Kassir Nastya, Labbé Line, Delaloye Jean-Romain, Mouksassi Mohamad-Samer, Lapeyraque Anne-Laure, Alvarez Fernando, Lallier Michel, Beaunoyer Mona, Théorêt Yves, Litalien Catherine
Br J Clin Pharmacol. 2014 Jun;77(6):1051-63. doi: 10.1111/bcp.12276.
The objectives of this study were to develop a population pharmacokinetic (PopPK) model for tacrolimus in paediatric liver transplant patients and determine optimal sampling strategies to estimate tacrolimus exposure accurately.
Twelve hour intensive pharmacokinetic profiles from 30 patients (age 0.4-18.4 years) receiving tacrolimus orally were analysed. The PopPK model explored the following covariates: weight, age, sex, type of transplant, age of liver donor, liver function tests, albumin, haematocrit, drug interactions, drug formulation and time post-transplantation. Optimal sampling strategies were developed and validated with jackknife.
A two-compartment model with first-order absorption and elimination and lag time described the data. Weight was included on all pharmacokinetic parameters. Typical apparent clearance and central volume of distribution were 12.1 l h(-1) and 31.3 l, respectively. The PopPK approach led to the development of optimal sampling strategies, which allowed estimation of tacrolimus pharmacokinetics and area under the concentration–time curve (AUC) on the basis of practical sampling schedules (three or four sampling times within 4 h) with clinically acceptable prediction error limit. The mean bias and precision of the Bayesian vs. reference (trapezoidal) AUCs ranged from -2.8 to -1.9% and from 7.4 to 12.5%, respectively.
The PopPK of tacrolimus and empirical Bayesian estimates represent an accurate and convenient method to predict tacrolimus AUC(0-12) in paediatric liver transplant recipients, despite high between-subject variability in pharmacokinetics and patient demographics. The developed optimal sampling strategies will allow the undertaking of prospective trials to define the tacrolimus AUC-based therapeutic window and dosing guidelines in this population.
本研究的目的是建立小儿肝移植患者他克莫司的群体药代动力学（PopPK）模型，并确定能准确估算他克莫司暴露量的最佳采样策略。
分析了30例接受口服他克莫司患者（年龄0.4 - 18.4岁）的12小时密集药代动力学曲线。PopPK模型探讨了以下协变量：体重、年龄、性别、移植类型、肝供体年龄、肝功能检查、白蛋白、血细胞比容、药物相互作用、药物剂型和移植后时间。采用留一法开发并验证了最佳采样策略。
具有一级吸收、消除和滞后时间的二室模型描述了数据。所有药代动力学参数均纳入了体重因素。典型的表观清除率和中央分布容积分别为12.1 l h(-1)和31.3 l。PopPK方法导致了最佳采样策略的开发，该策略允许根据实际采样时间表（4小时内三或四个采样时间）估算他克莫司药代动力学和浓度 - 时间曲线下面积（AUC），且预测误差限度在临床可接受范围内。贝叶斯法与参考（梯形法）AUC的平均偏差和精密度分别在 - 2.8%至 - 1.9%和7.4%至12.5%之间。
尽管他克莫司药代动力学和患者人口统计学存在较高的个体间变异性，但他克莫司的PopPK和经验贝叶斯估计是预测小儿肝移植受者他克莫司AUC(0 - 12)的准确且便捷的方法。所开发的最佳采样策略将有助于开展前瞻性试验，以确定该人群基于他克莫司AUC的治疗窗和给药指南。
