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目的:考察疾病因素对于环孢素A(CsA)在儿童体内药动学的影响,促进个体化用药。方法:收集150例包括再生障碍性贫血(AA)、嗜血细胞综合症(HPS)和难治性肾病综合症(RNS)不同病种患儿的Cs A血药浓度数据和临床资料。采用非线性混合效应模型法考察疾病种类因素对于CsA药动学的影响。采用Bayesian最大后验概率法获取并比较CsA在不同病种患者中药动学参数的差异。用拟合优度(goodness-of-fit)、自举法(bootstrap)、直观预测检验法(VPC)、正态化预测分布误差(NPDE)对最终模型的预测性能进行验证。结果:最终模型药动学参数的群体典型值分别为:吸收速率常数(k_a)1.22 h~(-1),吸收时滞时间(T_(lag))0.45h,表观分布容积(V_d)218.18 L,口服清除率(CL)14.45 L·h~(-1)。拟合优度、自举验证、VPC和NPDE结果表明最终模型稳定,预测结果可靠。模型结构显示只有患者的体质量和AST值是影响CsA清除率的显著性因素。CsA在AA、HPS和RNS患者中的药动学参数无显著性差异(P>0.05)。结论:本研究成功获取了CsA在儿童AA、HPS和RNS患者中的药动学参数,上述疾病因素不会显著影响CsA在儿童体内的药动学过程。
OBJECTIVE: To investigate the influence of disease factors on pharmacokinetics of CsA in children and to promote individualized medication. Methods: CsA blood concentration data and clinical data of 150 children with different diseases including aplastic anemia (AA), hemophilic syndrome (HPS) and refractory nephrotic syndrome (RNS) were collected. Nonlinear mixed effects model was used to investigate the influence of disease types on CsA pharmacokinetics. Bayesian maximum a posteriori probability method was used to obtain and compare the pharmacokinetic parameters of CsA in patients with different diseases. The prediction performance of the final model was validated by goodness-of-fit, bootstrap, visual predictive test (VPC), normalized predictive distribution error (NPDE). Results: The typical pharmacokinetic parameters of the final model were as follows: the absorption rate constant (k_a) 1.22 h -1, the lag time 0.45 h, the apparent volume of distribution (V_d) 218.18 L, oral clearance rate (CL) 14.45 L · h ~ (-1). Fitting goodness, bootstrap verification, VPC and NPDE results show that the final model is stable and the prediction results are reliable. The model structure shows that only the patient’s body mass and AST value are the significant factors that affect the clearance rate of CsA. The pharmacokinetic parameters of CsA in patients with AA, HPS and RNS were not significantly different (P> 0.05). Conclusion: The pharmacokinetic parameters of CsA in children with AA, HPS and RNS were successfully obtained in this study. The above-mentioned disease factors did not significantly affect the pharmacokinetics of CsA in children.