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Confounders and Pharmacological Characterization When Using the QT, JTp, and Tpe Intervals in Beagle Dogs
Emmanuel Boulay1,2, Eric Troncy2, Michael V Accardi1
1Charles River Laboratories, Laval, Quebec, Canada.
International Journal of Toxicology
|October 16, 2020
Summary
Body temperature and stress impact cardiac repolarization biomarkers like QTca and JTpca in dogs. These findings are crucial for interpreting nonclinical drug safety studies and assessing proarrhythmic risk.
Area of Science:
- Cardiovascular Pharmacology
- Electrocardiography
- Drug Safety Assessment
Background:
- The corrected QT (QTc) interval is a key biomarker for proarrhythmic risk, but its limitations are increasingly recognized.
- The J to T-peak (JTp) interval offers an alternative for assessing drug-induced proarrhythmic risk.
- Understanding confounding factors is vital for accurate ECG interpretation in nonclinical studies.
Purpose of the Study:
- To evaluate the impact of pharmacological agents and common physiological confounders on covariate-adjusted QT (QTca), JTp (JTpca), and T-peak to T-end (Tpeca) intervals.
- To assess how body temperature and stress (epinephrine) affect these ECG parameters in Beagle dogs.
- To investigate the effects of dofetilide, ranolazine, and verapamil on QTca, JTpca, and Tpeca.
Main Methods:
- Beagle dogs were subjected to hyperthermic (42 °C) or hypothermic (33 °C) conditions.
- Epinephrine was administered to simulate stress-induced changes.
- Dofetilide, ranolazine, and verapamil were administered at various doses to assess pharmacological effects on ECG intervals.
Main Results:
- Body temperature negatively correlated with QTca and JTpca, while Tpeca remained minimally affected.
- Epinephrine administration led to QTca and JTpca shortening, potentially due to heart rate undercorrection.
- Ranolazine showed no significant ECG changes; verapamil decreased QTca/JTpca and increased Tpeca; dofetilide increased QTca/JTpca with inconsistent Tpeca effects.
Conclusions:
- Physiological factors like body temperature and stress can confound ECG measurements (QTca, JTpca, Tpeca) in nonclinical studies.
- These findings underscore the importance of considering potential confounders when interpreting ECG data from Beagle dog drug safety studies.
- Accurate interpretation of proarrhythmic risk requires accounting for these physiological influences on cardiac repolarization biomarkers.
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