TM208治疗非小细胞肺癌移植瘤的药物动力学-药效动力学模型

doi:10.5246/jcps.2016.07.055

中国药学(英文版) ›› 2016, Vol. 25 ›› Issue (7): 502-511.DOI: 10.5246/jcps.2016.07.055

TM208治疗非小细胞肺癌移植瘤的药物动力学-药效动力学模型

花明¹, 冀希炜^1,3, 李润涛², 季双敏¹, 李健¹, 姚庆宇¹, 王丽杰¹, 郝方然¹, 卢炜^1,2, 周田彦^1,2*

1. 北京大学医学部药学院分子药剂学与新释药系统北京市重点实验室, 北京 100191
2. 北京大学医学部天然药物及仿生药物国家重点实验室, 北京 100191
3. 北京大学第一医院临床药理研究所, 北京 100191

收稿日期:2016-04-07 修回日期:2016-05-03 出版日期:2016-07-19 发布日期:2016-05-15
通讯作者: Tel.: +86-010-82805937, Fax: +86-010-82801717, E-mail: tianyanzhou@bjmu.edu.cn
基金资助:
National Natural Science Foundation of China (Grant No. 81273583).

Pharmacokinetic-pharmacodynamic modeling of the anticancer effect of TM208 on non-small cell lung cancer xenograft

Ming Hua¹, Xiwei Ji^1,3, Runtao Li², Shuangmin Ji¹, Jian Li¹, Qingyu Yao¹, Lijie Wang¹, Fangran Hao¹, Wei Lu^1,2, Tianyan Zhou^1,2*

1. Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China
2. State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center, Beijing 100191, China
3. Institute of Clinical Pharmacology, Peking University First Hospital, Beijing 100191, China

Received:2016-04-07 Revised:2016-05-03 Online:2016-07-19 Published:2016-05-15
Contact: Tel.: +86-010-82805937, Fax: +86-010-82801717, E-mail: tianyanzhou@bjmu.edu.cn
Supported by:
National Natural Science Foundation of China (Grant No. 81273583).

摘要/Abstract

摘要：

本文旨在研究一种新的抗癌化合物TM208在非小细胞肺癌(NSCLC)移植瘤中的治疗效果, 并建立药物动力学-药效动力学(PK-PD)模型, 描述和仿真给药之后肿瘤体积随着时间的变化情况。首先, 比较了TM208治疗组(TM208 100 mg/kg和TM208 150 mg/kg)和对照组(空白对照, 吉西他滨阳性对照)之间的肿瘤生长情况; 其次, 建立了肿瘤自然生长模型和基于空白对照以及TM208治疗组数据的PK-PD模型; 最后, 对模型进行了评价和验证并仿真不同给药方案下的药效。结果表明, NSCLC可能是TM208的一种潜在适应症, TM208 150 mg/kg QD可以作为有效剂量; 模型参数中肿瘤的初始体积为0.134 cm³, 生长速率为0.0869 day^–1; 而PK/PD模型显示药物对NSCLC细胞的直接杀伤系数为0.174 mL/μg/d, 其导致的隔室间传导速率为0.173 day^–1。不同给药方案的仿真结果表明, TM208 900 mg/kg QW与TM208 150 mg/kg QD的肿瘤抑制作用相当。总之, TM208在NSCLC移植瘤中的抗癌疗效得以证实, 所建立的PK-PD模型能定量地描述和预测血浆药物浓度和药效之间的关系, 该研究对今后TM208的转化研究具有参考作用。

关键词: 药物动力学-药效动力学模型, TM208, 非小细胞肺癌

Abstract:

In the present study, we aimed to investigate the anticancer effect of TM208 (4-methylpiperazine-1-carbodithioc-acid-3-cyano-3,3-diphenylpropyl ester hydrochloride) on non-small cell lung cancer (NSCLC). Moreover, pharmacokinetic-pharmacodynamic (PK-PD) model was developed to describe and simulate the time-course of the drug response in A549 xenograft model. The inhibition rates of two treatment groups (TM208 100 mg/kg group and TM208 150 mg/kg group) in A549 xenograft model were first compared with both vehicle and positive control groups. Subsequently, natural tumor growth model was built and finally PK-PD model was established based on the PD data of the vehicle control group and TM208 treatment groups. In addition, the model was further evaluated, and the anti-cancer efficacy under different regimens was simulated. Our results showed that NSCLC was one potential indication of TM208 and TM208 150 mg/kg QD would be an effective regimen. For parameters about tumor growth, the initial volume was 0.134 cm³ and the growth rate was 0.0869 day^–¹. For parameters about drug efficacy, the killing factor was 0.174 mL/μg/dand average transit rate among transit compartments was 0.173 day^–¹. Among various regimens in the step of simulation, TM208 900 mg/kg QW, which was a hypothetical regimen without experimental data support yet, showed similar anticancer effect compared with TM208 150 mg/kg QD. In conclusion, the anti-cancer effect of TM208 on NSCLC was demonstrated by the pre-clinical experiment and confirmed by the developed PK-PD model. Moreoever, results from model simulation would be helpful for further translational research of TM208.

Key words: Pharmacokinetic-pharmacodynamic model, TM208, Non-small cell lung cancer

中图分类号:

R969

Supporting:

花明, 冀希炜, 李润涛, 季双敏, 李健, 姚庆宇, 王丽杰, 郝方然, 卢炜, 周田彦. TM208治疗非小细胞肺癌移植瘤的药物动力学-药效动力学模型[J]. 中国药学(英文版), 2016, 25(7): 502-511.

Ming Hua, Xiwei Ji, Runtao Li, Shuangmin Ji, Jian Li, Qingyu Yao, Lijie Wang, Fangran Hao, Wei Lu, Tianyan Zhou. Pharmacokinetic-pharmacodynamic modeling of the anticancer effect of TM208 on non-small cell lung cancer xenograft[J]. Journal of Chinese Pharmaceutical Sciences, 2016, 25(7): 502-511.

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TM208治疗非小细胞肺癌移植瘤的药物动力学-药效动力学模型

Pharmacokinetic-pharmacodynamic modeling of the anticancer effect of TM208 on non-small cell lung cancer xenograft

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