ORIGINAL RESEARCH article
Front. Pharmacol.
Sec. Translational Pharmacology
Volume 16 - 2025 | doi: 10.3389/fphar.2025.1619547
Modelling of clinical TQT studies outcomes from preclinical cardiovascular safety pharmacology studies using the One-step QTc model
Provisionally accepted
- 1ERBC, Baugy, France
- 2Eli Lilly, Indianapolis, United States
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Retrospective translational analyses have shown a high rate of false negatives between clinical thorough QT studies (TQT) and preclinical cardiovascular safety pharmacology studies. The aim of this work was to model the results of clinical TQT studies from cardiovascular safety pharmacology studies conducted on a large set of reference drugs in beagle dogs by implanted telemetry. All preclinical studies were based on a standard four-animal crossover design comparing the vehicle to the reference drug. The model used was based on the one-step QTc correction model. This model was adapted in order to apply the same statistical method in preclinical studies as in clinical trials. The sensitivity of the model made it possible to detect QTc prolongation of at least 5 ms with all reference hERG blockers known to cause QT prolongation in humans. Modelling of moxifloxacin (10 mg/kg, po) effects was in agreement with data published from clinical TQT studies with moxifloxacin 400 mg showing a QTc prolongation greater than 5 ms between 1 and 4 hours post-dose. This study shows a noticeable reduction in the risk of false negatives with several references drugs associated with a phenomenon of concealed QTc prolongation. Moreover, several reference drugs did change the slope of the QT/HR slope justifying the principles of the one-step QTc model. In conclusion, modelling results of TQT studies with the one-step QTc model for applying the same statistical approach as in the clinic can improve the translational value of preclinical cardiovascular safety pharmacology studies and reduce the risk of false negatives.
Keywords: electrocardiogram, QT interval correction, safety pharmacology, hERG blockers, QT prolongation
Received: 28 Apr 2025; Accepted: 09 Sep 2025.
Copyright: © 2025 Champeroux, Fares and Leishman. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Pascal Champeroux, ERBC, Baugy, France
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