Pharmacodynamics of chemotherapeutic effects: Dose‐time‐response relationships for phase‐nonspecific agents

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.