Cardiotoxicity
Drug-induced damage to the heart muscle or cardiac conduction system. Cardiac safety assessment (including QTc interval monitoring) is a standard requirement in peptide drug development. Cardiovascular outcomes trials for metabolic peptide drugs specifically evaluate cardiac safety alongside efficacy.
Technical Context
Cardiac safety assessment (ICH S7B/E14): non-clinical hERG channel assay (assessing risk of QTc prolongation/torsades de pointes), action potential duration studies, telemetry studies in conscious animals (QTc, heart rate, blood pressure), and thorough QT/QTc study in humans (Phase I study specifically designed to evaluate cardiac repolarisation effects). The thorough QT study (TQT) is typically a randomised, double-blind, placebo- and positive-controlled (moxifloxacin), crossover design in healthy volunteers. For peptide drugs, QTc prolongation risk is generally low because peptides typically do not block ion channels. However, indirect cardiac effects are important: GLP-1 RAs increase heart rate by 2-4 bpm (mechanism debated — possibly related to sympathetic activation or direct sinoatrial node effects), which must be characterised and its clinical significance assessed in cardiovascular outcomes trials.