采用生理药动学模型预测抗肿瘤新药法米替尼在人体中的药动学

Predicting pharmacokinetics of anti-cancer drug,famitinib in human using physiologically based pharmacokinetic model

建立并优化法米替尼的大鼠和猴的生理药动学模型,并且在该模型的基础上进行了种属外推至人,预测法米替尼在人体中的药动学和组织分布。根据文献和本实验室此前的实验结果以及ACD/ADME suite和Sim CYP软件预测法米替尼的理化性质,采用Gastro Plus软件的PBPK模块建立并优化法米替尼的大鼠和猴的生理药动学模型,并且进行种属外推至人,预测法米替尼在人体中的药动学和组织分布。优化好的大鼠和猴的生理药动学模型可以很好地预测大鼠和猴的药动学,大鼠和猴的AUC_(0-∞)实测值与计算值的比值分别为1.00和0.97。种属外推至人的AUC_(0-∞)的实测值与预测值的比值分别为1.63(大鼠→人)和1.57(猴→人)。法米替尼的大鼠和猴的生理药动学模型成功建立,并且在此基础上进行种属外推至人,能够很好地预测人体内的药动学行为,为今后的进一步研究药物-药物相互作用提供参考。

This study is to establish physiologically based pharmacokinetic （PBPK） models of famitinib in rat and monkey, and then to predict the pharmacokinetics and tissue distribution of famitinib in human based on the PBPK models. According to published paper, previous studies and the chemical properties of famitinib predicted by ACD/ADME suite and SimCYP, the PBPK models of rat and monkey were established and optimized using GastroPlus. And then, the PBPK models were applied to predict the pharmacokinetic and tissue distribution of famitinib in human. The results showed that the PBPK models of rat and monkey can fit the observed data well, and the AUC_0-∞ ratios of observed and calculated data in rat and monkey were 1.00 and 0.97, respectively. The AUC_0-∞ ratios of observed and predicted data in human were 1.63 （rat to human） and 1.57 （monkey to human）, respectively. The rat and monkey PBPK models of famitinib were well established, and the PBPK models were applied in predicting pharmacokinetic of famitinib in human successfully. Hence, the PBPK model of famitinib in human could be applied in future drug-drug interaction study.