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

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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.