Application of in vivo animal models to characterize the pharmacokinetic and pharmacodynamic properties of drug candidates in discovery settings

Abstract

A goal of preclinical discovery is the identification of drug candidates suitable for clinical testing. Successful integration of in vitro and in vivo experimental data sets can afford projections of human dose regimens anticipated to be safe and therapeutically beneficial. While in vitro experiments guide new chemical syntheses and are essential to understanding drug action and disposition, in vivo characterizations provide unique insight into complex biological systems that control concentrations at the site of action and pharmacologic response. Pharmacokinetic and pharmacodynamic (PK/PD) concepts underlying drug disposition and response provide a quantitative framework with which to identify potential clinical candidates. To improve throughput in earlier stages of drug discovery, in vivo pharmacokinetic study designs such as cassette dosing and sparse sampling schemes have been utilized. In later stages of discovery, pharmacokinetic studies using chemical inhibitors or surgical and genetic animal models are used to characterize the underlying determinants of drug disposition. In a complimentary fashion, modeling of in vivo pharmacodynamic effects may quantitatively link biomarkers to pharmacological response, validate in vitro to in vivo correlations and underwrite predictions of efficacious exposure targets. When applied to in vivo discovery data, PK/PD models have aided in understanding mechanisms of pharmacological response such as receptor theory in the central nervous system and cell turnover concepts in infectious disease and oncology. This review considers the role of in vivo testing toward understanding the pharmacokinetic and pharmacodynamic attributes of lead candidates in drug discovery.