Risk assessment of human myelotoxicity of anticancer drugs: a predictive model and the in vitro colony forming unit granulocyte/macrophage (CFU-GM) assay.
Myelotoxicity is one of the major limitations to the use of anticancer drugs. It is desirable to evaluate human myelotoxicity before a Phase I study, however, this is difficult because of the differences in susceptibility between humans and animals. 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 (TPT), 9-aminocamptothecin (9-AC), and camptothecin (CAM). The myelotoxicity of camptothecin derivatives was 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). Then, using human and murine IC90 values for myelotoxicity of these compounds, in vivo toxicological data, and pharmacokinetic parameters (data referred to the literature), human MTDs were predicted retrospectively. The mechanism-based prediction model which is proposed uses the in vitro CFU-GM assay and in vivo parameters on the basis of free fraction of area under the concentration-curve (AUC) 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 application of this model for in vitro hematotoxicology could be very useful in the development of new anticancer agents.
Masubuchi
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Drug Metabolism and Physicochemistry Research Laboratory, Daiichi, Pharmaceutical Co., Ltd. 16-13 Kita-Kasai 1-Chome Edogawa-ku Tokyo 134-8630, Japan. masub4p6@daiichipharm.co.jp
D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects*; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects*; D019540:Area Under Curve; D001855:Bone Marrow Diseases / Q000139:chemically induced*; D002166:Camptothecin / Q000009:adverse effects* / Q000031:analogs & derivatives; D003627:Data Interpretation, Statistical; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D006801:Humans; D051379:Mice; D009503:Neutropenia / Q000139:chemically induced; D011237:Predictive Value of Tests; D018570:Risk Assessment; D013234:Stem Cells / Q000187:drug effects; D014410:Tumor Stem Cell Assay
D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D002166:Camptothecin