Department of Clinical Pharmacy, Assistance Publique - Hôpitaux de Paris, Hôpitaux Universitaires Paris-Sud, Le Kremlin Bicêtre, France.
Br J Clin Pharmacol. 2012 Sep;74(3):515-24. doi: 10.1111/j.1365-2125.2012.04213.x.
The aims were to estimate the mycophenolic acid (MPA) population pharmacokinetic parameters in paediatric liver transplant recipients, to identify the factors affecting MPA pharmacokinetics and to develop a limited sampling strategy to estimate individual MPA AUC(0,12 h).
Twenty-eight children, 1.1 to 18.0 years old, received oral mycophenolate mofetil (MMF) therapy combined with either tacrolimus (n= 23) or ciclosporin (n= 5). The population parameters were estimated from a model-building set of 16 intensive pharmacokinetic datasets obtained from 16 children. The data were analyzed by nonlinear mixed effect modelling, using a one compartment model with first order absorption and first order elimination and random effects on the absorption rate (k(a)), the apparent volume of distribution (V/F) and apparent clearance (CL/F).
Two covariates, time since transplantation (≤ and >6 months) and age affected MPA pharmacokinetics. k(a), estimated at 1.7 h(-1) at age 8.7 years, exhibited large interindividual variability (308%). V/F, estimated at 64.7 l, increased about 2.3 times in children during the immediate post transplantation period. This increase was due to the increase in the unbound MPA fraction caused by the low albumin concentration. CL/F was estimated at 12.7 l h(-1). To estimate individual AUC(0,12 h), the pharmacokinetic parameters obtained with the final model, including covariates, were coded in Adapt II(®) software, using the Bayesian approach. The AUC(0,12 h) estimated from concentrations measured 0, 1 and 4 h after administration of MMF did not differ from reference values.
This study allowed the estimation of the population pharmacokinetic MPA parameters. A simple sampling procedure is suggested to help to optimize pediatric patient care.
旨在评估儿童肝移植受者体内霉酚酸（MPA）的群体药代动力学参数，确定影响 MPA 药代动力学的因素，并建立一种估算单个体患者 MPA 曲线下面积（AUC（0，12 h））的有限采样策略。
28 名年龄在 1.1 至 18.0 岁的儿童接受了口服吗替麦考酚酯（MMF）联合他克莫司（n=23）或环孢素（n=5）治疗。通过对 16 名儿童的 16 个强化药代动力学数据集的模型构建集进行数据分析，估算出群体参数。采用一房室模型，具有一级吸收和一级消除，以及吸收速率（k(a)）、表观分布容积（V/F）和表观清除率（CL/F）的随机效应，对数据进行非线性混合效应建模。
有两个协变量，移植后时间（≤6 个月和＞6 个月）和年龄影响 MPA 的药代动力学。在 8.7 岁时，k(a)估计值为 1.7 h(-1)，个体间变异性很大（308%）。V/F 估计值为 64.7 l，在移植后即刻，儿童的 V/F 增加了约 2.3 倍。这种增加是由于低白蛋白浓度导致游离 MPA 分数增加。CL/F 估计值为 12.7 l h(-1)。为了估算个体 AUC（0，12 h），使用最终模型获得的药代动力学参数，包括协变量，在 Adapt II(®)软件中，采用贝叶斯方法进行编码。通过测量 MMF 给药后 0、1 和 4 小时的浓度估算出的 AUC（0，12 h）与参考值无差异。
本研究对 MPA 的群体药代动力学参数进行了估算。建议采用一种简单的采样程序，以帮助优化儿科患者的治疗。
