Population pharmacokinetic-pharmacodynamic modelling of mycophenolic acid in paediatric renal transplant recipients in the early post-transplant period
Population pharmacokinetic-pharmacodynamic modelling of mycophenolic acid in paediatric renal transplant recipients in the early post-transplant period
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DOI：
10.1111/bcp.12426
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发表时间：
2014-11-01
影响因子：
3.4
通讯作者：
Vinks, Alexander A.
中科院分区：
文献类型：
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作者：
Dong, Min;Fukuda, Tsuyoshi;Vinks, Alexander A.
AimThe的目的是本研究的目的是开发一个人口药代动力学和药效学（PK-PD）模型，霉酚酸（MPA）在儿科肾移植受者在移植后早期period.MethodsA共214 MPA血药浓度-时间数据点，从24例患者的PK模型开发。在总共24名患者中的17名中，外周血单核细胞中的肌苷一磷酸脱氢酶（IMPDH）酶活性测量值（n=97）可用于PK-PD建模。使用非线性混合效应建模开发PK-PD模型，依次通过1）开发群体PK模型和2）使用事后贝叶斯PK参数估计值将IMPDH活性纳入PK-PD模型。协变量分析包括患者人口统计学、合并用药和临床实验室数据。非参数引导和预测校正的视觉预测检查进行评估最终models.ResultsA两室模型与过境室吸收最好的描述MPA PK。剂量与MPA暴露量之间存在非线性关系，并在模型中用幂函数描述。最终群体PK参数估计值（及其95%置信区间）为CL/F，22（14.8，25.2）lh（-1）70kg（-1）; V-c/F，45.4（29.6，55.6）l; V-p/F，411（152.6，1472.6）l; Q/F，22.4（16.0，32.5）lh（-1）; K-a，2.5（1.45，4.93）h（-1）。PK研究中的协变量分析确定体重与CL/F显著相关。一个简化的抑制E-max模型充分描述了MPA浓度与IMPDH活性之间的关系。最终群体PK-PD参数估计值（及其95%置信区间）为：E-0，3.45（2.61，4.56）nmolh（-1）mg（-1）蛋白和EC 50，1.73（1.16，3.01）mgl（-1）。E-max固定为0。在我们的研究队列中有两名非洲裔美国患者，与白人患者相比，他们的IMPDH基线活性（E-0）较低（平均值2.13mgl（-1）vs.3.86mgl（-1））。目前的模型提供的信息，将有助于未来的研究，并可能在贝叶斯算法中实现，以允许PK-PD指导的治疗药物监测策略。
AimThe purpose of this study was to develop a population pharmacokinetic and pharmacodynamic (PK-PD) model for mycophenolic acid (MPA) in paediatric renal transplant recipients in the early post-transplant period.MethodsA total of 214 MPA plasma concentrations-time data points from 24 patients were available for PK model development. In 17 out of a total of 24 patients, inosine monophosphate dehydrogenase (IMPDH) enzyme activity measurements (n=97) in peripheral blood mononuclear cells were available for PK-PD modelling. The PK-PD model was developed using non-linear mixed effects modelling sequentially by 1) developing a population PK model and 2) incorporating IMPDH activity into a PK-PD model using post hocBayesian PK parameter estimates. Covariate analysis included patient demographics, co-medication and clinical laboratory data. Non-parametric bootstrapping and prediction-corrected visual predictive checks were performed to evaluate the final models.ResultsA two compartment model with a transit compartment absorption best described MPA PK. A non-linear relationship between dose and MPA exposure was observed and was described by a power function in the model. The final population PK parameter estimates (and their 95% confidence intervals) were CL/F, 22 (14.8, 25.2) lh(-1) 70kg(-1); V-c/F, 45.4 (29.6, 55.6) l; V-p/F, 411 (152.6, 1472.6)l; Q/F, 22.4 (16.0, 32.5) lh(-1); K-a, 2.5 (1.45, 4.93)h(-1). Covariate analysis in the PK study identified body weight to be significantly correlated with CL/F. A simplified inhibitory E-max model adequately described the relationship between MPA concentration and IMPDH activity. The final population PK-PD parameter estimates (and their 95% confidence intervals) were: E-0, 3.45 (2.61, 4.56) nmolh(-1)mg(-1) protein and EC50, 1.73 (1.16, 3.01) mgl(-1). E-max was fixed to 0. There were two African-American patients in our study cohorts and both had low IMPDH baseline activities (E-0) compared with Caucasian patients (mean value 2.13mgl(-1)vs. 3.86mgl(-1)).ConclusionAn integrated population PK-PD model of MPA has been developed in paediatric renal transplant recipients. The current model provides information that will facilitate future studies and may be implemented in a Bayesian algorithm to allow a PK-PD guided therapeutic drug monitoring strategy.