Comparison of the IKr blockers moxifloxacin, dofetilide and E-4031 in five screening models of pro-arrhythmia reveals lack of specificity of isolated cardiomyocytes

作者：Nalos L; Varkevisser R; Jonsson M K B; Houtman M J C; Beekman J D; van der Nagel R; Thomsen M B; Duker G; Sartipy P; de Boer T P; Peschar M; Rook M B; van Veen T A B; van der Heyden M A G; Vos M A^*

来源：British Journal of Pharmacology, 2012, 165(2): 467-478.

DOI：10.1111/j.1476-5381.2011.01558.x

• cardiac safety pharmacology
• human embryonic stem cell-derived cardiomyocytes
• isolated cardiomyocytes
• beat-to-beat variability of repolarization
• methoxamine-sensitized rabbit
• chronic AV block dog
• moxifloxacin
• dofetilide

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).
EXPERIMENTAL APPROACH
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.
KEY RESULTS
At clinically relevant concentrations (5-12 mu M), moxifloxacin was free of pro-arrhythmic properties in all assays with the exception of the isolated CM, in which 10 mu M induced EADs in 35% of the CAVB CM and in 23% of the rabbit CM. At supra-therapeutic concentrations (>= 100 mu M), 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 I(Kr) blocking drugs moxifloxacin and dofetilide or E4031.

• 出版日期2012-1