An evaluation of hERG current assay performance: Translating preclinical safety studies to clinical QT prolongation

Pharmacology and Therapeutics

Volumn 129, Issue 2, 2011, Pages 109-119

  Gintant, Gary ^a  

^a ABBOTT LABORATORIES   (United States)

Author keywords

Assay sensitivity and specificity; hERG current assay; In vitro assay performance; Likelihood ratios; QT prolongation; Safety margins

Indexed keywords

17 METHYLNALTREXONE; ALFUZOSIN; ALVIMOPAN; CONIVAPTAN; DARIFENACIN; DASATINIB; DESVENLAFAXINE; DOFETILIDE; DULOXETINE; LAMOTRIGINE; LAPATINIB; MARAVIROC; MOXIFLOXACIN; NEBIVOLOL; NELFINAVIR; NILOTINIB; PALIPERIDONE; PALONOSETRON; POTASSIUM CHANNEL HERG; RENZAPRIDE; SILDENAFIL; SILODOSIN; SITAGLIPTIN; SOLIFENACIN; SUNITINIB; TADALAFIL; TAPENTADOL; TOLTERODINE; UNINDEXED DRUG; VARDENAFIL;

ARTICLE; CONTINGENCY TABLE; CONTROLLED STUDY; DIAGNOSTIC TEST ACCURACY STUDY; DRUG BLOOD LEVEL; DRUG SAFETY; DRUG SCREENING; HERG CURRENT ASSAY; HUMAN; IC 50; MAXIMUM PLASMA CONCENTRATION; PRIORITY JOURNAL; QT PROLONGATION; RECEIVER OPERATING CHARACTERISTIC; RETROSPECTIVE STUDY; SENSITIVITY AND SPECIFICITY;

EID: 79151474418     PISSN: 01637258     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.pharmthera.2010.08.008     Document Type: Review

References (43)

1. D.G. Altman, and J.M. Bland Diagnostic tests 1: sensitivity and specificity BMJ 308 1994 1552
2. E. Berger, K. Patel, S. Anwar, W. Davies, and D.J. Sheridan Investigation of the effects of physiological and vasodilation-induced autonomic activation on the QTc Interval in healthy male subjects Br J Clin Pharmacol 60 1 2005 17 23
3. A. Bril, B. Gout, and M. Bonhomme Combined potassium and calcium channel blocking activities as a basis for antiarrhythmic efficacy with low proarrhythmic risk: experimental profile of BRL32872 J Pharmacol Exp Ther 276 2 1996 637 646
4. J.C. Brimecombe, G.E. Kirsch, and A.M. Brown Test article concentrations in the hERG assay: losses through the perfusion, solubility and stability J Pharmacol Toxicol Meth 59 1 2009 29 34
5. L.R. Cantilena, J. Koerner, R. Temple, and D.C. Throckmorton FDA evaluation of cardiac repolarization data for 19 drugs and drug candidates Clin Pharmacol Ther 79 2 2006 P29
6. B. Darpo, T. Nebout, and P.T. Sager Clinical evaluation of QT/QTc prolongation and proarrhythmic potential for nonantiarrhythmic drugs: the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use E14 guideline J Clin Pharmacol 46 5 2006 498 507
7. M.L. De Bruin, M. Pettersson, R.H. Meyboom, A.W. Hoes, and H.G. Leufkens Anti-HERG activity and the risk of drug-induced arrhythmias and sudden death Eur Heart J 26 6 2005 590 597
8. Deeks, and Altman Diagnostic tests 4: likelihood ratios BMJ 329 7458 2004, 17 168 169
9. A. Dennis, L. Wang, X. Wan, and E. Ficker hERG channel trafficking: novel targets in drug-induced long QT syndrome Biochem Soc Trans 35 Pt 5 2007 1060 1063
10. L.L. Eckhardt, S. Rajamani, and C.T. January Protein trafficking abnormalities: a new mechanism in drug-induced long QT syndrome Br J Pharmacol 145 1 2005 3 4
11. B. Fermini, and A.A. Fossa The impact of drug-induced QT interval prolongation on drug discovery and development Nat Rev Drug Discov 2 6 2003 439 447
12. C.E. Garnett, N. Beasley, V.A. Bhattaram, P.R. Jadhav, R. Madabushi, and N. Stockbridge Concentration-QT relationships play a key role in the evaluation of proarrhythmic risk during regulatory review J Clin Pharmacol 48 1 2008 13 18
13. G.A. Gintant, Z. Su, R.L. Martin, and B.F. Cox Utility of hERG assays as surrogate markers of delayed cardiac repolarization and QT safety Toxicol Pathol 34 2006 81 90
14. J.C. Hancox, M.J. McPate, A. El Harchi, and Y.H. Zhang The hERG potassium channel and hERG screening for drug-induced Torsades de Pointes Pharmacol Ther 119 2 2008 118 132
15. L.M. Hondeghem, L. Carlsson, and G. Duker Instability and triangulation of the action potential predict serious proarrhythmia, but action potential duration prolongation is antiarrhythmic Circulation 103 15 2001 2004 2013
16. International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use. The Non-Clinical Evaluation of the Potential for Delayed Ventricular Repolarization (QT Interval Prolongation) by Human Pharmaceuticals: S7B. Geneva, Switzerland: International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use. 2005. Available at http://www.ich.org/LOB/media/MEDIA2192.pdf
17. International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use. The Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs: E-14. Geneva, Switzerland: International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use; 2005. Available at http://www.ich.org/LOB/media/MEDIA1476.pdf
18. J.A. Ingelfinger, F. Mosteller, L.A. Thibodeau, and J.H. Ware Biostatistics in clinical medicine Diagnostic Testing: Introduction to Probability 1983 MacMillan Publ. Co., Inc. Chapter 1
19. R. Jaeschke, G.H. Guyatt, D.L. Sackett for the Evidence-Based Medicine Working Group Users' guides to the medical literature. III. How to use and article about a diagnostic test. B. What are the results and will they help me in caring for my patients? JAMA 217 9 1994 703 707
20. D.M. Jonker, L.A. Kenna, D. Leishmann, R. Wallis, P.A. Milligan, and E.N. Jonsson A pharmacokinetic-pharmacodynamic model for the quantitative prediction of dofetilide clinical QT prolongation from human ether-a-go-go-related gene current inhibition data Clin Pharmacol Ther 77 6 2005 572 582
21. G.E. Kirsch, E.S. Trepakova, J.C. Brimecombe, S.S. Sidach, H.D. Erickson, and M.C. Kochan Variability in the measurement of hERG potassium channel inhibition: effects of temperature and stimulus pattern J Pharmacol Toxicol Meth 50 2 2004 93 101
22. A.E. Lacerda, Y.A. Kuryshev, Y. Chen, M. Renganathan, H. Eng, and S.J. Danthi Alfuzosin delays cardiac repolarization by a novel mechanism J Pharmacol Exp Ther 324 2 2008 427 433
23. N. Lee, S. Authier, M.K. Pugsley, and M.J. Curtis The continuing evolution of Torsades de Pointes liability testing methods: is there an end in sight? Toxicol Appl Pharmacol 243 2010 146 153
24. R.L. Martin, J.S. McDermott, H.J. Salmen, J. Palmatier, B.F. Cox, and G.A. Gintant The utility of hERG and repolarization assays in evaluating delayed cardiac repolarization: influence of multi-channel block J Cardiovasc Pharmacol 43 3 2004 369 379
25. J.W. Mason, J.A. Florian, C.E. Garnett, T.E. Moon, D.S. Selness, and R.R. Spaulding Pharmacokinetics and pharmacodynamics of three moxifloxacin dosage forms: implications for blinding in active-controlled cardiac repolarization studies J Clin Pharmacol 50 11 2010 1249 1259 [Epub ahead of print]
26. J. Morganroth Cardiac repolarization and the safety of new drugs defined by electrocardiography Clin Pharmacol Ther 81 1 2007 108 113
27. A.A. Panju, B.R. Hemmelgarn, G.H. Guyatt, and D.L. Simel The ration clinical examination. Is the patient having a myocardial infarction? JAMA 280 14 1998 1256 1263
28. M.K. Pugsley, S. Authier, and M.J. Curtis Review: frontiers in pharmacology. Principles of safety pharmacology Br J Pharmacol 154 2008 1382 1399
29. W.S. Redfern, L. Carlsson, A.S. Davis, W.G. Lynch, I. MacKenzie, and S. Palethorpe Relationships between preclinical cardiac electrophysiology, clinical QT interval prolongation and Torsade de Pointes for a broad range of drugs: evidence for a provisional safety margin in drug development Cardiovasc Res 58 1 2003 32 45
30. E.P. Rock, J. Finkle, H.J. Fingert, B.P. Booth, C.E. Garnett, and S. Grant Assessing proarrhythmic potential of drugs when optimal studies are infeasible Am Heart J 157 5 2009 827 836 836
31. D.M. Roden Cellular basis of drug-induced Torsades de Pointes Br J Pharmacol 154 7 2008 1502 1507
32. D.L. Sackett, R.B. Haynes, G.H. Guyatt, and P. Tugwell Clinical Epidemiology: A Basic Science for Clinical Medicine Second Edition 1991 Little, Brown & Co Boston
33. Kr potassium channel Cell 81 2 1995 299 307
34. R.R. Shah Drug-induced QT interval shortening: potential harbinger of proarrhythmia and regulatory perspectives Br J Pharmacol 159 1 2010 58 69
35. D.L. Simel, G.P. Samsa, and D.B. Matcher Likelihood ratios with confidence: sample size estimation for diagnostic test studies J Clin Epidemiol 44 8 1991 763 770
36. J.A. Swets Measuring the accuracy of diagnostic systems Science 240 4857 1988 1285 1293
37. R. Towart, J.T. Linders, A.N. Hermans, J. Rohrbacher, H.J. van der Linde, and M. Ercken Blockade of the I(Ks) potassium channel: an overlooked cardiovascular liability in drug safety screening? J Pharmacol Toxicol Meth 60 1 2009 1 10
38. E.S. Trepakova, J. Koerner, S.D. Pettit, J.P. Valentin HESI Pro-Arrhythmia Committee A HESI consortium approach to assess the human predictive value of non-clinical repolarization assays J Pharmacol Toxicol Meth 60 1 2009 45 50
39. H.M. Vargas, A.S. Bass, A. Breidenbach, H.S. Feldman, G.A. Gintant, and A.R. Harmer Scientific review and recommendations on preclinical cardiovascular safety evaluation of biologics J Pharmacol Toxicol Meth 58 2 2008 72 76
40. R. Wallis Integrated risk assessment and predictive value to humans of non-clinical repolarization assays Br J Pharmacol 159 1 2010 115 121
41. H.J. Witchel, J.T. Milnes, J.S. Mitcheson, and J.C. Hancox Troubleshooting problems with in vitro screening of drugs for QT interval prolongation using hERG K+ channels expressed in mammalian cell lines and Xenopus oocytes J Pharmacol Toxicol Meth 48 2002 65 80
42. S. Zhang, Z. Zhou, Q. Gong, J.C. Makielski, and C.T. January Mechanism of block and identification of the verapamil binding domain to HERG potassium channels Circ Res 84 9 1999 989 998
43. K.H. Zou, A.J. O'Malley, and L. Mauri Receiver-operating characteristic analysis for evaluating diagnostic tests and predictive models Circulation 115 2007 654 657