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本研究旨在考察口服氯氮平(clozapine)在中国精神分裂症患者中的群体药物动力学特征,探讨各项动力学参数与人口统计学因素及CYP1A2酶基因多态性的关系,通过建立群体药物动力学模型指导临床个体化给药。研究中采集了临床服用氯氮平的183例精神分裂症患者的626份稳态血样本资料,随机分组为建模组(168例)和外部验证组(15例)。用非线性混合效应模型(NONMEM)程序中的一级评估法(first-order estimation,FO)对建模组的数据进行分析,估算清除率(CL/F)、表观分布容积(V/F)和吸收速率常数(Ka)的群体值,并且定量评价人口统计学指标和CYP1A2酶基因型因素对药物动力学参数的影响。建模中单室一级吸收和消除模型能够较好地拟合数据。最终模型包含了经体表面积归一化的单日剂量(DBSA)和吸烟(SMOK)因素对CL/F的影响。CL/F(非吸烟组)、V/F和Ka的群体典型值分别为28.5 L.h-1(5.05%)、1 290 L(16.7%)和2.26 h-1(fixed),相应的个体间变异分别为42.2%和10.0%。研究发现吸烟组的清除率有所上升。观测值与预测值之间的残留误差SD为45.8μg.L-1。
This study aimed to investigate the population pharmacokinetics of oral clozapine in Chinese schizophrenics and explore the relationship between the kinetic parameters and demographic factors and CYP1A2 gene polymorphism. Pharmacokinetic models guide clinical individualized administration. Sixty-two steady-state blood samples from 183 schizophrenic patients taking clozapine clinically were collected and randomly divided into model group (168 patients) and external validation group (15 patients). Data from the modeling group were analyzed using first-order estimation (FO) in a nonlinear mixed-effects model (NONMEM) program to estimate clearances (CL / F), apparent volume of distribution ) And absorption rate constants (Ka), and quantitatively evaluated the effect of demographic and CYP1A2 enzyme genotyping parameters on pharmacokinetic parameters. The single-chamber one-stage absorption and elimination model in modeling can better fit the data. The final model includes the effects of DBSA and SMOK factors on CL / F normalized by body surface area. The typical values of CL / F (non-smoking group), V / F and Ka populations were 28.5 Lh-1 (5.05%), 1290 L (16.7%) and 2.26 h-1 (fixed) Respectively 42.2% and 10.0%. The study found that smoking group clearance increased. The residual error SD between observed and predicted values was 45.8 μg.L-1.