Pharmacokinetic-pharmacodynamic modelling in pre-clinical investigations: principles and perspectives

A new approach to preclinical pharmacodynamic investigations is presented which allows, in addition to information on the nature of the pharmacological properties of new chemical entities, also important quantitative pharmacodynamic information to be derived. A single intravenous dose is administered to chronically instrumented rats and the time course of the pharmacological effect is determined in conjunction with plasma or serum concentrations. Datasets obtained in this way are subjected to simultaneous pharmacokinetic/pharmacodynamic modelling to obtain estimates of pharmacodynamic parameters such as EC50, Emax. Hill factor and the rate of biophase equilibration.