11):1399-1405. doi: 10.1007/s40262-018-0638-5.
Valganciclovir is used as oral prophylaxis for cytomegalovirus (CMV) infection in kidney transplant recipients. However, limited pharmacokinetic data exist to guide dosing in this patient group. This study aimed to describe the population pharmacokinetics of valganciclovir in a large sample of kidney transplant recipients and predict optimal dosing based on Monte Carlo simulations.
Therapeutic drug monitoring (TDM) data from adult kidney transplant recipients who received valganciclovir prophylaxis during a 10-year study period were collected retrospectively. A non-parametric pharmacokinetic analysis and Monte Carlo simulations to determine the probabilities of reaching an area under the drug concentration-time curve (AUC) target of 40-50 mg·h/L with various dosing regimens at different levels of renal function were conducted using the Pmetrics™ package for R.
This study included 792 ganciclovir concentration measurements derived from 97 patients. A one-compartment oral absorption model best described the data. The final covariate model was as follows: CL(ganciclovir) = TVCL × (CL/51), where CL is the clearance, TVCL is the typical value of ganciclovir clearance, creatinine clearance (CL) according to the Cockcroft-Gaultt equation and 51 is the mean CL determined in the study. In the simulations, the probability of reaching the targeted AUC was insufficient when using the recommended dosing regimens for prophylaxis, especially in patients with impaired renal function at CL < 50 mL/min.
Higher doses of valganciclovir corrected to renal function are suggested for use as oral prophylaxis for CMV infection in kidney transplant recipients. Further study is required to establish TDM targets to ensure adequate drug concentrations while avoiding potentially toxic drug exposures.
缬更昔洛韦被用作肾移植受者巨细胞病毒（CMV）感染的口服预防药物。然而，目前仅有有限的药代动力学数据可用于指导该患者人群的剂量。本研究旨在描述一个大样本肾移植受者群体中缬更昔洛韦的群体药代动力学，并基于蒙特卡罗模拟预测最佳给药剂量。
本研究回顾性收集了在为期 10 年的研究期间接受缬更昔洛韦预防治疗的成年肾移植受者的治疗药物监测（TDM）数据。使用 R 中的 Pmetrics 软件包进行非参数药代动力学分析和蒙特卡罗模拟，以确定在不同肾功能水平下，各种剂量方案达到 40-50 mg·h/L 药物浓度-时间曲线下面积（AUC）目标的概率。
本研究纳入了 97 名患者的 792 次更昔洛韦浓度测量值。单室口服吸收模型最能描述数据。最终的协变量模型如下：CL（更昔洛韦）= TVCL×（CL/51），其中 CL 为清除率，TVCL 为更昔洛韦清除率的典型值，根据 Cockcroft-Gault 方程计算的肌酐清除率（CL）和 51 为研究中确定的平均 CL。在模拟中，当使用推荐的预防剂量方案时，达到目标 AUC 的概率不足，尤其是在 CL<50 mL/min 的肾功能受损患者中。
建议根据肾功能调整更高剂量的缬更昔洛韦作为肾移植受者 CMV 感染的口服预防药物。需要进一步研究以确定 TDM 目标，在确保药物浓度充足的同时避免潜在的药物毒性暴露。
