应用群体药动学模型及蒙特卡洛模拟优化淋巴结核患者使用异烟肼注射剂最佳给药方案  

Using the population pharmacokinetic model and Monte Carlo simulation to explore the optimal dosing regimen for isoniazid injection in patients with lymphatic tuberculosis

作　　者：张欢 刘小玉 丁巧燕 张宇 李思思 马丽华 周铭 Zhang Huan;Liu Xiaoyu;Ding Qiaoyan;Zhang Yu;Li Sisi;Ma Lihua;and Zhou Ming(Department of Pharmacy,Pulmonary Hospital of Wuhan,Wuhan 430032;Department of Surgery,Pulmonary Hospital of Wuhan,Wuhan 430032)

机构地区：[1]武汉市肺科医院药学部,武汉430032 [2]武汉市肺科医院外科,武汉430032

出　　处：《中国抗生素杂志》2024年第9期1068-1074,共7页Chinese Journal of Antibiotics

基　　金：湖北省自然科学基金资助(No.2023AFB1029);湖北省自然科学基金资助(No.2022CFC018);湖北省卫生健康委科研基金资助(No.WJ2023M146);武汉市卫生健康科研基金资助(No.WX21D33)。

摘　　要：目的应用非线性混合效应法(NLME)建立异烟肼注射剂在中国淋巴结核患者群体的药动学(PPK)模型,采用蒙特卡洛模拟优化异烟肼注射剂在不同NAT2代谢基因型淋巴结核患者中的给药方案。方法纳入武汉市肺科医院淋巴结核患者28例,收集66个血药浓度数据和相关临床资料。采用NLME法建立PPK模型,考察NAT2代谢基因型等因素对异烟肼注射剂体内药动学特征的影响。采用诊断图、Bootstrap法、NPDE法和VPC法评价PPK模型的预测能力。采用蒙特卡洛模拟法探索不同NAT2代谢基因型患者的最佳给药方案。结果异烟肼注射剂具有一级吸收的二室模型特征,患者NAT2代谢基因型是影响其清除率的重要因素,快、中间和慢代谢基因型患者清除率分别为:53.7、44.6和25.4 L/h,表观分布容积为29.8 L。模型评价表明,模型参数估算可靠、模型稳定。蒙特卡洛模拟结果显示,NAT2快、中间、慢代谢基因型的淋巴结核患者,异烟肼注射剂最佳给药剂量分别为600、450和300 mg。结论本研究成功建立中国淋巴结核患者异烟肼注射剂PPK模型,定量描述NAT2代谢基因型对异烟肼注射剂药动学的影响,针对不同基因型患者制定最佳给药方案,为异烟肼个体化治疗提供参考。Objective Using the nonlinear mixed-effects method(NLME)to develop a pharmacokinetic(PPK)model of isoniazid(INH)injection in a population of Chinese patients with lymphatic tuberculosis,Monte Carlo simulation was used to optimize the dosing regimen of isoniazid injection in patients with lymphatic tuberculosis of different NAT2 metabolism genotypes.Method Twenty-eight patients with lymphatic tuberculosis from Wuhan Lung Hospital were included,and 66 blood drug concentration data and related clinical information were collected.The NLME method was used to establish a PPK model to investigate the effect of factors such as NAT2 metabolism genotype on the in vivo pharmacokinetic profile of isoniazid injection.Diagnostic plots,the bootstrap method,normalized prediction distribution error(NPDE)and the visual predictive check(VPC)test were used to evaluate the prediction performance of the PPK model.Monte Carlo simulation was used to explore the drug dosing regimen for patients with different NAT2 metabolizing genotypes.Results Isoniazid injection was characterized by a two-compartment model of primary absorption,and the NAT2 metabolism genotype was an important factor influencing its clearance.Clearance rates for patients with fast,intermediate and slow metabolism genotypes were 53.7,44.6,and 25.4 L/h,respectively,with an apparent volume of distribution of 29.8 L.Model evaluation showed reliable estimation of model parameters and model stability.Monte Carlo simulation results showed that the optimal dosage of isoniazid injection administered to patients with NAT2 fast,intermediate,and slow metabolism genotypes of lymphoid tuberculosis was 600 mg,450 mg,and 300 mg,respectively.Conclusion In this study,a PPK model for isoniazid injection in Chinese lymphatic tuberculosis patients was successfully established the effects of NAT2 metabolic genes on the PK of isoniazid(INH)injection were quantitatively described,and the optimal dosing regimen for patients with different genotypes was formulated,which provided a reference for

关 键 词：异烟肼注射剂 群体药动学 蒙特卡洛模拟 淋巴结核 

分 类 号：R969.1[医药卫生—药理学]