These authors contributed equally.
Comparison of the IKr blockers moxifloxacin, dofetilide and E-4031 in five screening models of pro-arrhythmia reveals lack of specificity of isolated cardiomyocytes
Article first published online: 16 DEC 2011
© 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society
British Journal of Pharmacology
Volume 165, Issue 2, pages 467–478, January 2012
How to Cite
Nalos, L., Varkevisser, R., Jonsson, M., Houtman, M., Beekman, J., van der Nagel, R., Thomsen, M., Duker, G., Sartipy, P., de Boer, T., Peschar, M., Rook, M., van Veen, T., van der Heyden, M. and Vos, M. (2012), Comparison of the IKr blockers moxifloxacin, dofetilide and E-4031 in five screening models of pro-arrhythmia reveals lack of specificity of isolated cardiomyocytes. British Journal of Pharmacology, 165: 467–478. doi: 10.1111/j.1476-5381.2011.01558.x
- Issue published online: 16 DEC 2011
- Article first published online: 16 DEC 2011
- Accepted manuscript online: 30 JUN 2011 01:38PM EST
- Received; 25 February 2011; Revised; 28 April 2011; Accepted; 17 June 2011
- cardiac safety pharmacology;
- human embryonic stem cell-derived cardiomyocytes;
- isolated cardiomyocytes;
- beat-to-beat variability of repolarization;
- methoxamine-sensitized rabbit;
- chronic AV block dog;
BACKGROUND AND PURPOSE
Drug development requires the testing of new chemical entities for adverse effects. For cardiac safety screening, improved assays are urgently needed. Isolated adult cardiomyocytes (CM) and human embryonic stem cell-derived cardiomyocytes (hESC-CM) could be used to identify pro-arrhythmic compounds. In the present study, five assays were employed to investigate their sensitivity and specificity for evaluating the pro-arrhythmic properties of IKr blockers, using moxifloxacin (safe compound) and dofetilide or E-4031 (unsafe compounds).
Assays included the anaesthetized remodelled chronic complete AV block (CAVB) dog, the anaesthetized methoxamine-sensitized unremodelled rabbit, multi-cellular hESC-CM clusters, isolated CM obtained from CAVB dogs and isolated CM obtained from the normal rabbit. Arrhythmic outcome was defined as Torsade de Pointes (TdP) in the animal models and early afterdepolarizations (EADs) in the cell models.
At clinically relevant concentrations (5–12 µM), moxifloxacin was free of pro-arrhythmic properties in all assays with the exception of the isolated CM, in which 10 µM induced EADs in 35% of the CAVB CM and in 23% of the rabbit CM. At supra-therapeutic concentrations (≥100 µM), moxifloxacin was pro-arrhythmic in the isolated rabbit CM (33%), in the hESC-CM clusters (18%), and in the methoxamine rabbit (17%). Dofetilide and E-4031 induced EADs or TdP in all assays (50–83%), and the induction correlated with a significant increase in beat-to-beat variability of repolarization.
CONCLUSION AND IMPLICATIONS
Isolated cardiomyocytes lack specificity to discriminate between TdP liability of the IKr blocking drugs moxifloxacin and dofetilide or E4031.