Characterization of four basic models of indirect pharmacodynamic responses.

Four basic models of indirect pharmacodynamic responses were characterized in terms of changing dose, Imax or Smax, and IC50 or SC50 to examine the effects of these fundamental drug properties on response profiles. Standard pharmacokinetic parameters were used for generating plasma concentration, and response-time profiles using computer simulations. Comparisons to theoretical expectations were made. In all four models, the maximum response (Rmax) (inhibition or stimulation) and the time of its occurrence (TRmax) were dependent on the model, dose, Imax or Smax, and IC50 or SC50 values. An increase in dose or a decrease in IC50 or SC50 by the same factor produced, as theoretically expected, identical and superimposable pharmacodynamic response patterns in each of the models. Some parameters (TRmax, ABEC) were nearly proportional to log dose, while others (Rmax, CRmax) were nonlinear. Assessment of expected response signature patterns as demonstrated in this report may be helpful in experimental designs and in assigning appropriate models to pharmacodynamic data.