ABSTRACT
In this chapter we seek to describe the stages of drug discovery, focusing on the utility of animal pain models and of pharmacokinetic/pharmacodynamic relationships (PK/PD) at each stage. In simple terms, the study of PK and PD in drug discovery is often paired and described in reciprocal terms, where PK is the analysis of how the body affects a drug, while PD is the analysis of how a drug affects the body. PK is dened by how a compound is absorbed, distributed, metabolized, and excreted; and PD is the measure of a compound’s ability to interact with its intended target
16.1 Introduction .................................................................................................. 349 16.2 Stages of Drug Discovery ............................................................................. 350
16.2.1 Target Validation .............................................................................. 350 16.2.2 Hit-to-Lead and Lead Optimization ................................................. 351 16.2.3 Screening .......................................................................................... 351 16.2.4 Development Candidate Proling ..................................................... 351
16.3 Role of Small Animal Models in Pain Drug Discovery ............................... 352 16.4 Which PK Parameters to Consider ............................................................... 355 16.5 Brain and Spinal Cord Penetration ............................................................... 356 16.6 PK/PD Modeling .......................................................................................... 358 16.7 Concluding Remarks .................................................................................... 365 References ..............................................................................................................366
leading to a biologic effect. In this chapter, we briey describe the stages of drug discovery and the process of dening structure−activity relationship (SAR) both in vitro, through optimization of several key characteristics collectively referred to as pharmaceutical proling, and in vivo, through the combined use of PK assessment and animal pain models to assess compound efcacy, noting the types and endpoints employed, and why it is important to pair these efcacy models with models of side effects. We follow this with data investigating penetration of compounds into the brain versus that in spinal cord and also correlate efcacy in rodent pain models with clinical efcacy. We hope to convey the importance of PK and of PK/ PD relationships in the process of developing pain drugs [aspects of the PK/PD relationships described in this chapter have been published elsewhere (Whiteside et al. 2008)].
