Abstract
Pediatric drug development is a critical global issue. Children undergo organ growth and exhibit different drug responses compared to adults. Therefore, it is important to consider physiological characteristics in pediatrics for evaluating drug efficacy and safety. We have investigated the development of novel therapeutics for pediatric heart failure (PHF) by focusing on the neonate-specific function of angiotensin II. PHF is a leading causes of child death. Nevertheless, the pharmacological treatment remains a long-standing unmet need. Angiotensin II is a key regulator of systemic circulation through binding to AT1 receptors (AT1R), which are coupled to G proteins and β-arrestins. Previously, we reported that TRV027, a β-arrestin-biased AT1R agonist, exerted a significant inotropic effect on the neonatal mouse heart. Moreover, chronic administration of TRV027 improved the cardiac contractility and survival rate of the PHF model mice. Remarkably, TRV027 did not induce significant changes in heart rate or cardiac oxygen consumption as well as any obvious abnormalities in various organs. In contrast, candesartan, an AT1R blocker, failed to improve survival rate of PHF model mice and led to postnatal dysgenesis and dysfunction of the kidney. Our findings suggest that TRV027 is an effective and safe candidate for PHF therapeutic drugs. In this session, we would like to present recent insights into the stage-specific physiological function of the neonatal heart and discuss non-clinical assessments for evaluating efficacy and safety in pediatric drug research and development.
