Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center.
Division of Pharmaceutical Sciences, James L. Winkle College of Pharmacy, University of Cincinnati; and.
Ther Drug Monit. 2023 Jun 1;45(3):376-382. doi: 10.1097/FTD.0000000000001045. Epub 2023 Jan 10.
Considerable interpatient and interoccasion variability has been reported in tacrolimus pharmacokinetics (PK) in the pediatric renal transplant population. This study investigated tacrolimus PK in a 2-year-old post-renal transplant patient and a known CYP3A5 expresser who developed posterior reversible encephalopathy syndrome (PRES) and had significantly elevated tacrolimus blood concentrations during tacrolimus treatment. A model-informed PK assessment was performed to assist with precision dosing. Tacrolimus clearance was evaluated both before and after the development of PRES on post-transplant day (PTD) 26.
A retrospective chart review was conducted to gather dosing data and tacrolimus concentrations, as part of a clinical pharmacology consultation service. Individual PK parameters were estimated by Bayesian estimation using a published pediatric PK model. Oral clearance (CL/F) was estimated for 3 distinct periods-before CNS symptoms (PTD 25), during the PRES event (PTD 27-30), and after oral tacrolimus was restarted (PTD 93).
Bayesian estimation showed an estimated CL/F of 15.0 L/h in the days preceding the PRES event, compared with a population mean of 16.3 L/h (95% confidence interval 14.9-17.7 L/h) for CYP3A5 expressers of the same age and weight. Samples collected on PTD 27-30 yielded an estimated CL/F of 3.6 L/h, a reduction of 76%, coinciding with clinical confirmation of PRES and therapy discontinuation. On PTD 93, an additional assessment showed a stable CL/F value of 14.5 L/h 1 month after reinitiating tacrolimus and was used to recommend a continued maintenance dose.
This is the first report to demonstrate acutely decreased tacrolimus clearance in PRES, likely caused by the downregulation of metabolizing enzymes in response to inflammatory cytokines. The results suggest the ability of model-informed Bayesian estimation to characterize an acute decline in oral tacrolimus clearance after the development of PRES and the role that PK estimation may play in supporting dose selection and individualization.
在儿科肾移植人群中，已报道他克莫司药代动力学（PK）存在较大的个体间和个体间变异性。本研究调查了一名 2 岁肾移植后患者的他克莫司 PK，该患者为已知的 CYP3A5 表达者，在他克莫司治疗期间发生了后部可逆性脑病综合征（PRES），并出现显著升高的他克莫司血药浓度。进行了模型指导的 PK 评估以协助精准给药。在移植后第 26 天（PTD）出现 PRES 之前和之后评估了他克莫司清除率。
作为临床药理学咨询服务的一部分，进行了回顾性图表审查以收集剂量数据和他克莫司浓度。使用已发表的儿科 PK 模型通过贝叶斯估计估算个体 PK 参数。在 3 个不同时期分别估算了口服清除率（CL/F）-在 CNS 症状之前（PTD 25），在 PRES 事件期间（PTD 27-30）以及在重新开始口服他克莫司后（PTD 93）。
贝叶斯估计显示，在 PRES 事件之前的日子里，估计的 CL/F 为 15.0 L/h，而同一年龄和体重的 CYP3A5 表达者的人群平均值为 16.3 L/h（95%置信区间 14.9-17.7 L/h）。在 PTD 27-30 采集的样本得出估计的 CL/F 为 3.6 L/h，减少了 76%，与 PRES 的临床确认和治疗中断同时发生。在 PTD 93，进一步的评估显示，在重新开始使用他克莫司 1 个月后，CL/F 值稳定在 14.5 L/h，这用于推荐维持剂量。
这是首次报道 PRES 中他克莫司清除率急性下降，可能是由于代谢酶对细胞因子的下调而导致。结果表明，模型指导的贝叶斯估计能够描述 PRES 发生后口服他克莫司清除率的急性下降，以及 PK 估计在支持剂量选择和个体化方面可能发挥的作用。
