Physiologic corrections for ECG intervals beyond QT

Abstract

Quantitative assessment of ECG intervals informs investigators of drug activation within the heart. A limitation to understanding a test article's influence on specific ion channels can be due to extreme alterations in physiologic parameters, namely heart rate (HR) and body temperature (BT). While it's well understood that ECG intervals exhibit an expected inverse relationship to HR, it may be difficult to determine if changes in ECG intervals are disproportionately shortened or prolonged at extreme HRs. As QT prolongation is a known biomarker for increased Torsadogenic potential, in alignment with ICHS7B, HR correction formulae are employed to correct for QT interval duration. However, no direct guidance directs the correction of alternate intervals. Due to this, investigators are left to correlative comparisons between magnitude of change in HR and magnitude of change in the PR interval. While greater risks are known to be associated with ventricular arrhythmias, disproportionate shortening or prolongation of the PR interval may represent AV node dissociation, which could lead to AV Nodal reentry and subsequent potential of more significant ventricular arrhythmias. Recent studies have also suggested increased risk of atrial arrhythmias, heart failure, and mortality in patients with PR prolongation. In addition to direct HR influence, associations between BT and QT duration have been characterized in the dog (Van der Linde, 2008), but have not been completely profiled in the non-human primate (NHP). To address these gaps in physiologic corrections, an investigation of historical data was performed to determine if corrections were possible. Internal review (~60 animals/species – Beagle Dogs, NHPs) was utilized to establish the relationships between PR vs RR and QT vs BT intervals. Through this investigation, a species-specific correction for BT was established for NHP and exhibited equitable concordance to an individual animal correction. Therefore, this correction was believed to be an adequate precursory correction formula to adopt during acquisition to monitor for QT/BT. Contrarily, population-based corrections for PR vs RR exhibited variance, and individual study-based corrections were found to be most applicable. It is believed that employment of these additional physiological corrections may better profile the associated risks of new chemical entities.