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

L Nalos; R Varkevisser; Mkb Jonsson; Mjc Houtman; Jd Beekman; R van der Nagel; Morten Bækgaard Thomsen; G Duker; P Sartipy; Tp de Boer; M Peschar; Mb Rook; Tab van Veen; Mag van der Heyden; Ma Vos

doi:10.1111/j.1476-5381.2011.01558.x

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

L Nalos, R Varkevisser, Mkb Jonsson, Mjc Houtman, Jd Beekman, R van der Nagel, Morten Bækgaard Thomsen, G Duker, P Sartipy, Tp de Boer, M Peschar, Mb Rook, Tab van Veen, Mag van der Heyden, Ma Vos

Physiology of circulation, kidney and lung

56 Citations (Scopus)

Abstract

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 I _Kr 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 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 I _Kr blocking drugs moxifloxacin and dofetilide or E4031.

Original language	English
Journal	British Journal of Pharmacology
Volume	165
Issue number	2
Pages (from-to)	467-478
DOIs	https://doi.org/10.1111/j.1476-5381.2011.01558.x
Publication status	Published - Jan 2012

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10.1111/j.1476-5381.2011.01558.x

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Nalos, L., Varkevisser, R., Jonsson, M., Houtman, M., Beekman, J., van der Nagel, R., Thomsen, M. B., Duker, G., Sartipy, P., de Boer, T., Peschar, M., Rook, M., van Veen, T., van der Heyden, M., & 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(2), 467-478. https://doi.org/10.1111/j.1476-5381.2011.01558.x

Comparison of the IKr blockers moxifloxacin, dofetilide and E-4031 in five screening models of pro-arrhythmia reveals lack of specificity of isolated cardiomyocytes. / Nalos, L; Varkevisser, R; Jonsson, Mkb et al.

In: British Journal of Pharmacology, Vol. 165, No. 2, 01.2012, p. 467-478.

Research output: Contribution to journal › Journal article › Research › peer-review

Nalos, L, Varkevisser, R, Jonsson, M, Houtman, M, Beekman, J, van der Nagel, R, Thomsen, MB, Duker, G, Sartipy, P, de Boer, T, Peschar, M, Rook, M, van Veen, T, van der Heyden, M & 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, vol. 165, no. 2, pp. 467-478. https://doi.org/10.1111/j.1476-5381.2011.01558.x

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

abstract = "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 I Kr 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 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 I Kr blocking drugs moxifloxacin and dofetilide or E4031.",

author = "L Nalos and R Varkevisser and Mkb Jonsson and Mjc Houtman and Jd Beekman and {van der Nagel}, R and Thomsen, {Morten B{\ae}kgaard} and G Duker and P Sartipy and {de Boer}, Tp and M Peschar and Mb Rook and {van Veen}, Tab and {van der Heyden}, Mag and Ma Vos",

note = "{\textcopyright} 2011 The Authors. British Journal of Pharmacology {\textcopyright} 2011 The British Pharmacological Society.",

year = "2012",

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doi = "10.1111/j.1476-5381.2011.01558.x",

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volume = "165",

pages = "467--478",

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T1 - Comparison of the IKr blockers moxifloxacin, dofetilide and E-4031 in five screening models of pro-arrhythmia reveals lack of specificity of isolated cardiomyocytes

AU - Nalos, L

AU - Varkevisser, R

AU - Jonsson, Mkb

AU - Houtman, Mjc

AU - Beekman, Jd

AU - van der Nagel, R

AU - Thomsen, Morten Bækgaard

AU - Duker, G

AU - Sartipy, P

AU - de Boer, Tp

AU - Peschar, M

AU - Rook, Mb

AU - van Veen, Tab

AU - van der Heyden, Mag

AU - Vos, Ma

PY - 2012/1

Y1 - 2012/1

N2 - 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 I Kr 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 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 I Kr blocking drugs moxifloxacin and dofetilide or E4031.

AB - 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 I Kr 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 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 I Kr blocking drugs moxifloxacin and dofetilide or E4031.

U2 - 10.1111/j.1476-5381.2011.01558.x

DO - 10.1111/j.1476-5381.2011.01558.x

M3 - Journal article

C2 - 21718297

SN - 0007-1188

VL - 165

SP - 467

EP - 478

JO - British Journal of Pharmacology

JF - British Journal of Pharmacology

IS - 2

ER -

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

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