A predictive model of human myelotoxicity using five camptothecin derivatives and the in vitro colony-forming unit granulocyte/macrophage assay.
OBJECTIVE
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.


METHODS
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.


CONCLUSIONS
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.
Drug Metabolism and Physicochemical Property Research Laboratory, Daiichi Pharmaceutical Co., Ltd., Tokyo, Japan. masub4p6@daiichipharm.co.jp
Noriko
N
Masubuchi
Richard D
RD
May
Ryo
R
Atsumi
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D001854:Bone Marrow Cells / Q000187:drug effects; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology; D003114:Colony-Forming Units Assay / Q000379:methods*; D004285:Dogs; D042381:Granulocyte Precursor Cells / Q000187:drug effects*; D006098:Granulocytes / Q000166:cytology / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D000077146:Irinotecan; D008264:Macrophages / Q000166:cytology / Q000187:drug effects; D020714:Maximum Tolerated Dose; D051379:Mice; D008954:Models, Biological
D000972:Antineoplastic Agents, Phytogenic; C080125:9-aminocamptothecin; D000077146:Irinotecan; C095887:exatecan; D002166:Camptothecin