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中国防痨杂志 ›› 2020, Vol. 42 ›› Issue (4): 372-379.doi: 10.3969/j.issn.1000-6621.2020.04.013

• 论著 • 上一篇    下一篇

抗结核药物体外药代动力学/药效学研究模型的建立及应用

赵皎洁,付雷,王彬,张蕾,胡明豪,陆宇()   

  1. 101149 首都医科大学附属北京胸科医院 耐药结核病研究北京市重点实验室 北京市结核病胸部肿瘤研究所药物研究室
  • 收稿日期:2020-02-11 出版日期:2020-04-10 发布日期:2020-04-07
  • 通信作者: 陆宇 E-mail:luyu4876@hotmail.com
  • 基金资助:
    “十三五”国家科技重大专项(2019ZX09721001-007-003)

Establishment and application of pharmacodynamics and pharmacokinetics model in vitro

ZHAO Jiao-jie,FU Lei,WANG Bin,ZHANG Lei,HU Ming-hao,LU Yu()   

  1. Beijing Key Laboratory of Drug Resistance Tuberculosis Research,Department of Pharmacology,Beijing Tuberculosis and Thoracic Tumor Research Institute,Beijing Chest Hospital,Capital Medical University,Beijing 101149,China
  • Received:2020-02-11 Online:2020-04-10 Published:2020-04-07
  • Contact: Yu LU E-mail:luyu4876@hotmail.com

摘要:

目的 利用中空纤维系统建立体外药代动力学/药效学研究(pharmacokinetics/pharmacodynamics,PK/PD)的方法,并利用该方法获得异烟肼PK/PD参数及目标靶值,为后续新药的体外PK/PD研究提供方法学参考。方法 组装中空纤维系统,在中空纤维培养筒外腔接种处于对数生长期浓度为1×10 6 菌落形成单位(CFU)/ml的H37Rv菌株,共15ml。在系统中模拟人体25、50、150、300、1200mg/d给药剂量下的异烟肼浓度-时间分布,分别于给药后0.5、1、3.5、6.5、9.5、13、24、24.5、25、27.5、30.5、33.5、37、48h进行取样,利用高效液相色谱(high-performance liquid chromatographic,HPLC)测定异烟肼浓度。给药7d内每天对培养筒外腔菌液进行取样,监测系统中总菌量、异烟肼耐药等随时间变化的情况,并用PKSolver插件计算相关PK/PD参数。结果 结核分枝杆菌中空纤维感染模型中,异烟肼在给药第1天就表现出明显的早期杀菌活性,而杀菌作用停止的时间出现在给药3~5d。在给药7d后,50~1200mg/d剂量组结核分枝杆菌耐药菌群在所有菌群中占比≥39%。游离药物的血浆药物浓度-时间(0~24h)曲线下面积(AUC0~24)与最低抑菌浓度(minimal inhibitory concentration,MIC)的比值(AUC0~24/MIC)是异烟肼对H37Rv的PK/PD参数中拟合效果最好的。给药前2d药物的最大效应(Emax)为3.02CFU/ml,当AUC0~24/MIC=52.23时达到半最大效应浓度(EC50)。结论 首次在国内建立的结核分枝杆菌中空纤维感染模型构建成功,AUC0~24/MIC是异烟肼对H37Rv的目标PK/PD参数。

关键词: 分枝杆菌,结核, 药代动力学/药效学, 异烟肼, 体外研究

Abstract:

Objective To establish hollow-fiber pharmacodynamic model of tuberculosis(HFM-TB) for the pharmacokinetics/pharmacodynamics (PK/PD) study in vitro, and the method will be used to obtain the isoniazid PK/PD parameters, the HFM-TB provides a tool for the PK/PD study of new drugs in vitro. Methods The hollow fiber system was assembled, and the H37Rv strain in the logarithmic phase of growth was inoculated into the outer comparment of the hollow fiber culture tube at a concentration of 1×10 6 colony forming units (CFU)/ml for a total of 15 ml. The concentration-time distribution of isoniazid in the system were simulated in human patients at doses of 25, 50, 150, 300 and 1200 mg/d, Samples were taken at 0.5, 1, 3.5, 6.5, 9.5,13, 24, 24.5, 25, 27.5, 30.5, 33.5, 37 and 48 h,after administration. The concentrations of isoniazid were determined by high-performance liquid chromatographic (HPLC). The total bacteria load and isoniazid resistance in the system were monitored through the samples taken from the outer compartment of the culture tube daily for 7 days after administration. The PK/PD parameters were calculated by PKSolver plug-in. Results In the HFM-TB, isoniazid showed significant early bactericidal activity on the first day of administration, while the time when the bactericidal effect ceased was 3-5 days after administration. After 7 days of administration, the proportion of drug-resistant TB at the 50-1200 mg/d dose group accounted for ≥39% of all. AUC0-24/MIC was the best fitting effect of PK/PD parameters for isoniazid. The maximum effect (Emax) was 3.02 CFU/ml, and EC50 reached when AUC0-24/MIC=52.23, after 2 days of administration. Conclusion The HFM-TB was successfully established in China for the first time. AUC0-24/MIC is the target PK/PD parameter of isoniazid for H37Rv.

Key words: Mycobacterium tuberculosis, Pharmacokinetics/Pharmacodynamics, Isoniazid, In vitro