Characterization of four basic models of indirect pharmacodynamic responses

Abstract

Four basic models of indirect pharmacodynamic responses were characterized in terms of changing dose, I_max or S_max, 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 (R_max) (inhibition or stimulation) and the time of its occurrence (TR_max) were dependent on the model, dose, I_max or S_max, 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 (TR_max, ABEC) were nearly proportional to log dose, while others (R_max, CR_max) 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.