Advancing nonclinical blood pressure assessment: Current practices and future directions in drug development

Drug-induced hypertension or hypotension can have significant clinical consequences, yet BP regulation involves complex, multi-level mechanisms, making translational assessment of pressor effects more challenging than for endpoints such as cardiac repolarization (hERG/QT). Current nonclinical BP studies primarily use telemetry in conscious, freely moving non-rodents, enabling continuous high-fidelity hemodynamic monitoring. These models show reasonable concordance with human data, but some translational challenges exist. The Health and Environmental Sciences Institute (HESI) Global Integrative Strategies Working Group (WG) was established to improve nonclinical cardiovascular (CV) safety assessment through more informative, translational preclinical models. After earlier success characterizing drug-induced effects on cardiac contractility, the WG focused on drug-associated blood pressure (BP) changes. Provided here is the importance of nonclinical models in predicting BP changes and associated challenges. A HESI Global multi-site study focused on addressing these gaps is also introduced. The study aimed to evaluate the reproducibility and translatability of the standard telemetered dog model using compounds with well-characterized mechanisms (midodrine, nifedipine, hydralazine, prazosin, milrinone). Early results show consistent hemodynamic profiles across laboratories, with final results published separately, showing utility of this model for BP liability assessment.