氯氮平在中国精神分裂症人群的群体药物动力学研究

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 (K_a) 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K_a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45.8 μg·L⁻¹。

Population pharmacokinetics research of clozapine in Chinese schizophrenic patients

The goal of this study is to investigate the population pharmacokinetics of oral given clozapine in Chinese schizophrenic patients and to identify possible relationships between population parameters and covariates including demography factors and CYP1A2 genetic polymorphism, so as to create the population pharmacokinetics model to guide individual clinical delivery.  Details of drug dosage history, sampling time and concentration of 626 data points from 183 patients were collected retrospectively.  The 183 patients were randomly allocated  either to the index group (n = 168) or to the validation group (n = 15).  Population pharmacokinetic data analysis was performed using the nonlinear mixed-effects model (NONMEM) program on the index group.  The values of apparent clearance (CL/F), apparent volume of distribution (V/F) and the constant of absorption rate were  estimated.  A number of covariates including demographic index, coadministration of other drugs and CYP1A2 genotypes were evaluated statistically for their influence on these parameters.  The final population model   related clearance with day-dose/BSA (DBSA) and smoke habit (SMOK).  Predictive performance of the final model evaluated with the validation group showed insignificant bias between observed and model predicted  concentrations.  Typical value of CL/F (non-smoking group), V/F and the constant of absorption rate were  28.5 L·h⁻¹ (5.05%), 1 290 L (16.7%) and 2.26 h⁻¹ (fixed), inter-patient variability (CV) in CL/F and V/F was 42.2% and 10.0%, respectively.  It was observed that the values of CL/F in the two smoking groups were higher than that in the non-smoking group.  The residual variability (SD) between observed and model-predicted  concentrations was 45.8 μg·L⁻¹.