A tutorial for model-based evaluation and translation of cardiovascular safety in preclinical trials.

ABSTRACT

Assessment of drug-induced effects on the cardiovascular (CV) system remains a critical component of the drug discovery process enabling refinement of the therapeutic index. Predicting potential drug-related unintended CV effects in the preclinical stage is necessary for first-in-human dose selection and preclusion of adverse CV effects in the clinical stage. According to the current guidelines for small molecules, nonclinical CV safety assessment conducted via telemetry analyses should be included in the safety pharmacology core battery studies. However, the manual for quantitative evaluation of the CV safety signals in animals is available only for electrocardiogram parameters (i.e., QT interval assessment), not for hemodynamic parameters (i.e., heart rate, blood pressure, etc.). Various model-based approaches, including empirical pharmacokinetic-toxicodynamic analyses and systems pharmacology modeling could be used in the framework of telemetry data evaluation. In this tutorial, we provide a comprehensive workflow for the analysis of nonclinical CV safety on hemodynamic parameters with a sequential approach, highlight the challenges associated with the data, and propose respective solutions, complemented with a reproducible example. The work is aimed at helping researchers conduct model-based analyses of the CV safety in animals with subsequent translation of the effect to humans seamlessly and efficiently.