中国药物警戒 ›› 2026, Vol. 23 ›› Issue (9): 1034-1039.
DOI: 10.19803/j.1672-8629.20260324

• 安全与合理用药 • 上一篇    下一篇

精神分裂症患者奥氮平群体药代动力学模型分析

涂顺1, 张星海2, 陈彬彬1, 齐杰2, 赵恒利2#, 黄志源1,*   

  1. 1厦门市仙岳医院,厦门医学院附属仙岳医院,福建省精神医学中心,福建省精神疾病临床医学研究中心,福建 厦门 361012;
    2山东第一医科大学附属中心医院临床研究中心,山东 济南 250013;
    3中国药科大学基础医学与临床药学学院,江苏 南京 211198
  • 收稿日期:2026-04-27 出版日期:2026-09-15 发布日期:2026-09-15
  • 通讯作者: *黄志源,男,博士,主任医师,精神心理疾病中西医结合临床诊疗与机制研究。E-mail: hzy2023@xmmc.edu.cn。#为共同通信作者。
  • 作者简介:涂顺,男,硕士,药师,群体药动学。
  • 基金资助:
    厦门市自然科学基金资助项目（3502Z202372101）; 山东省自然科学基金资助项目（ZR2024QH164）

Population pharmacokinetic modeling of olanzapine in patients with schizophrenia

Tu Shun1, Zhang Xinghai2, Chen Binbin1, Qi Jie2, Zhao Hengli2#, Huang Zhiyuan1,*   

  1. 1Xiamen Xianyue Hospital, Xianyue Hospital Affiliated to Xiamen Medical College, Fujian Psychiatric Center, Fujian Clinical Research Center for Mental Disorders, Xiamen Fujian 361012, China;
    2Department of Clinical Research Center, Central Hospital Affiliated to Shandong First Medical University, Jinan Shandong 250013, China;
    3School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing Jiangsu 211198, China
  • Received:2026-04-27 Online:2026-09-15 Published:2026-09-15

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摘要： 目的 建立精神分裂症患者奥氮平群体药代动力学（PPK）模型,识别影响其药代动力学特征的关键协变量,为个体化给药提供参考。方法 纳入31名患者的221个奥氮平血浆浓度数据。采用一阶条件估算法（FOCE-ELS）在Phoenix NLME软件中建立非线性混合效应模型。结构模型选用不含吸收滞后时间的一级吸收和消除一室模型,协变量通过逐步正向纳入与反向剔除法进行筛选,并结合拟合优度图、可视化预测检验（VPC）及非参数自助法进行内部验证。结果 最终模型估算的群体表观清除率（CL/F）和表观分布容积（V/F）典型值分别为28.95 L·h-1和248.76 L。协变量分析显示,总胆红素是影响吸收速率常数（Ka）的显著正向因素;性别、年龄、体重、丙氨酸氨基转移酶、天冬氨酸氨基转移酶及肌酐可能受样本量限制,在结果中未显示显著影响。模型内部验证显示良好的预测性能和稳定性。结论 总胆红素水平可能影响奥氮平的吸收过程,在精神分裂症患者的个体化用药方案制定中应予以考虑。

关键词: 奥氮平, 精神分裂症, 总胆红素, 非线性混合效应模型, 治疗药物监测, 群体药代动力学

Abstract: Objective To establish a population pharmacokinetic (PPK) model of olanzapine in patients with schizophrenia so as to identify key covariates influencing its pharmacokinetic characteristics and to provide evidence for individualized dosing. Methods A total of 221 measurements of olanzapine plasma concentrations from 31 patients were included in the final analysis. A nonlinear mixed-effects model was developed in Phoenix NLME (version 8.7; Certara USA, Princeton, NJ) using first-order conditional estimation with extended least squares. A one-compartment model with first-order absorption and elimination without an absorption lag time was selected as the structural model. Covariates were screened through a stepwise forward inclusion followed by backward elimination approach. Internal validation was performed using goodness-of-fit plots, prediction-corrected visual predictive checks (pcVPC), and nonparametric bootstrapping. Results The typical values of apparent clearance (CL/F) and apparent volume of distribution (V/F) of the population were estimated by the final model at 28.95 L·h-1 and 248.76 L, respectively. Covariate analysis identified total bilirubin as a statistically significant positive factor influencing the absorption rate constant (Ka). Gender, age, body weight, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and creatinine did not make much difference, which might be attributed to the limited sample size. Internal validation confirmed satisfactory predictive performance and stability of the final model. Conclusion Total bilirubin levels may influence the absorption of olanzapine and should be taken into consideration when individualized dosing regimens are formulated for patients with schizophrenia.

Key words: Olanzapine, Schizophrenia, Total Bilirubin, Nonlinear Mixed-Effects Model, Therapeutic Drug Monitoring, Population Pharmacokinetics (PPK)

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