Department of Pharmacology and Toxicology, CHU Limoges, Limoges University Hospital, Limoges Cedex, 87042, France.
INSERM UMR 850, Limoges, France.
Clin Pharmacokinet. 2017 Dec;56(12):1491-1498. doi: 10.1007/s40262-017-0533-5.
A new once-daily formulation of tacrolimus (Envarsus) has recently been developed, with alleged different pharmacokinetics from previous tacrolimus formulations. The objectives of this study were to develop population pharmacokinetic models and Bayesian estimators based on limited sampling strategies for Envarsus in kidney and liver transplant recipients.
Full tacrolimus concentration-time profiles (13 samples) were drawn from 57 liver (113 profiles) and 49 kidney (97 profiles) graft recipients transplanted for at least 6 months and switched from Prograf to Envarsus. The two databases were split into a development (75%) and a validation (25%) dataset. Pharmacokinetic models characterised by a single compartment with first-order elimination and absorption in two phases described by a sum of two gamma distributions were developed using non-parametric (Pmetrics) and parametric (ITSIM) approaches in parallel. The best limited sampling strategy for each patient group was determined using the multiple model optimal algorithm. The performance of the models and derived Bayesian estimators was evaluated in the validation set.
The best limited sampling strategy was 0, 8 and 12 h post-dose, leading to a relative bias ± standard deviation (root-mean-square error) between observed and modelled inter-dose area under the curve in the validation dataset of: 0.32 ± 6.86% (6.87%) for ITSIM and 3.4 ± 13.4% (13.2%) for Pmetrics in kidney transplantation; and 0.89 ± 7.32% (7.38%) for ITSIM and -2.62 ± 8.65% (8.89%) for Pmetrics in liver transplantation.
Population pharmacokinetic models and Bayesian estimators for Envarsus in kidney and liver transplantation were developed and are now available online for area under the curve-based tacrolimus dose adjustment.
最近开发了一种新的他克莫司（Envarsus）每日一次的制剂，据称其药代动力学与之前的他克莫司制剂不同。本研究的目的是为至少接受过 6 个月肾和肝移植的患者开发基于有限采样策略的 Envarsus 的群体药代动力学模型和贝叶斯估算器。
从至少接受过 6 个月肾（49 例，97 例）和肝（57 例，113 例）移植且从普乐可复转为 Envarsus 的患者中采集了完整的他克莫司浓度-时间曲线（13 个样本）。两个数据库分为开发（75%）和验证（25%）数据集。使用非参数（Pmetrics）和参数（ITSIM）方法同时开发了具有单室一阶消除和两相吸收的双伽马分布模型，以描述药代动力学。使用多模型最优算法确定每个患者组的最佳有限采样策略。在验证集中评估模型和推导的贝叶斯估算器的性能。
最佳的有限采样策略为 0、8 和 12 小时给药后，在验证数据集内观察到的和模型预测的剂量间隔 AUC 之间的相对偏差±标准偏差（均方根误差）为：肾移植中 ITSIM 为 0.32±6.86%（6.87%），Pmetrics 为 3.4±13.4%（13.2%）；肝移植中 ITSIM 为 0.89±7.32%（7.38%），Pmetrics 为-2.62±8.65%（8.89%）。
开发了用于肾和肝移植的 Envarsus 的群体药代动力学模型和贝叶斯估算器，现在可以在线提供基于 AUC 的他克莫司剂量调整。
