A new approach for prediction of clinical efficacy of anticancer drugs based on toxicokinetic and pharmacokinetic analysis

在此之前，我们报道了具有细胞周期期非特异性作用的抗癌药物，其杀伤细胞的方式取决于药物的浓度曲线下面积（AUC），并将这类药物命名为I类药物。如果有可能预测药物临床可达到的auc。在本研究中，假设人与猴之间的最大血浆auc比人与小鼠之间的最大血浆auc更接近，我们测量了以最大耐受剂量（MTDs）给药的猴子体内蛋白质未结合部分（AUCfree）的血浆auc，并将其与各自临床报道的auc进行了比较。我们检测了顺铂、丝裂霉素C、依托泊苷、ninustin、环磷酰胺、阿霉素和SM5887 7种I型药物和CPT-11 1种II型药物。我们发现，除ninustin外，在猴子中测试的I型药物的最大血浆AUCfree与各自的临床结果一致，尽管ninustin的剩余病例略高于人类。然而，在CPT-11的情况下，猴子血浆中其活性代谢物（SN-38的内酯形式）的最大AUCfree量远低于人类。这些结果表明，通过对猴子的毒代动力学和药代动力学分析来预测临床可达到的血浆中ⅰ型药物的AUCfree的可能性。

Previously, we have reported that anticancer agents with cell cycle phase-nonspecific action showed a cell-killing manner with depending on the area under concentration curve(AUC)of the agent, and this type of agent was designated the type I drug. If it is possible topredict clinically achievable AUCs of the drug. In this study, assuming that the maximum plasma AUCs are more approximate between human and monkey thanhuman and mouse, we measured plasma AUCs of protein unbound fractions(AUCfree)of the drug in monkeys administrated with the maximum tolerated doses(MTDs), and compared the AUCs with respective clinical ones reported. We examined seven type I drugs, cisplatin, mitomycin C,etoposide, ninustin, cyclophasphamide, adryamicin and SM5887, and one type II drug, CPT-11. We found that the maximum plasma AUCfree of type I drugs tested other than ninustin in monkeys showed good agreement with the respective clinical ones, although the remaining case of ninustine showed somewhat higher than that in humans. In the case of CPT-11, however, the maximum plasma AUCfree of its active metabolite(lactone form of SN-38)in monkey was much lower than that in humans. These results indicates that the possibility of predicting clinically achievable plasma AUCfree of the type I agents by toxicokinetic and pharmacokinetic analysis on monkeys.