Preclinical to clinical translation of hemodynamic effects in cardiovascular safety pharmacology studies

Abstract

Cardiovascular (CV) safety-related attrition is an important contributor to the loss of promising drug candidates during development. CV safety pharmacology studies are conducted to identify these safety effects. Understanding translation of CV endpoints (specifically, heart rate [HR], and blood pressure [BP]) across preclinical animal models and to the clinic is critical in developing a robust CV derisking strategy. To this end, we investigated translation of HR and BP endpoints using data from 83 compounds that were tested in telemetry studies in rat and large animal (LA; dog or monkey) and 79 compounds that were tested in LA telemetry studies and human phase I clinical trials. Sensitivity, specificity as well as predictive values were calculated for rat to LA model comparison and for LA to human studies comparison. The rat CV model showed good concordance (sensitivity ¼ 84% and specificity ¼ 71%) for LA BP and HR changes. Similarly, LA CV measures of HR and BP showed good concordance (sensitivity ¼ 78% and specificity ¼ 79%) to clinical changes. The CV effects generally occurred within 0.3-3 free plasma concentration across species. Directionality of BP and HR change was conserved between LA to humans. However, for rat to LA comparisons the directionality of change was opposite for 23%-26% compounds. In conclusion, these data establish the translation of HR and BP from preclinical to clinical studies and emphasize the importance of preclinical animal models in the examination of CV safety of drugs.