In vivo integrated safety assessment of the cardiovascular system in drug development

Drug-induced cardiotoxicity still remains a major cause of concern, and non-clinical integrated risk assessments from both functional and structural alterations in the cardiovascular system are strongly required in the creation of drugs with superior safety profiles. Although systemic blood pressure, heart rate, and electrocardiogram are the main items in safety pharmacology studies, direct cardiac function assessments such as cardiac output and ventricular contractility, mentioned in ICH S7A guideline, are also desirable. General toxicology studies are important to detect structural changes through clinical pathology and histopathological examination, and translational biomarkers and metabolomics analysis with high extrapolation to humans also provide useful insights. In this paper, we will introduce our basic research to investigate the cardiac effects of milrinone, a cAMP phosphodiesterase III inhibitor in cynomolgus monkeys, and share the importance of comprehensive risk assessment in non-clinical in vivo studies.