Confounders and Pharmacological Characterization When Using the QT, JTp, and Tpe Intervals in Beagle Dogs

Abstract

Introduction: Corrected QT (QTc) interval is an essential proarrhythmic risk biomarker, but recent data have identified limitations to its use. The J to T-peak (JTp) interval is an alternative biomarker for evaluating drug-induced proarrhythmic risk. The aim of this study was to evaluate pharmacological effects using spatial magnitude leads and DII electrocardiogram (ECG) leads and common ECG confounders (ie, stress and body temperature changes) on covariate adjusted QT (QTca), covariate adjusted JTp (JTpca), and covariate adjusted T-peak to T-end (Tpeca) intervals. Methods: Beagle dogs were exposed to body hyper- (42 °C) or hypothermic (33 °C) conditions or were administered epinephrine to assess confounding effects on heart rate corrected QTca, JTpca, and Tpeca intervals. Dofetilide (0.1, 0.3, 1.0 mg/kg), ranolazine (100, 140, 200 mg/kg), and verapamil (7, 15, 30, 43, 62.5 mg/kg) were administered to evaluate pharmacological effects. Results: Covariate adjusted QT (slope −12.57 ms/°C) and JTpca (−14.79 ms/°C) were negatively correlated with body temperature but Tpeca was minimally affected. Epinephrine was associated with QTca and JTpca shortening, which could be related to undercorrection in the presence of tachycardia, while minimal effects were observed for Tpeca. There were no significant ECG change following ranolazine administration. Verapamil decreased QTca and JTpca intervals and increased Tpeca, whereas dofetilide increased QTca and JTpca intervals but had inconsistent effects on Tpeca. Conclusion: Results highlight potential confounders on QTc interval, but also on JTpca and Tpeca intervals in nonclinical studies. These potential confounding effects may be relevant to the interpretation of ECG data obtained from nonclinical drug safety studies with Beagle dogs.

Translational Models and Tools to Reduce Clinical Trials and Improve Regulatory Decision Making for QTc and Proarrhythmia Risk (ICH E14/S7B Updates)

“…For clinical data, this includes new clinical drug studies, 62–69 comparison of different measurement algorithms, 70–73 improved heart rate assessment correction, 74 and multiple studies from independent groups re‐analyzing the FDA clinical trial data 70,71,75,76 . For nonclinical studies, this includes drugs overlapping with clinical study drugs and many interesting drugs without clinical data 35,77–82 . For example, a recent nonclinical in vivo study focused on vanoxerine, 80 an interesting drug with large QTc prolongation that has multi‐ion channel effects, and was hypothesized by a sponsor to be of relatively low risk for TdP 83 .…”

“…Characterizing the exposure-response relationship is important to determine the potential amount of QTc prolongation in certain patient subgroups that may be subjected to higher drug exposures and evaluate whether the QTc prolongation plateaus, suggesting an indirect mechanism that may be of lower risk. There are multiple potential indirect mechanisms that can lead to QTc prolongation (i.e., not acting through direct ion channel effects), such as from autonomic nervous system effects, 33,34 changes in body temperature, 35 electrolyte abnormalities, 36 and others still being defined (Figure 6c). 37 Further investigation should differentiate which mechanisms can be associated with TdP vs. those that are not.…”

“…70,71,75,76 For nonclinical studies, this includes drugs overlapping with clinical study drugs and many interesting drugs without clinical data. 35,[77][78][79][80][81][82] For example, a recent nonclinical in vivo study focused on vanoxerine, 80 an interesting drug with large QTc prolongation that has multi-ion channel effects, and was hypothesized by a sponsor to be of relatively low risk for TdP. 83 However, in a phase III trial for atrial fibrillation, 3 of the first 26 patients developed TdP.…”