However, for some drugs, responses take time for their development and are not apparently related to plasma concentrations because of an equilibration delay between the plasma compartment and biophase. A static function such as a linear model, an E max model, or a sigmoid E max model can often be applied to characterize the relationship between plasma concentrations and pharmacodynamic profiles of drugs. Reversible pharmacodynamic effects of drugs can be broadly classified as direct and indirect responses.ĭirect responses are effects produced by drugs that act immediately on measured variables, and are observed in relation to drug concentrations at the site of action (biophase). In addition, mechanism-based physiologic models can be useful for estimating inaccessible pharmacodynamic steps and parameters.

The selection of an appropriate model should, if possible, be based on the mechanism of action of the drug and other facets of biological reality. In order to understand and predict the pharmacologic behaviour of drugs, it is important to quantify the time course of pharmacodynamic responses in relation to the plasma drug concentrations. Indirect response models which have a logical mechanistic basis account for time-delays in many responses and are widely applicable in clinical pharmacology. These models can be readily extended to accommodate additional complexities such as nonstationary or circadian baselines, equilibration delay, depletion or accumulation of a precursor pool, sigmoidicity, or other mechanisms.

A list of other uses of these models is provided. The applicability of these basic IDR models to characterize pharmacodynamic responses of diverse drugs such as inhibition of gastric acid secretion by nizatidine and stimulation of MX protein synthesis by interferon α-2a is demonstrated. The principles underlying IDR models and their response patterns are described.

This review describes four basic physiologic indirect pharmacodynamic response (IDR) models which have been proposed to characterize the pharmacodynamics of drugs that act by indirect mechanisms such as inhibition or stimulation of the production or dissipation of factors controlling the measured effect.

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