Pharmacodynamics of chemotherapeutic effects: dose-time-response relationships for phase-nonspecific agents.

Abstract Pharmacodynamic relationships were developed to characterize the necrobiotic effects of phase-nonspecific chemotherapeutic agents which attach irreversibly to cell receptors. The site of drug action is considered to be a specific body compartment, and target cell inactivation by the agent results from a bimolecular drug-receptor interaction. Turnover of cells is assumed to occur by natural synthetic and degradative processes. Based on these premises, a log-linear relationship was evolved to relate the fraction of surviving cells to the drug level-time integral at the pharmacologic site. The integral was shown to be proportional to the dose and independent of the mode of administration when the entire drug level-time course is evaluated. Data from the literature for the effects of cyclophosphamide on three cell systems of mice demonstrate the usefulness and certain therapeutic implications of the equations.