Development of translational pharmacokinetic-pharmacodynamic models

Abstract

Contemporary models in the field of pharmacokinetic-pharmacodynamic (PK-PD) modeling often incorporate the fundamental principles of capacity limitation and operation of turnover processes to describe the time course of pharmacological effects in mechanistic terms. This permits the identification of drug- and system-specific factors that govern drug responses. There is considerable interest in utilizing mechanism-based PK-PD models in translational pharmacology, whereby in silico, in vitro, and preclinical data may be effectively coupled with relevant models to streamline the discovery and development of new therapeutic agents. These translational PK-PD models form the subject of this review.

Figure 1

Major components contributing to assembly of mechanism-based pharmacokinetic–pharmacodynamic (PK–PD) models. GI, gastrointestinal.

Figure 2

Time frames of turnover, life span, and half-life of various physiological materials, structures, and functions in humans. AChE, acetylcholinesterase; cAMP, adenosine 3′,5′-monophosphate; EEG, electroencephalogram; IgG, immunoglobulin G.

Figure 3

Components of mechanism-based pharmacokinetic–pharmacodynamic (PK–PD) models for translation of animal data to human clinical pharmacology. Predictive techniques (top of arrows) can be augmented by selective measurements (bottom of arrows). PBPK, physiology-based PK; QSPR, quantitative structure–PK/PD relationship.