A pharmacodynamic model for cell-cycle-specific chemotherapeutic agents

A pharmacodynamic model is proposed and equations are developed for the quantitative analysis of dose-time-cell-survival curves produced by the administration of cell-cycle-specific chemo-therapeutic agents. The essential feature of the model is an irreversible, bimolecular mechanism of drug-receptor interaction which serves as the interface between the pharmacokinetics of the drug and the cell-cycle-cell-proliferation kinetics of the normal and neoplastic cells. A preliminary cell system which allows adequate characterization of the experimental data is a two-compartment model where cells are assumed to exist in their proliferative and nonproliferative phases. The chemotherapeutic model was used to analyze dose-time-cell-survival curves found in the literature for the effects of vincristine, vinblastine, arabinosylcytosine, and cyclophosphamide on lymphoma and hematopoietic cells in the mouse femur. Similarity in the values of the cell-kill constants for these drugs on the two cell types indicates that, in the cell systems studied, the proliferative state of the cells is the primary in vivodeterminant of selective chemotherapy.Presented, in part, at the A.Ph.A. Academy of Pharmaceutical Sciences Symposium on Pharmacokinetics in Disease, Houston, Texas, April 1972, and at the Fogarty International Conference on Pharmacology and Pharmacokinetics, Washington, D.C., November 1972.