INTEGRATED FUNCTIONS FOR 4 BASIC MODELS OF INDIRECT PHARMACODYNAMIC RESPONSE

The integrated solutions (ABEC, area between baseline and effect curve ) of four basic models of indirect pharmacodynamic responses are devel oped. These models assume that drug can inhibit or stimulate the produ ction or loss of the response variable. For two models (I and III) wit h monoexponential drug disposition, explicit formulas for the ABEC wer e obtained, where ABEC is a function of ln (1 + (D/V)/IC50) or ln (1 (D/V)/SC50) where D = dose, V = volume, and IC50 or SC50 = 50% effect ive concentration. Two other models (II and IV) were treated asymptoti cally with respect to small and large doses. Approximate formulas [e.g ., ABEC = constant(1) . ln (1 + (D/V)/IC50) + constant (2)] were deriv ed and the asymptotic behavior of the ABEC was established. In additio n, simulations were performed to assess the effects of drug absorption rates and polyexponential disposition on ABEC values. These models sh ow how pharmacokinetic and pharmacodynamic factors jointly determine t he net response to a single dose of drug.