COMPARISON OF 4 BASIC MODELS OF INDIRECT PHARMACODYNAMIC RESPONSES

Four basic models for characterizing indirect pharmacodynamic response s after drug administration have been developed and compared. The mode ls are based on drug effects (inhibition or stimulation) on the factor s controlling either the input or the dissipation of drug response. Ph armacokinetic parameters of methylprednisolone were used to generate p lasma concentration and response-time profiles using computer simulati ons. It was found that the responses produced showed a slow onset and a slow return to baseline. The time of maximal response was dependent on the model and dose. In each case, hysteresis plots showed that drug concentrations preceded the response. When the responses ware fitted with pharmacodynamic models based on distribution to a hypothetical ef fect compartment, the resulting parameters were dose-dependent and inf erred biological implausibility. Indirect response models must be trea ted as distinct from conventional pharmacodynamic models which assume direct action of drugs. The assumptions, equations, and data patterns for the four basic indirect response models provide a starting point f or evaluation of pharmacologic effects where the site of action preced es or follows the measured response variable.