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A Predictive Model of Human Myelotoxicity Using Five Camptothecin Derivatives and the In vitro Colony-Forming Unit Granulocyte/Macrophage Assay

¹ Drug Metabolism and Physicochemical Property Research Laboratory, Daiichi Pharmaceutical Co., Ltd., Tokyo, Japan; and ² Southern Research Institute, Birmingham, Alabama

Purpose: 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.

Experimental Design: 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).

Results: 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.

Conclusion: 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.