Mechanistic Pharmacokinetic/pharmacodynamic Modeling in Isolated Perfused Organs and at the Whole-Body Level

In the past, the development of pharmacokinetic/pharmacodynamic (PK/PD) models for quantitating the time course of drug responses was mainly based on two types of models, the empirical effect compartment model that simply accounts for the delay between effect and plasma concentration (hysteresis) and the mechanism-based so-called indirect response model. The first approach traces back to a paper by Segre (1) and its application was popularized by Holford and Sheiner (2); indirect response models were introduced by Jusko's group (3). (omitted)