Fig. 1.

Basic components of pharmacodynamic models. The time-course of drug concentrations in a relevant biological fluid (e.g., plasma, C_p) or the biophase (C_e) is characterized by a mathematical function that serves to drive PD models. The biosensor process involves the interaction between the drug and the pharmacologic target (R), and may be described using various receptor-occupancy models, may require equations that consider the kinetics of the drug–receptor complex formation and dissociation, or may encompass irreversible drug–target interactions. Many drugs act via indirect mechanisms and the biosensor process may serve to stimulate or inhibit the production (k_in) or loss (k_out) of endogenous mediators. These altered mediators may not represent the final observed drug effect (E) and further time-dependent transduction processes may occur, thus requiring additional modeling components. System complexities such as drug interactions, functional adaptation, changes with pathophysiology, and other factors may play a role in regulating drug effects after acute and long-term drug exposure (adapted from ref. 33).