Indirect pharmacodynamic models for responses with multicompartmental distribution or polyexponential disposition

Basic indirect response models where drug alters the production (k(in)) of the response variable (R) based on the Hill function previously assumed one -compartment distribution of the response variable and simple first-order l oss (k(out)) of R. These models were extended using convolution theory to c onsideration of two-compartment distribution of R and/or polyexponential lo ss of R. Theoretical equations and methods of data analysis were det eloped and simulations are provided to demonstrate expected response behavior bas ed on biexponential response dissipation. The inhibition model was applied to our previous data for inhibition of circadian cortisol secretion by pred nisolone. The presence of multicompartment response variables and/or polyex ponential loss complicates the response patterns and resolution of pharmaco logic parameters of indirect response models and requires careful experimen tal and data analysis approaches in order to properly evaluate such pharmac odynamic responses. The occurrence of these alternative distribution or dis position components does nor alter the area under the effect curve (AUCE) w hich remains identical to the basic models. Model misselection was addresse d by testing fittings comparing the basic and new models. Use of the former for these more complex models does not severely perturb the calculated car dinal dynamic parameters. These models may provide improved insights into i ndirect responses with complexities in distribution or disposition.