Role of baseline parameters in determining indirect pharmacodynamic responses

Indirect Response Models account for the pharmacodynamics of numerous drugs which inhibit or stimulate the production (k(in)) or loss (k(out)) of the response variable (R). The dose and pharmacokinetics, capacity (S(max), I(max)), and potency (SC(50), IC(50)) factors of the Hill function incorporated in these models are the primary determinants of overall responsiveness. However, the initial or baseline value for the response (R(0) = k(in)/k(out)) should also be considered as an important factor for the net response. Using Indirect Response Model III (stimulation of input) as an example, the net area under the effect curve (AUEC(NET)) can be proportional to the R(0) values. Such a feature is demonstrated in this report by computer simulations, by examination of the integral of the simulated response vs time profiles, and with examples from the literature. Also shown is an adjustment of R(0) when the therapeutic agent is an endogenous substance. These analyses show that the role of R(0) and k(in) should not be overlooked as determinants of indirect responses and source of variation among subjects or patient groups.