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

In the present study, we aimed to investigate the anticancer effect of TM208 （4-methylpiperazine-l-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/gg/d and average transit rate among transit compartments was 0.173 day i. 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.