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Journal of Chinese Pharmaceutical Sciences ›› 2016, Vol. 25 ›› Issue (7): 502-511.DOI: 10.5246/jcps.2016.07.055

• Original articles • Previous Articles     Next Articles

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

Ming Hua1, Xiwei Ji1,3, Runtao Li2, Shuangmin Ji1, Jian Li1, Qingyu Yao1, Lijie Wang1, Fangran Hao1, Wei Lu1,2, Tianyan Zhou1,2*   

  1. 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).

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 day1. For parameters about drug efficacy, the killing factor was 0.174 mL/μg/dand average transit rate among transit compartments was 0.173 day1. 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

CLC Number: 

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