中国药物警戒 ›› 2022, Vol. 19 ›› Issue (7): 708-711.
DOI: 10.19803/j.1672-8629.2022.07.03

• 机制性模型在药物研发和评价中的应用专栏（一） • 上一篇    下一篇

基于生理药代动力学模型对青霉胺片治疗威尔逊病的研究与评价

王晨1, 高婕1, 刘英2, 陈涛3, 许明哲1,*   

  1. 1中国食品药品检定研究院,北京 102629;
    2河南省食品药品检验所,河南 郑州 450018;
    3上海凡默谷信息有限公司,上海 200127
  • 收稿日期:2022-01-19 出版日期:2022-07-15 发布日期:2022-07-12
  • 通讯作者: *许明哲,男,博士,主任药师,药物质量评价与药事管理。E-mail：xumzhe@nifdc.org.cn
  • 作者简介:王晨,男,硕士,主任药师,抗感染药物质量评价。
  • 基金资助:
    重大新药创制国家科技重大专项2017年度（2017ZX09101001）

Physiological pharmacokinetic model based evaluation of the efficacy of penicillamine tablets against Wilson's disease

WANG Chen1, GAO Jie1, LIU Ying2, CHEN Tao3, XU Mingzhe1,*   

  1. 1National Institutes for Food and Drug Control, Beijing 102629, China;
    2Henan Food and Drug Inspection Institute, Zhengzhou Henan 450018, China;
    3PharmoGo Co., Ltd., Shanghai 200127, China
  • Received:2022-01-19 Online:2022-07-15 Published:2022-07-12

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摘要： 目的 基于生理药代动力学理论模型研究方法对青霉胺片治疗威尔逊病的有效性水平进行研究和评价。方法 建立青霉胺生理药代动力学模型并根据文献数据进行验证,计算相应组织器官中的药物浓度-时间曲线,结合青霉胺对于Wilson病的有效性特征,采用恰当的评价参数以各器官中药时曲线为依据进行有效性研究与评价,并对其影响因素进行讨论。结果 单次口服青霉胺250 mg,人体内静脉血中药物达峰浓度（Cmax）模型计算结果和文献结果分别为3.172和3.050 μg·mL-1,曲线下面积（AUC0-24 h）分别为22.928和23.549 μg·h·mL-1,模型计算和文献结果间决定系数（r2）为0.947,模型与文献结果一致;进一步计算单次给药24 h内肾脏、肝脏、心脏、肌肉和脑部Cmax分别为4.962、4.783、2.385、1.641、0.616 μg·mL-1,AUC0-24 h分别为35.863、32.518、17.240、12.003、4.450 μg·h·mL-1。结论 口服青霉胺片在相应器官中药物浓度分布有差异,应根据用药目的进行给药方案的设计与调整;优选在空肠部位具有更大比例溶液状态的制剂可有助于提高药物的有效性水平。本方法可用于青霉胺及其制剂有效性评价,并可进一步应用于影响药物有效性各因素的考察研究。

关键词: 青霉胺片, 有效性评价, 生理药代动力学模型, 威尔逊病

Abstract: Objective To study and evaluate the efficacy of penicillamine tablets against Wilson's disease based on a physiological pharmacokinetic model. Methods A physiologically based pharmacokinetic (PBPK) model of penicillamine was established using software and validated with data collected from literature. Plasma concentration-time curves in the corresponding tissues and organs were calculated. The efficacy was evaluated based on the plasma concentration-time curves in related organs via appropriate parameters. Determinants of efficacy were also identified. Results For the single oral administration of 250 mg of penicillamine tablets, the maxiumen concentrations (Cmax) were 3.172 and 3.050 μg·mL-1 respectively based on the model and literature, and the corresponding average areas under the curve (AUC0-24 h) were 22.928 and 23.549 μg·h·mL-1 respectively. The determining factor (r2 value) between the results of calculation by the model and actual measurement in literature was 0.947, suggesting that there was no difference between the two results. Further calculation showed that the cmax of the brain, muscle, liver, heart, brain and kidney was 4.962, 4,783, 2.385, 1.641 and 0.616 μg·mL-1 respectively, while the AUC0-24h was 35.863, 32.518, 17.240, 12.003 and 4.450 μg·h·mL-1 within 24 hours of oral administration. Conclusion There is difference in the distribution of penicillamine tablets in various organs after oral administration. The administration scheme has to be designed and optimized according to the purpose of treatment. Dosage forms that are more likely to exist in the liquid state in the jejunum should be recommended since they can improve the efficacy. The approach established in this study can be used to evaluate the efficacy of penicillamine tablets in the human body and investigate the determinants of efficacy.

Key words: penicillamine tablets, efficacy evaluation, PBPK model, Wilson's disease

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