Key result
Treatment-specific slope correction prevents false-positive QTc prolongation vs. vehicle slope during large HR increases.
Why the study?
A reliable method is required to determine heart rate corrected QT-interval (QTc) in nonclinical studies, but the standard individual animal correction may not perform adequately with large heart rate changes.
Using a treatment-specific slope for individual animal QT correction prevents false-positive QTc prolongation in the presence of large magnitude heart rate changes in preclinical studies.
Answers are grounded in this paper and cite their sources.
May reduce false-positive QT signals in canine studies with large HR changes; leaves open validation for human cardiovascular safety assessment.
The ICH E14/S7B Q&As emphasize importance of robust in vivo cardiovascular studies, in appropriate non-rodent (dog/NHP) species, to perform an integrated risk assessment. It is well established that the QT-interval is inversely correlated with heart rate (HR) and a reliable method is required to determine heart rate corrected QT-interval (QTc-interval) for accurate assessment of QT liability in nonclinical studies. The individual animal correction method using QT/HR relationship (slope) from each animal's vehicle or baseline data is the recommended best practice. However, this method may not perform adequately in the presence of large HR changes. We evaluated the performance of two different individual animal corrections 1) using vehicle slope (QTcVeh) and 2) using treatment specific slope (QTcT) for two compounds. Hydralazine, a direct vasodilator, was included as it caused a large HR increase but does not have a QT-liability (hERG negative). Dofetilide was included as it is a direct hERG blocker without confounding HR changes. Each compound was tested separately in standard crossover paradigm in dogs ( N = 4) at doses of 0.1, 1 and 3 mg/kg (Hydralazine) or 0.01, 0.03 and 0.15 mg/kg (Dofetilide). QTcVeh was calculated using the 24-h QT/HR slope from the vehicle treatment. QTcT was calculated using the 24-h QT/HR slope from the treatment phase at each dose level. Hydralazine caused marked decreases in blood pressure (−6 to −39 mmHg) and increases in HR (+18 to +81 bpm), with significant decreases in QT (−13 to −29 msec) at ≥1 mg/kg. QTcVeh was also increased (+9 to +11 msec), whereas QTcT did not show any statistically significant increase demonstrating adequate correction. Dofetilide did not cause any change in HR but did exhibit dose dependent increases in QT (+12 to +27 msec) as well as both QTcVeh (+10 to +27 msec) and QTcT (+10 to +28 msec). These results show that individual animal correction using the ‘standard’ vehicle slope does not perform adequately in the presence of large magnitude HR increases. In such instances, an alternative approach (e.g. using treatment specific slope) should be considered to prevent a false positive for QTc prolongation.
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Bhatt et al. (2026) studied Confounding heart rate changes affecting QT interval assessment (n=4). Treatment specific QT/HR slope (QTcT) correction vs. Standard vehicle slope (QTcVeh) correction was evaluated on Heart rate corrected QT-interval (QTc-interval) prolongation. Individual animal correction using a treatment-specific slope prevented false positive QTc prolongation in the presence of large magnitude heart rate increases compared to standard vehicle slope.
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