Abstract
Inhibiting the human ether-a-go-go-related gene (hERG)-encoded potassium ion channel is positively correlated with QT-interval prolongation in vivo, which is considered a risk factor for the occurrence of Torsades de Pointes (TdP). A pharmacokinetic/pharmacodynamic model was developed for four compounds that reached the clinic, to relate drug-induced QT-interval change in awake dogs and humans and to derive a translational scaling factor a 1. Overall, dogs were more sensitive than humans to QT-interval change, an a 1 of 1.5 was found, and a 10% current inhibition in vitro produced a higher percent QT-interval change in dogs as compared to humans. The QT-interval changes in dogs were predictive for humans. In vitro and in vivo information could reliably describe the effects in humans. Robust translational knowledge is likely to reduce the need for expensive thorough QT studies; therefore, expanding this work to more compounds is recommended.
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Acknowledgments
We thank the healthy volunteers, patients and their families, investigators, study centre staff, and Janssen study personnel, in particular those who provided input into the analysis and/or who reviewed the article but who are not listed as authors. This research was sponsored by Janssen Research & Development, Beerse, Belgium.
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Preclinical in vivo studies were conducted in accordance with ‘the provision of the European Convention’ on the protection of vertebrate animals, which are used for experimental and other scientific purposes, and with ‘the Appendices A and B’, made in Strasbourg on 18 March 1986 (Belgian Act of 18 October 1991). The clinical studies were conducted in accordance with the principles set forth in the Declaration of Helsinki, the International Conference on Harmonization, and the Guidelines for Good Clinical Practice. Written informed consent was obtained from each subject prior to participation in the trials.
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K.V.A., A.T., D.G., F.D.R., and A.V. are employees of Janssen R&D, a division of Janssen Pharmaceutica NV. A.V. also works as a Guest Professor at the Faculty of Pharmaceutical Sciences at Ghent University.
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Marostica, E., Van Ammel, K., Teisman, A. et al. PK/PD Modelling of the QT Interval: a Step Towards Defining the Translational Relationship Between In Vitro, Awake Beagle Dogs, and Humans. AAPS J 18, 1000–1012 (2016). https://doi.org/10.1208/s12248-016-9920-3
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DOI: https://doi.org/10.1208/s12248-016-9920-3