The Dog's Role in the Preclinical Assessment of QT Interval Prolongation

Abstract

During the development of a new therapeutic, few pharmacodyamic outcomes currently receive as much scrutiny as the effect of a potential medication on the electrocardiographic QT interval. The recent withdrawal from marketing of several drugs due to potential drug-related cardiac arrhythmias have greatly increased concern about drug-related changes on the QT interval. In order to reduce the incidence of these idiosyncratic episodes, regulatory agencies have suggested that sponsors use more rigorous methodology during the safety evaluation of new pharmaceuticals. Along with enhanced electrocardiographic assessments during clinical trials, advanced preclinical examinations of effect on QT interval and ventricular repolarization have become de rigueur. In this arena, the beagle dog is the preclinical species often associated with the most reliable predictivity for human safety assessment. To this end, canine models of cardiovascular safety assessment are discussed along with the relevance of these assays to human electrocardiography.

Overt and Latent Cardiac Effects of Ozone Inhalation in Rats: Evidence for Autonomic Modulation and Increased Myocardial Vulnerability

“…Nevertheless, increased HRV may also have links to adverse health outcomes. For example, Farkas et al (2008) showed that increased parasympathetic tone is a precursor to drug-induced torsade de pointes (a precursor arrhythmia to ventricular fibrillation; Gralinski 2003) and is associated with increased apnea severity in obese patients (Reynolds et al 2007), adverse cardiovascular events in type II diabetics (Eguchi et al 2010), and increased mortality in heart failure (Stein et al 2005). The relationship between increased parasympathetic tone, O 3 exposure, and cardiac dysfunction requires further study.…”

Role of Autonomic Reflex Arcs in Cardiovascular Responses to Air Pollution Exposure

“…Importantly, increased HRV may also have links to adverse health outcomes. Increased parasympathetic tone is a precursor to drug-induced torsade de pointes [27] (a precursor arrhythmia to ventricular fibrillation [28]) and is associated with increased apnea severity in obese patients [29], adverse cardiovascular events in type II diabetics [30], and increased mortality in heart failure [31]. While the mechanisms triggering changes in HRV, and thus autonomic tone, have not been fully delineated and are likely numerous and diverse in nature, the best studied mechanism with respect to acute air pollution-induced effects is the activation of pulmonary neural reflexes.…”

Dog left ventricular midmyocardial myocytes for assessment of drug‐induced delayed repolarization: short‐term variability and proarrhythmic potential

“…As the distribution of ion channel proteins and ionic currents that determine the AP shape and duration are strikingly similar in dog and human ventricles (Szabo et al. , 2005), the beagle dog is a commonly used preclinical species to test the effects of new drugs on cardiac repolarization (Gralinski, 2003), and repolarization of the midmyocardial ventricyular myocytes usually determines the end of the T‐wave (Antzelevitch, 2007), which means that data from these myocytes may better relate to QT measurements, the main motivation of this investigation was to determine if left ventricular midmyocardial myocytes (LVMMs) from beagle dogs could be used as a preclinical model to assess drug effects on AP repolarization. In particular, we set out to: (i) test the effects of six reference drugs (four of them with a known TdP risk) on APD; (ii) determine what temporal STV(APD), triangulation and incidence of early afterdepolarizations (EADs) data they yield in the presence of the validation set; and (iii) compare data from LVMMs to those obtained in PFs from beagle dogs.…”