Mechanistic Pharmacokinetic/Pharmacodynamic Models II

Several major classes of drugs exert their pharmacological effects by means of irreversible interactions with cells and/or proteins or by altering signal transduction processes. The goal of this chapter is to review mechanism-based pharmacokinetic/pharmacodynamic (PK/PD) models that have been developed to characterize the pharmacological properties of diverse compounds that utilize these mechanisms of drug action. State-of-the-art models often reflect the fundamental principles of capacity-limitation and biological turnover processes, attempting to resolve the drug- and system specific properties that control the time-course of pharmacological responses. Prolonged drug exposure may result in the development of drug tolerance and/or a rebound phenomenon may occur when the agent is no longer administered, whereby additional modeling components are required to capture these functional adaptation processes. Approaches to integrating sources of system complexities into structural models are discussed and serve to demonstrate the unique application of PK/PD modeling to characterize and interpret data derived from complex pharmacological systems.