Direct, indirect, and signal transduction response modeling

Based on the paradigm of mechanistic modeling, three types of pharmacodynamic models are introduced: direct effect, indirect response, and signal transduction. The underlying pharmacological and biological assumptions about the model structures and operations are provided along with examples of their applications. A brief historical perspective is introduced for each model class. Mathematical equations defining the model are presented and explored to link model parameters with model characteristics such as the shape of the response curve. The impact of dose on the time courses of pharmacodynamic responses is evaluated for large doses and exemplified with computer simulations. A common theme is the extent of delay between drug pharmacokinetics and response. When relevant, alternative parameterizations and parameter identifiability are discussed. Only the simplest forms of models are provided with some guidelines on how to build more complex models based on a systems pharmacology approach.