Translation of Safety Pharmacology Studies

Nonclinical safety pharmacology studies are widely used to assess undesirable effects of investigational compounds on cardiovascular, central nervous, and respiratory systems. These studies are conducted prior to first-in-human clinical trials, using multiple in vitro and in vivo experimental assays or models. Results from safety pharmacology studies are used to make critical go/no-go decisions that inform successful development of novel therapies. To enable this impactful decision-making, it is vital to quantitatively understand the translation of effects observed in nonclinical safety pharmacology studies across models, species, and, most importantly, to the clinical outcome. The following chapter discusses standard approaches used to understand quantitative translation of safety pharmacology assays along with utility and limitations of parameters such as sensitivity, specificity, predictive values, etc. Currently available, systematic translation analyses for safety pharmacology studies are also discussed. Overall, robust data is available for establishing translation of cardiovascular assays, especially assays for assessing the risk of delayed ventricular repolarization, QT prolongation, and torsade de pointes. These assays have high predictive capacity with results translating well into the clinical setting. Similarly, hemodynamic endpoints (blood pressure and heart rates) assessed as part of the in vivo telemetry studies also predict the clinical outcome with high sensitivity and specificity. In contrast, systematic analyses of central nervous system (CNS) and respiratory assays are relatively sparse. The limited analyses that are available indicate that these assays do not translate well to the clinical setting.