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Consideration of Pharmacokinetic Pharmacodynamic Relationships in the Discovery of New Pain Drugs.


In: Kruger L, Light AR, editors.


Translational Pain Research: From Mouse to Man. Boca Raton, FL: CRC Press/Taylor & Francis; 2010. Chapter 16.
Frontiers in Neuroscience.


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 defined 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 leading to a biologic effect. In this chapter, we briefly describe the stages of drug discovery and the process of defining structure-activity relationship (SAR) both in vitro, through optimization of several key characteristics collectively referred to as pharmaceutical profiling, and in vivo, through the combined use of PK assessment and animal pain models to assess compound efficacy, noting the types and endpoints employed, and why it is important to pair these efficacy 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 efficacy in rodent pain models with clinical efficacy. 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)].

Copyright © 2010 by Taylor and Francis Group, LLC.

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