Chapter 4 - Defining Neuropharmacokinetic Parameters in CNS Drug Discovery to Determine Cross-Species Pharmacologic Exposure–Response Relationships

Abstract

Publisher Summary This chapter highlights the importance of both unbound brain compound concentrations and the unbound brain-to-unbound plasma compound concentration relationship, as defined by rat neuropharmacokinetic studies, to optimize the cross-species (i.e., animals and humans) translational pharmacology of small molecules targeting transmembrane proteins within the central nervous system (CNS). The current challenges in neuroscience drug discovery and development are largely attributed to overcoming the blood–brain barrier (BBB) for adequate compound exposure and the shortage of clinically translatable animal disease models. Thus, the chapter highlights what may be done using laboratory animals to enhance the progression of small-molecule neurotherapeutics, most specifically those targeting transmembrane proteins, from the laboratory to patients. The application of rat-derived neuropharmacokinetic parameters across species and the importance of both Cb,u and Cb,u:Cp,u should provide an ever greater chance at delivering adequate concentrations of a centrally acting compound to its intended target to test assuredly a pharmacological mechanism in any species, particularly humans.