Comprehensive in vitro Proarrhythmia Assay, a novel in vitro/in silico paradigm to detect ventricular proarrhythmic liability: A visionary 21st century initiative

Expert Opinion on Drug Safety

Volumn 13, Issue 6, 2014, Pages 745-758

  Cavero, Icilio ^a   Holzgrefe, Henry ^b  

^a Charles River Laboratories Department of Toxicology ^*  (France)

^b CHARLES RIVER LABORATORIES   (United States)

Author keywords

Cardiac action potential modeling; Cardiac ion channel assays; Comprehensive in vitro proarrhythmia assay; Human stem cell derived cardiomyocyte; Safety pharmacology

Indexed keywords

ARSENIC TRIOXIDE; ASTEMIZOLE; CISAPRIDE; CLOBUTINOL; DEXTROPROPOXYPHENE; DROPERIDOL; DRUG METABOLITE; GREPAFLOXACIN; ION CHANNEL; RANOLAZINE; SPARFLOXACIN; TERFENADINE; THIORIDAZINE;

ACTION POTENTIAL; ASSAY; COMPREHENSIVE IN VITRO PROARRHYTHMIA ASSAY; COMPUTER MODEL; CONSENSUS; DRUG EFFECT; DRUG MARKETING; DRUG SAFETY; HEART MUSCLE CELL; HEART MUSCLE REFRACTORY PERIOD; HEART PROARRHYTHMIA; HEART REPOLARIZATION; HEART VENTRICLE ARRHYTHMIA; HUMAN; IN VITRO STUDY; ION CURRENT; LONG QT SYNDROME 5; MEMBRANE STEADY POTENTIAL; NONHUMAN; QT INTERVAL; QT PROLONGATION; REVIEW; ROMANO-WARD SYNDROME; STANDARDIZATION; ADVERSE DRUG REACTION; ANIMAL; CHEMICALLY INDUCED; COMPUTER SIMULATION; DRUG APPROVAL; DRUG EFFECTS; DRUG SCREENING; HEART ARRHYTHMIA; METABOLISM; PATHOPHYSIOLOGY; PROCEDURES;

ACTION POTENTIALS; ANIMALS; ARRHYTHMIAS, CARDIAC; COMPUTER SIMULATION; DRUG APPROVAL; DRUG EVALUATION, PRECLINICAL; DRUG-RELATED SIDE EFFECTS AND ADVERSE REACTIONS; HUMANS; MYOCYTES, CARDIAC;

EID: 84901311299     PISSN: 14740338     EISSN: 1744764X     Source Type: Journal    
DOI: 10.1517/14740338.2014.915311     Document Type: Review

References (88)

1. Kannankeril P, Roden DM, Darbar D. Drug-induced long QT syndrome. Pharmacol Rev 2010;62:760-81
2. Sauer AJ, Newton-Cheh C. Clinical and genetic determinants of torsade de pointes risk. Circulation 2012;125:1684-94
3. Heist EK, Ruskin JN. Drug-induced arrhythmia. Circulation 2010;122:1426-35
4. Shah RR. Drug-induced QT interval prolongation: Does ethnicity of the thorough QT study population matter?. Br J Clin Pharmacol 2013;75:347-58
5. Levy RL. Clinical studies of quinidine. IV. The clinical toxicology of quinidine. J Am Med Assoc 1922;79:1108-13
6. Stockbridge N, Morganroth J, Shah RR, et al. Dealing with global safety issues: Was the response to QT-liability of non-cardiac drugs well-coordinated?. Drug Saf 2013;36:167-82
7. Committee for Proprietary Medicinal Products. Points to consider: The assessment of the potential for QT interval prolongation by noncardiovascular medicinal products, CPMP/986/96. London: Committee for Proprietary Medicinal Products. 1997. Available from: Http://www.fda.gov/ohrms/dockets/ac/03/briefing/ pubs/cpmp. pdf [Accessed April 2014
8. Cavero I, Crumb W. ICH S7B draft guideline on the non-clinical strategy for testing delayed cardiac repolarisation risk of drugs: A critical analysis. Expert Opin Drug Saf 2005;4:509-30 (Pubitemid 40723724
9. ICH Harmonised Tripartite Guideline. The non-clinical evaluation of the potential for delayed ventricular repolarization (QT interval prolongation) by human pharmaceuticals. S7B. 2005. Available from: Www.ich.org/products/ guidelines/safety/article/safetyguidelines. html [Accessed March 2014
10. ICH Harmonised Tripartite Guideline. The clinical evaluation of QT/QTc interval prolongation and proarrhythmic potential for non-Antiarrhythmic drugs. E14. 2005. Available from: Www.ich.org/fileadmin/Public-Web-Site/ICH-Products/ Guidelines/Efficacy/E14/E14-Guideline.pdf [Accessed March 2014
11. Garnett CE, Zhu H, Malik M, et al. Methodologies to characterize the QT/corrected QT interval in the presence of drug-induced heart rate changes or other autonomic effects. Am Heart J 2012;163:912-30
12. Straus SM, Sturkenboom MC, Bleumink GS, et al. Non-cardiac QTcprolonging drugs and the risk of sudden cardiac death. Eur Heart J 2005;26:2007-12 (Pubitemid 41435722
13. Sager PT, Gintant G, Turner JR, et al. Rechanneling the cardiac proarrhythmia safety paradigm: A meeting report from the Cardiac Safety Research Consortium. Am Heart J 2014;16:292-300
14. Available from: Www.hesiglobal.org/files/public/Committee% 20PresentationsCardiac%20Safety/SOT-031512-final.pdf [Accessed March 2014
15. Stockbridge N. Benefits and limitations overview 2013. Available from: Www.hesiglobal.org/files/1% 20Stockbridge.pdf [Accessed March 2014
16. Adsit GS, Vaidyanathan R, Galler CM, et al. Channelopathies from mutations in the cardiac sodium channel protein complex. J Mol Cell Cardiol 2013;61:34-43
17. Remme CA, Wilde AAM. Targeting sodium channels in cardiac arrhythmia. Cur Opin Pharmacol 2014;15:53-60
18. Moreno JD, Clancy CE. Pathophysiology of the cardiac late Na current and its potential as a drug target. J Mol Cell Cardiol 2012;52:608-19
19. Remme CA, Wilde AA. Late sodium current inhibition in acquired and inherited ventricular (dys)function and arrhythmias. Cardiovasc Drugs Ther 2013;27:91-101
20. Venetucci L, Denegri M, Napolitano C, Priori SG. Inherited calcium channelopathies in the pathophysiology of arrhythmias. Nat Rev Cardiol 2012;9:561-75
21. Lacerda AE, Kuryshev YA, Yan GX, et al. Vanoxerine: Cellular mechanism of a new antiarrhythmic. J Cardiovasc Electrophysiol 2010;21:301-10
22. Huang ZJ, Dai DZ, Li N, et al. Calcium antagonist property of CPU228, a dofetilide derivative, contributes to its low incidence of torsades de pointes in rabbits. Clin Exp Pharmacol Physiol 2007;34:310-17
23. Abriel H, Zaklyazminskaya EV. Cardiac channelopathies: Genetic and molecular mechanisms. Gene 2013;517:1-11
24. Charpentier F, Mérot J, Loussouarn G, et al. Delayed rectifier K+ currents and cardiac repolarization. J Mol Cell Cardiol 2010;48:37-44
25. Shimizu W, Horie M. Phenotypic manifestations of mutations in genes encoding subunits of cardiac potassium channels. Circ Res109:97-109
26. Pierson JB, Berridge BR, Brooks MB, et al. A public-private consortium advances cardiac safety evaluation: Achievements of the HESI Cardiac Safety Technical Committee. J Pharmacol Toxicol Methods 2013;68:7-12
27. Nantasenamat C, Isarankura-Na-Ayudhya C, Prachayasittikul V. Advances in computational methods to predict the biological activity of compounds. Expert Opin Drug Discov 2010;5:633-54
28. Available from: Https://gostardb.com/gostar/ [Accessed March 2014
29. Inanobe A, Kamiya N, Murakami S, et al. In silico prediction of the chemical block of human ether-A-go-go-related gene (hERG) K+ current. J Physiol Sci 2008;58:459-70
30. Mirams GR, Cui Y, Sher A, et al. Simulation of multiple ion channel block provides improved early prediction of compounds' clinical torsadogenic risk. Cardiovasc Res 2011;91:53-61
31. Noble D. Successes and failures in modeling heart cell electrophysiology. Heart Rhyth 2011;8:1798-803
32. Noble D. Computational models of the heart and their use in assessing the actions of drugs. J Pharmacol Sci 2008;107:107-17 (Pubitemid 351931011
33. O'Hara T, Vira'g L, Varró A, et al. Simulation of the undiseased human cardiac ventricular action potential: Model formulation and experimental validation. PLoS Comput Biol 2011;7:e1002061
34. Britton OJ, Bueno-Orovio A, Van Ammel K, et al. Experimentally calibrated population of models predicts and explains intersubject variability in cardiac cellular electrophysiology. Proc Natl Acad Sci USA 2013;110:E2098-105
35. Mercola M, Colas A, Willems E. Induced pluripotent stem cells in cardiovascular drug discovery. Circ Res 2013;112:534-48
36. Critical Path Opportunities Report. 2009. Available from: Http://www.fda. gov/downloads/scienceresearch/specialtopics/criticalpathinitiative/ucm186110. pdf [Accessed March 2014
37. Toxicity Testing in the 21st Century: A vision and a strategy, National Research Council. National Academies Press, Washington, DC; 2007
38. Available from: Www.seurat-1.eu [Accessed March 2014
39. Holsapple MP, Afshari CA, Lehman-McKeeman LD. Forum series: The "vision" for toxicity testing in the 21st century: Promises and conundrums. Toxicol Sci 2009;107:307-8
40. SEURAT-1: Development of a research strategy for the replacement of in vivo repeated dose systemic toxicity testing. Available from: Www.alttox.org/ttrc/eu/way-forward/gocht-schwarz-berggrenwhelan/ [Accessed March 2014
41. UK Home Office Animals in Science Regulation Unit (ASRU), the Department for Business, Innovation and Skills (BIS) and Government Office for ScienceWorking to reduce the use of animals in scientific research. 2014. Available from: Www.gov.uk/government/uploads/system/uploads/attachment-data/ file/277942/bis-14-589-working-To-educe-The-use-of-animals-inresearch. pdf [Accessed March 2014
42. Rampe D, Brown AM. A history of the role of the hERG channel in cardiac risk assessment. J Pharmacol Toxicol Methods 2013;68:13-22
43. Park E, Willard J, Bi D, et al. The impact of drug-related QT prolongation on FDA regulatory decisions. Int J Cardiol 2013;168:4975-6
44. Chaitman BR. Efficacy safety of Metabolic Modulator Drug In Chronic Stable Angina Review Of Evidence From Clinical Trials. J Cardiovasc Pharmacol Ther 2004;9(Suppl 1)S47-64
45. Chaitman BR. Ranolazine for the treatment of chronic angina and potential use in other cardiovascular conditions. Circulation 2006;113:2462-72 (Pubitemid 43948054
46. Karwatowska-Prokopczuk E, Wang W, Cheng ML, et al. The risk of sudden cardiac death in patients with non-ST elevation acute coronary syndrome and prolonged QTc interval: Effect of ranolazine. Europace 2013;15:429-36
47. Moreno JD, Yang PC, Bankston JR, et al. Ranolazine for congenital and acquired late INa-linked arrhythmias: In silico pharmacological screening. Circ Res 2013;113:e50-61
48. Kowey PR. TQT: Impact on clinical development. Available from: Www. hesiglobal.org/files/4%20Kowey.pdf [Accessed March 2014
49. Beasley CM Jr, Dmitrienko A, Mitchell MI. Design and analysis considerations for thorough QT studies employing conventional (10 s, 12-lead) ECG recordings. Expert Rev Clin Pharmacol 2008;1:815-39
50. Turner Jr. Fifteen years of cardiac safety: History, state-of-The-science research, and glimpses into the future. Intern Pharm Industry 2013;5:98-104
51. Cavero I. Exploratory safety pharmacology: A new safety paradigm to de-risk drug candidates prior to selection for regulatory science investigations. Expert Opin Drug Saf 2009;8:627-47
52. Heijman J, Voigt N, et al. Cardiac safety assay. Curr Opin Pharmacol 2014;15:16-21
53. ICH Harmonised Tripartite Guideline. Safety pharmacology studies for human pharmaceuticals. S7A. 2000. Available from: Www.ich.org/fileadmin/Public- Web-Site/ICH-Products/Guidelines/Safety/S7A/Step4/S7A-Guideline.pdf [Accessed March 2014
54. Guidance for industry qualification process for drug development tools. 2010. Available from: Www.fda.gov/downloads/Drugs/Guidance ComplianceregulatoryInformation/ Guidances/UCM230597.pdf [Accessed March 2014
55. Dunlop J, Bowlby M, Peri R, et al. High-Throughputelectrophysiology: An emerging paradigm for ion-channel screening and physiology. Nat Rev Drug Discov 2008;7:358-68
56. Stoelzle S, Obergrussberger A, Brüggemann A, et al. State-of-The-Art automated patch clamp devices: Heat activation, action potentials, and high throughput in ion channel screening. Front Pharmacol 2011;2:76
57. Gintant G. Ions, equations and electrons: The evolving role of computer simulations in cardiac electrophysiology safety evaluations. Br J Pharmacol 2012;167:929-31
58. Di Veroli GY, Davies MR, Zhang H, et al. hERG Inhibitors with similar potency but different binding kinetics do not pose the same proarrhythmic risk: Implications for drug safety assessment. J Cardiovasc Electrophysiol 2013;25:197-207
59. Di Veroli GY, Davies MR, Zhang H, et al. High-Throughput screening of drug-binding dynamics to HERG improves early drug safety assessment. Am J Physiol Heart Circ Physiol 2013;304:H104-17
60. Abriel H, de Lange E, Kucera JP, et al. Computational tools to investigate genetic cardiac channelopathies. Front Physiol 2013;4:390
61. Rudy Y, Silva Jr. Computational biology in the study of cardiac ion channels and cell electrophysiology. Q Rev Biophys 2006;39:57-11
62. Fink M, Noble D. Markov models for ion channels: Versatility versus identifiability and speed. Philos Trans A Math Phys Eng Sci 2009;367(1896):2161- 79
63. Hodgkin AL, Huxley AF. A quantitative description of membrane current and its application to conduction and excitation in nerve. J Physiol 1952;117:500-44
64. Hunter P, Nielsen P. A strategy for integrative computational physiology. Physiology (Bethesda) 2005;20:316-25 (Pubitemid 41457397
65. Noble D, Garny A, Noble PJ. How the Hodgkin-Huxley equations inspired the cardiac physiome project. J Physiol 2012;590:2613-28
66. Zemzemi N, Bernabeu MO, Saiz J, et al. Computational assessment of druginduced effects on the electrocardiogram: From ion channel to body surface potentials. Br J Pharmacol 2013;168:718-33
67. Mirams GR, Davies MR, Cui Y, et al. Application of cardiac electrophysiology simulations to pro-Arrhythmic safety testing. Br J Pharmacol 2012;167:932-45
68. Silva JR, Pan H, Wu D, et al. A multiscale model linking ion-channel molecular dynamics and electrostaticsto the cardiac action potential. Proc Natl Acad Sci USA 2009;106:11102-6
69. Elshrif MM, Cherry EM. A quantitative comparison of the behavior of human ventricular cardiac electrophysiology models in tissue. PLoS One 2014;9:e84401
70. Grandi E, Pasqualini FS, Bers DM. A novel computational model of the human ventricular action potential and Ca transient. J Mol Cell Cardiol 2010;48:112-21
71. Carusi A, Burrage K, Rodríguez B. Bridging experiments, models and simulations: An integrative approach to validation in computational cardiac electrophysiology. Am J Physiol Heart Circ Physiol 2012;303:H144-55
72. Wilhelms M, Hettmann H, Maleckar MM, et al. Benchmarking electrophysiological models of human atrial myocytes. Front Physiol 2013;3:487
73. Niederer SA, Smith NP. At the heart of computational modelling. J Physiol 2012;590(Pt 6):1331-8
74. Jonsson MK, Vos MA, Mirams GR, et al. Application of human stem cell-derived cardiomyocytes in safety pharmacology requires caution beyond hERG. J Mol Cell Cardiol 2012;52:998-1008
75. Roden DM, Hong CC. Stem cell-derived cardiomyocytes as a tool for studying proarrhythmia: A better canary in the coal mine?. Circulation 2013;127:1641-3
76. Robertson C, Tran DD, George SC. Concise review: Maturation phases of human pluripotent stem cell-derived cardiomyocytes. Stem Cells 2013;31:829-37
77. Kim C, Majdi M, Xia P, et al. Non-cardiomyocytes influence the electrophysiological maturation of human embryonic stem cell derived cardiomyocytes during differentiation. Stem Cells Dev 2010;19:783-95
78. Ma J, Guo L, Fiene SJ, et al. High purity human-induced pluripotent stem cell-derived cardiomyocytes: Electrophysiological properties of action potentials and ionic currents. Am J Physiol Heart Circ Physiol 2011;301:H2006-17
79. Guo L, Abrams RM, Babiarz JE, et al. Estimating the risk of drug-induced proarrhythmia using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Sci 2011;123:281-9
80. Harris K, Aylott M, Cui Y, et al. Comparison of electrophysiological data from human-induced pluripotent stem cell-derived cardiomyocytes to functional preclinical safety assays. Toxicol Sci 2013;134:412-26
81. Navarrete EG, Liang P, Lan F, et al. Screening drug-induced arrhythmia events using human induced pluripotent stem cell-derived cardiomyocytes and low-impedance microelectrode arrays. Circulation 2013;128(11 Suppl 1):S3-S13
82. U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research CDER). Guidance for industry safety testing of drug metabolites. 2008. Available from: Www.fda.gov/ OHRMS/DOCKETS/98fr/FDA-2008-D-0065-GDL.pdf [Accessed March 2014
83. Kuryshev YA, Ficker E, Wang L, et al. Pentamidine-induced long QT syndrome and block of hERG trafficking. J Pharmacol Exp Ther 2005;312:316-23 (Pubitemid 40096484
84. Wan X, Dennis AT, Obejero-Paz C, et al. Oxidative inactivation of the lipid phosphatase phosphatase and tensin homologon chromosome ten (PTEN) as a novel mechanism of acquired long QT syndrome. J Biol Chem 2011;286:2843-52
85. Dennis A, Wang L, Wan X, et al. hERG channel trafficking: Novel targets in druginduced long QT syndrome. Biochem Soc Trans 2007;35(Pt 5):1060-3 (Pubitemid 350206429
86. Montgomery RL, Davis CA, Potthoff MJ, et al. Histone deacetylases 1 and 2 redundantly regulate cardiac morphogenesis, growth, and contractility. Genes Dev 2007;21:1790-802 (Pubitemid 47076478
87. Beattie KA, Luscombe C, Williams G, et al. Evaluation of an in silico cardiac safety assay: Using ion channel screening data to predict QT interval changes in the rabbit ventricular wedge. J Pharmacol Toxicol Methods 2013;68:88-96
88. Davies MR, Mistry HB, Hussein L, et al. An in silico canine cardiac midmyocardial action potential duration model as a tool for early drug safety assessment. Am J Physiol Heart Circ Physiol 2012;302:H1466-80