Breadth of Pharmacology Modeling: Fundamentals of Pharmacokinetics, Pharmacodynamics, and Mechanistic Modeling.

The basic principles of pharmacokinetics and pharmacodynamics represent the foundational knowledge base upon which complex quantitative systems pharmacology models of drug action are built. This chapter provides a high-level overview of fundamental factors that determine the disposition and physiological responses to drugs and the application of compartmental models to characterize the time-course of drug exposure and pharmacological effects. Many of these processes are subject to capacity-limitation, which is defined by a nonlinear function containing a driving substrate concentration and parameters representing the capacity of the process and a substrate affinity constant. Most contemporary mechanism-based pharmacodynamic models are developed by integrating an appropriate drug exposure forcing function, a mathematical model of the interaction between the drug and its target (i.e., binding and transduction), and the physiological turnover (or production and loss) of the biomarker of drug response. Numerous complexities can be introduced to basic models, such as homeostatic feedback, tolerance mechanisms, disease progression, drug interactions, circadian rhythms, and many others. These basic and advanced models can be viewed as the groundwork for the development of comprehensive quantitative systems pharmacology models that are applicable across biological spatiotemporal scales.