Department of Clinical Pharmacy and Toxicology, Leiden University Medical Centre, Leiden, Netherlands.
Department of Gastroenterology and Hepatology, Leiden University Medical Centre, Leiden, Netherlands.
Br J Clin Pharmacol. 2021 Nov;87(11):4262-4272. doi: 10.1111/bcp.14842. Epub 2021 May 4.
Meltdose tacrolimus (Envarsus) is marketed as a formulation with a more consistent exposure. Due to the narrow therapeutic window, therapeutic drug monitoring is essential to maintain adequate exposure. The primary objective of this study was to develop a population pharmacokinetic (PK) model of Envarsus among liver transplant patients and select a limited sampling strategy (LSS) for AUC estimation. The secondary objective was to investigate potential covariates including CYP3A/IL genotype suitable for initial dose optimization when converting to Envarsus.
Adult liver transplant patients were converted from prolonged release tacrolimus (Advagraf) to Envarsus and blood samples were obtained using whole blood and dried blood spot sampling. Subsequently the population PK parameters were estimated using nonlinear-mixed effect modelling. Demographic factors, and recipient and donor CYP3A4, CYP3A5, IL-6, -10 and -18 genotype were tested as potential covariates to explain interindividual variability.
Fifty-five patients were included. A 2-compartment model with delayed absorption was the most suitable to describe population PK parameters. The population PK parameters were as follows: clearance, 3.27 L/h; intercompartmental clearance, 9.6 L/h; volume of distribution of compartments 1 and 2, 95 and 500 L, respectively. No covariates were found to significantly decrease interindividual variability. The best 3-point LSS was t = 0,4,8 with a median bias of 1.8% (-12.5-12.5).
The LSS can be used to adequately predict the AUC. No clinically relevant covariates known to influence the PK of Envarsus, including CYP3A status, were identified and therefore do not seem useful for initial dose optimization.
稳可信（Envarsus）是一种具有更稳定暴露量的制剂，以作为他克莫司的一种剂型上市。由于治疗窗较窄，因此进行治疗药物监测对于维持足够的暴露量非常重要。本研究的主要目的是建立肝移植患者中 Envarsus 的群体药代动力学（PK）模型，并选择用于 AUC 估算的有限采样策略（LSS）。次要目的是研究潜在的协变量，包括在转换为 Envarsus 时适合初始剂量优化的 CYP3A/IL 基因型。
将成人肝移植患者从长期释放他克莫司（Advagraf）转换为 Envarsus，并使用全血和干血斑采样获取血样。随后，使用非线性混合效应建模来估算群体 PK 参数。测试人口统计学因素以及受体和供体 CYP3A4、CYP3A5、IL-6、-10 和-18 基因型是否适合作为潜在协变量，以解释个体间的变异性。
共纳入 55 例患者。具有延迟吸收的 2 室模型最适合描述群体 PK 参数。群体 PK 参数如下：清除率为 3.27 L/h；隔室间清除率为 9.6 L/h；第 1 和第 2 隔室的分布容积分别为 95 和 500 L。未发现协变量可显著降低个体间的变异性。最佳的 3 点 LSS 为 t = 0、4、8，中位数偏倚为 1.8%（-12.5-12.5）。
该 LSS 可用于充分预测 AUC。未发现已知影响 Envarsus PK 的临床相关协变量，包括 CYP3A 状态，因此对于初始剂量优化似乎没有用。
