Masubuchi Noriko, May Richard D, Atsumi Ryo
Drug Metabolism and Physicochemical Property Research Laboratory, Daiichi Pharmaceutical Co., Ltd., Tokyo, Japan.
Clin Cancer Res. 2004 Oct 1;10(19):6722-31. doi: 10.1158/1078-0432.CCR-04-0721.
Many promising anticancer drugs are limited by myelosuppression. It is difficult to evaluate human myelotoxicity before a Phase I study because of the susceptibility of humans and animals to hematotoxicity. The purpose of this study was to establish a reliable method to predict the human maximum tolerated dose (MTD) of five camptothecin derivatives: SN-38, DX-8951f, topotecan, 9-aminocamptothecin, and camptothecin.
The myelotoxicity of SN-38 and DX-8951f were evaluated on bone marrow from mice, dogs, and humans using a 14-day colony-forming unit, granulocyte-macrophage (CFU-GM) assay to determine the 50%, 75%, and 90% inhibitory concentration values (IC50, IC75, and IC90, respectively).
Species differences in myelotoxicity were observed for SN-38 and DX-8951f. Using human and murine IC90s for myelotoxicity of these compounds and other camptothecin compounds (topotecan, 9-aminocamptothecin, and camptothecin), in vivo toxicological data, and pharmacokinetic parameters (data referred to in the literature), human MTDs were predicted retrospectively. The mechanism-based prediction model that is proposed uses the in vitro camptothecin assay and in vivo parameters on the basis of free fraction of area under the concentration-curve at the MTD (r2 = 0.887) and suggests that the human MTDs were well predicted for the five camptothecin derivatives by this model rather than by other models.
The human MTDs of the camptothecin drugs were successfully predicted using the mechanism-based prediction model. The application of this model for in vitro hematotoxicology could play an important role for the development of new anticancer agents.
许多有前景的抗癌药物受到骨髓抑制的限制。由于人类和动物对血液毒性的易感性，在I期研究之前很难评估人类骨髓毒性。本研究的目的是建立一种可靠的方法来预测五种喜树碱衍生物的人类最大耐受剂量（MTD）：SN-38、DX-8951f、拓扑替康、9-氨基喜树碱和喜树碱。
使用14天集落形成单位、粒细胞-巨噬细胞（CFU-GM）测定法，对小鼠、狗和人类的骨髓评估SN-38和DX-8951f的骨髓毒性，以确定50%、75%和90%抑制浓度值（分别为IC50、IC75和IC90）。
观察到SN-38和DX-8951f在骨髓毒性方面存在物种差异。利用这些化合物和其他喜树碱化合物（拓扑替康、9-氨基喜树碱和喜树碱）的人类和小鼠骨髓毒性IC90、体内毒理学数据以及药代动力学参数（文献中引用的数据），对人类MTD进行回顾性预测。所提出的基于机制的预测模型利用体外喜树碱测定法和基于MTD浓度曲线下面积的游离分数的体内参数（r2 = 0.887），表明该模型比其他模型能更好地预测这五种喜树碱衍生物的人类MTD。
使用基于机制的预测模型成功预测了喜树碱药物的人类MTD。该模型在体外血液毒理学中的应用可为新型抗癌药物的开发发挥重要作用。
