Evaluating the QT-liability of a drug during its development

Pharmaceutical Medicine

Volumn 22, Issue 3, 2008, Pages 151-164

  Shah, Rashmi R ^a   Morganroth, Joel ^b  

^a Rashmi Shah Consultancy Ltd   (United Kingdom)

^b eResearchTechnology   (United States)

Author keywords

Adverse reaction monitoring; Arrhythmias; Research and development; Torsade de pointes

Indexed keywords

ARRHYTHMOGENESIS; CARDIOVASCULAR EFFECT; CLINICAL PRACTICE; CONCENTRATION RESPONSE; DRUG EFFECT; DRUG RESEARCH; ELECTROCARDIOGRAM; ENANTIOMER; HEART ARRHYTHMIA; HEART ELECTROPHYSIOLOGY; HEART REPOLARIZATION; IN VITRO STUDY; IN VIVO STUDY; PRACTICE GUIDELINE; PRIORITY JOURNAL; QT INTERVAL; REVIEW; RISK;

EID: 44349105190     PISSN: 11782595     EISSN: None     Source Type: Journal    
DOI: 10.1007/BF03256697     Document Type: Review

References (94)

1. Shah RR. The significance of QT interval during drug development. Br J Clin Pharmacol 2002; 54: 188-202
2. Clayton RH, Murray A, Higham PD, et al. Self-terminating ventricular tachyarrhythmias: a diagnostic dilemma? Lancet 1993; 341: 93-5
3. Locati EH, Maison-Blanche P, Dejode P, et al. Spontaneous sequences of onset of torsade de pointes in patients with acquired prolonged repolarization: quantitative analysis of Holter recordings. J Am Coll Cardiol 1995; 25: 1564-75
4. Eggeling T, Osterhues HH, Hoeher M, et al. Value of Holter monitoring in patients with the long QT syndrome. Cardiology 1992; 81: 107-14
5. Shah RR. Can pharmacogenetics help rescue drugs withdrawn from the market? Pharmacogenomics 2006; 7: 889-908
6. Escande D. Pharmacogenetics of cardiac K+ channels. Eur J Pharmacol 2000; 410: 281-7
7. de Ponti F, Poluzzi E, Cavalli A, et al. Safety of non-antiarrhythmic drugs that prolong the QT interval or induce torsade de pointes: an overview. Drug Saf 2002; 25: 263-86
8. Lacerda AE, Kuryshev YA, Chen Y, et al. Alfuzosin delays cardiac repolarization by a novel mechanism. J Pharmacol Exp Ther 2008; 324: 427-33
9. Bazett HC. An analysis of the time-relations of electrocardiograms. Heart 1920; 7: 353-70
10. Fridericia LS. Die systolendauer in elektrokardiogram bei normalen menschen und bei herzkranken. Acta Med Scand 1920; 53: 469-86
11. Funck-Brentano C, Jaillon P. Rate-corrected QT interval: techniques and limita-tions. Am J Cardiol 1993; 72: 17B-22B
12. Malik M. Problems of heart rate correction in assessment of drug-induced QT interval prolongation. J Cardiovasc Electrophysiol 2001; 12: 411-20
13. Malik M, Farbom P, Batchvarov V, et al. The relationship between QT and RR intervals is highly individual among healthy subjects: implications for heart rate correction of the QT interval. Heart 2002; 87: 220-8
14. Malik M, Hnatkova K, Batchvarov V. Differences between study-specific and subject-specific heart rate corrections of the QT interval in investigations of drug induced QTc prolongation. Pacing Clin Electrophysiol 2004; 27: 791-800
15. Desai M, Li L, Desta Z, et al. Variability of heart rate correction methods for the QT interval. Br J Clin Pharmacol 2003; 55: 511-7
16. Abbott GW, Sesti F, Splawski I, et al. MiRP1 forms IKr potassium channels with HERG and is associated with cardiac arrhythmias. Cell 1999; 97: 175-87
17. Sanguinetti MC, Jiang C, Curran ME, et al. A mechanistic link between an inherited and an acquired cardiac arrhythmia: HERG encodes the IKr potassium channel. Cell 1995; 81: 299-307
18. Robertson GA, Jones EMC, Wang J. Gating and assembly of heteromeric hERG1a/1b channels underlying IKr in the heart. In: Chadwick DJ, Goode J, editors. The hERG cardiac potassium channel: structure, function and long QT syndrome. Novartis Foundation Symposium No. 266. Chichester: John Wiley & Sons Ltd, 2005: 4-18
19. Mitcheson J, Perry M, Stansfeld P, et al. Structural determinants for high-affinity block of hERG potassium channels. In: Chadwick DJ, Goode J, editors. The hERG cardiac potassium channel: structure, function and long QT syndrome. Novartis Foundation Symposium No. 266. Chichester: John Wiley & Sons Ltd, 2005: 136-54
20. Committee for Proprietary Medicinal Products. Points to consider: the assessment of the potential for QT interval prolongation by non-cardiovascular medicinal products (CPMP/986/96). EMEA, 1997 Dec 17 [online]. Available from URL: http://www.fda.gov/ohrms/dockets/ac/03/briefing/pubs/cpmp.pdf [Accessed 2008 Jan 26]
21. Haverkamp W, Breithardt G, Camm AJ, et al. The potential for QT prolongation and proarrhythmia by non-antiarrhythmic drugs: clinical and regulatory implications. Report on a Policy Conference of the European Society of Cardiology. Eur Heart J 2000; 21: 1216-31
22. Shah RR. Cardiac repolarisation and drug regulation: assessing cardiac safety 10 years after the CPMP guidance. Drug Saf 2007; 30: 1093-110
23. Committee for Medicinal Products for Human Use. The non-clinical evaluation of the potential for delayed ventricular repolarization (QT interval prolongation) by human pharmaceuticals: S7B (CHMP/ICH/423/02). EMEA, 2005 May 12 [online]. Available from URL: http://www.ich.org/LOB/media/MEDIA2192.pdf [Accessed 2008 Jan 26]
24. Committee for Medicinal Products for Human Use. Note for guidance on the clinical evaluation of QT/QTc interval prolongation and proarrhythmic potential for non-antiarrhythmic drugs: E14 (CHMP/ICH/2/04). EMEA, 2005 May 25 [online]. Available from URL: http://www.emea.europa.eu/pdfs/human/ich/000204en.pdf [Accessed 2008 Jan 26]
25. Health Canada, Ministry of Health, Health Products and Food Branch. Guide for the analysis and review of QT/QTc interval data. File number: 06-124690-618. Health Canada, 2006 Nov 30 [online]. Available from URL: http://www. hc-gc.ca/dhp-mps/alt_formats/hpfb-dgpsa/pdf/prodpharma/ qt_review_examen _e.pdf [Accessed 2008 Jan 26]
26. Health Canada, Ministry of Health, Health Products and Food Branch. QT/QTc interval prolongation: guidance for product monograph content. File number: 06-124456-677. Health Canada, 2006 Nov 30 [online]. Available from URL: http://www.hc-sc.gc.ca/dhp-mps/alt_formats/hpfb-dgpsa/pdf/prodpharma/ qt_pm_mp_e.pdf [Accessed 2008 Jan 26]
27. Health Canada, Ministry of Health, Health Products and Food Branch. Question and answer document regarding the ICH S7B and E14 guidances. File number: 06-124711-745. Health Canada, 2006 Nov 30 [online]. Available from URL: http://www.hc-sc.gc.ca/dhp-mps/alt_formats/hpfb-dgpsa/pdf/prodpharma/ qt_qa_qr_e.pdf [Accessed 2008 Jan 26]
28. Escande D. Inhibition of repolarizing ionic currents by drugs. Eur Heart J Suppl 2001; 3 Suppl. K: K17-22
29. Garnett CE, Beasley N, Bhattaram VA, et al. Concentration-QT relationships play a key role in the evaluation of proarrhythmic risk during regulatory review. J Clin Pharmacol 2008; 48: 13-8
30. Lawrence CL, Pollard CE, Hammond TG, et al. Nonclinical proarrhythmia models: predicting torsades de pointes. J Pharmacol Toxicol Methods 2005; 52: 46-59
31. International Conference on Harmonisation. Maintenance of the ICH guidance on non-clinical safety studies for the conduct of human clinical trials for pharmaceuticals (ICH M3/R1). ICH Steering Committee, 2000 Nov 9 [online]. Available from URL: http://www.ich.org/LOB/media/MEDIA506.pdf [Accessed 2008 Jan 26]
32. Committee for Medicinal Products for Human Use. Guideline on strategies to identify and mitigate risks for first-in-human clinical trials with investigational medicinal products. EMEA/CHMP/SWP/28367/07. EMEA, 2007 Jul 19 [on-line]. Available from URL: http://www.emea.europa.eu/pdfs/human/ swp/2836707enfin.pdf [Accessed 2008 Jan 26]
33. International Conference on Harmonisation. Safety Pharmacology Studies for Human Pharmaceuticals (ICH S7A). ICH Steering Committee, 2000 Nov 8 [online]. Available from URL: http://www.ich.org/LOB/media/MEDIA504.pdf [Accessed 2008 Apr 10]
34. International Conference on Harmonisation. Toxicokinetics: the assessment of systemic exposure in toxicity studies (ICH S3A). ICH Steering Committee, 1994 Oct 27 [online]. Available from URL: http://www.ich.org/LOB/media/MEDIA495. pdf [Accessed 2008 Apr 10]
35. Thomas D, Kiehn J, Katus HA, et al. Defective protein trafficking in hERG associated hereditary long QT syndrome (LQT2): molecular mechanisms and restoration of intracellular protein processing. Cardiovasc Res 2003; 60: 235-41
36. Eckhardt LL, Rajamani S, January CT. Protein trafficking abnormalities: a new mechanism in drug-induced long QT syndrome. Br J Clin Pharmacol 2005; 145: 3-4
37. Ficker E, Kuryshev YA, Dennis AT, et al. Mechanisms of arsenic-induced prolongation of cardiac repolarization. Mol Pharmacol 2004; 66: 33-44
38. Dennis A, Wang L, Wan X, et al. hERG channel trafficking: novel targets in drug-induced long QT syndrome. Biochem Soc Trans 2007; 35 Pt 5: 1060-3
39. Wang L, Wible BA, Wan X, et al. Cardiac glycosides as novel inhibitors of human ether-a-go-go-related gene channel trafficking. J Pharmacol Exp Ther 2007; 320: 525-34
40. Rajamani S, Eckhardt LL, Valdivia CR, et al. Drug-induced long QT syndrome: hERG K+ channel block and disruption of protein trafficking by fluoxetine and norfluoxetine. Br J Pharmacol 2006; 149: 481-9
41. Takemasa H, Nagatomo T, Abe H, et al. Coexistence of hERG current block and disruption of protein trafficking in ketoconazole-induced long QT syndrome. Br J Pharmacol. 2008; 153: 439-47
42. Wible BA, Hawryluk P, Ficker E, et al. HERG-Lite: a novel comprehensive high-throughput screen for drug-induced hERG risk. J Pharmacol Toxicol Methods 2005; 52: 136-45
43. Charpentier F, Drouin E, Gauthier C, et al. Early after-depolarizations and triggered activity: mechanisms and autonomic regulation. Fundam Clin Pharmacol 1993; 7: 39-49
44. Zeng J, Rudy Y. Early after-depolarizations in cardiac myocytes: mechanism and rate dependence. Biophys J 1995; 68: 949-64
45. Liu J, Laurita KR. The mechanism of pause-induced torsade de pointes in long QT syndrome. J Cardiovasc Electrophysiol 2005; 16: 981-7
46. Milberg P, Reinsch N, Osada N, et al. Verapamil prevents torsade de pointes by reduction of transmural dispersion of repolarization and suppression of early after-depolarizations in an intact heart model of LQT3. Basic Res Cardiol 2005; 100: 365-71
47. Wu L, Shryock JC, Song Y, et al. Antiarrhythmic effects of ranolazine in a guinea pig in vitro model of long-QT syndrome. J Pharmacol Exp Ther 2004; 310: 599-605
48. Singh BN, Wadhani N. Antiarrhythmic and proarrhythmic properties of QT-prolonging antianginal drugs. J Cardiovasc Pharmacol Ther 2004; 9 Suppl. 1: S85-97
49. Antzelevitch C, Belardinelli L, Zygmunt AC, et al. Electrophysiological effects of ranolazine, a novel antianginal agent with antiarrhythmic properties. Circulation 2004; 110: 904-10
50. Shah RR, Hondeghem LM. Refining detection of drug-induced proarrhythmia: QT interval and TRIaD. Heart Rhythm 2005; 2: 758-72
51. Antzelevitch C, Oliva A. Amplification of spatial dispersion of repolarization underlies sudden cardiac death associated with catecholaminergic polymorphic VT, long QT, short QT and Brugada syndromes. J Intern Med 2006; 259: 48-58
52. Martin RL, Su Z, Limberis JT, et al. In vitro preclinical cardiac assessment of tolterodine and terodiline: Multiple factors predict the clinical experience. J Cardiovasc Pharmacol 2006; 48: 199-206
53. Fenichel RR, Malik M, Antzelevitch C, et al. Drug-induced torsades de pointes and implications for drug development. J Cardiovasc Electrophysiol 2004; 15: 475-95
54. Hartigan-Go K, Bateman ND, Daly AK, et al. Stereoselective cardiotoxic effects of terodiline. Clin Pharmacol Ther 1996; 60: 89-98
55. Volperian VR, Zhou Z, Mohammad S, et al. Torsade de pointes with an antihistamine metabolite: potassium channel blockade with desmethylastemizole. J Am Coll Cardiol 1996; 28: 1556-61
56. Shah RR. Interpretation of clinical ECG data: understanding the risk from non-antiarrhythmic drugs. In: Morganroth J, Gussak I, editors. Cardiac safety of noncardiac drugs: practical guidelines for clinical research and drug development. Totowa (NJ): Humana Press Inc., 2004: 259-98
57. 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: 310-7
58. Rampe D, Murawsky MK, Grau J, et al. The antipsychotic agent sertindole is a high affinity antagonist of the human cardiac potassium channel HERG. J Pharmacol Exp Ther 1998; 286: 788-93
59. Kang J, Chen XL, Wang H, et al. Cardiac ion channel effects of tolterodine. J Pharmacol Exp Ther 2004; 308: 935-40
60. Thomas D, Wimmer AB, Wu K, et al. Inhibition of human ether-a-go-go-related gene potassium channels by alpha1-adrenoceptor antagonists prazosin, doxazosin, and terazosin. Naunyn Schmiedebergs Arch Pharmacol 2004; 369: 462-72
61. Cheng J, Niwa R, Kamiya K, et al. Carvedilol blocks the repolarizing K+ currents and the L-type Ca++ current in rabbit ventricular myocytes. Eur J Pharmacol 1999; 376: 189-201
62. Murdoch M, Keating GM. Sertindole: a review of its use in schizophrenia. CNS Drugs 2006; 20: 233-55
63. Malhotra BK, Glue P, Sweeney K, et al. Thorough QT study with recommended and supratherapeutic doses of tolterodine. Clin Pharmacol Ther 2007; 81: 377-85
64. Milton KA, Edwards G, Ward SA, et al. Pharmacokinetics of halofantrine in man: effects of food and dose size. Br J Clin Pharmacol 1989; 28: 71-7
65. Valenzuela C, Delpon E, Tamkun MM, et al. Stereoselective block of a human cardiac potassium channel (Kv1.5) by bupivacaine enantiomers. Biophys J 1995; 69: 418-27
66. Abernethy DR, Wesche DL, Barbey JT, et al. Stereoselective halofantrine disposition and effect: concentration-related QTc prolongation. Br J Clin Pharmacol 2001; 51: 231-7
67. European Medicines Evaluation Agency. EMEA Public Statement on the recommendation to suspend the marketing authorisation for Orlaam (levacetylmethadol) in the European Union. EMEA/8776/01. EMEA, 2001 Apr 19 [online]. Available from URL: http://www.emea.europa.eu/pdfs/ human/press/pus/877601en.pdf [Accessed 2008 Jan 26]
68. Eap CB, Crettol S, Rougier JS, et al. Stereoselective block of hERG channel by (S)-methadone and QT interval prolongation in CYP2B6 slow metabolizers. Clin Pharmacol Ther 2007; 81: 719-28
69. Bayer R, Schwarzmaler J, Pernice R. Basic mechanism underlying prenylamine-induced torsade de pointes: differences between prenylamine and fendiline due to basic actions of the isomers. Curr Med Res Opin 1988; 11: 254-72
70. Lilly pulls out of R-fluoxetine deal. Scrip 2000 Oct 25; 2586: 24
71. Olatunde A, Price Evans DA. Blood quinidine levels and cardiac effects in white British and Nigerian subjects. Br J Clin Pharmacol 1982; 14: 513-8
72. Shin J-G, Kang W-K, Shon J-H, et al. Possible interethnic differences in quinidine-induced QT prolongation between healthy Caucasian and Korean subjects. Br J Clin Pharmacol 2006; 63: 206-15
73. Ozawa S, Soyama A, Saeki M, et al. Ethnic differences in genetic polymorphisms of CYP2D6, CYP2C19, CYP3As and MDR1/ABCB1. Drug Metab Pharmacokin 2004; 19: 83-95
74. Solus JF, Arietta BJ, Harris JR, et al. Genetic variation in eleven phase I drug metabolism genes in an ethnically diverse population. Pharmacogenomics 2004; 5: 895-931
75. Ackerman MJ, Tester DJ, Jones GS, et al. Ethnic differences in cardiac potassium channel variants: Implications for genetic susceptibility to sudden cardiac death and genetic testing for congenital long QT syndrome. Mayo Clin Proc 2003; 78: 1479-87
76. Priori SG, Napolitano C, Schwartz PJ. Low penetrance in the long-QT syndrome: clinical impact. Circulation 1999; 99: 529-33
77. Kannankeril PJ, Roden DM, Norris KJ, et al. Genetic susceptibility to acquired long QT syndrome: pharmacologic challenge in first-degree relatives. Heart Rhythm 2005; 2: 134-40
78. Shah RR. Pharmacogenetic aspects of drug-induced torsade de pointes: potential tool for improving clinical drug development and prescribing. Drug Saf 2004; 27: 145-72
79. Judson RS, Salisbury BA, Reed CR, et al. Pharmacogenetic issues in thorough QT trials. Mol Diag Ther 2006; 10: 153-62
80. Grisanti S, Morganroth J, Shah RR. A practical approach to cardiac safety: implementing ICH E14 to define cardiac safety in new drug development. Applied Clin Trials 2005 Oct; Suppl.: 10-6
81. Darpo B, Nebout T, Sager PT. Clinical evaluation of QT/QTc prolongation and proarrhythmic potential for non-antiarrhythmic drugs: the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use E14 Guideline. J Clin Pharmacol 2006; 46: 498-507
82. Morganroth J. Cardiac repolarization and the safety of new drugs defined by electrocardiography. Clin Pharmacol Ther 2007; 81: 108-13
83. Morganroth J. Response to "Design of the thorough QT study". Clin Pharmacol Ther 2008; 83: 529-30
84. Serra DB, Affrime MB, Bedigian MP, et al. QT and QTc interval with standard and supratherapeutic doses of darifenacin, a muscarinic M3 selective receptor antagonist for the treatment of overactive bladder. J Clin Pharmacol 2005; 45: 1038-47
85. Kubitza D, Mueck W, Becka M. Randomized, double-blind, crossover study to investigate the effect of rivaroxaban on QT-interval prolongation. Drug Saf 2008; 31: 67-77
86. Davis JD, Hackman F, Layton G, et al. Effect of single doses of maraviroc on the QT/QTc interval in healthy subjects. Br J Clin Pharmacol 2008; 65 Suppl. 1: 68-75
87. Shah MH, Binkley P, Chan K, et al. Cardiotoxicity of histone deacetylase inhibitor depsipeptide in patients with metastatic neuroendocrine tumors. Clin Cancer Res 2006; 12: 3997-4003
88. Morganroth J. Evaluation of the effect on cardiac repolarization (QTc interval) of oncologic drugs. Ernst Schering Res Found Workshop. 2007; 59: 171-84
89. Strevel EL, Ing DJ, Siu LL. Molecularly targeted oncology therapeutics and prolongation of the QT interval. J Clin Oncol 2007; 25: 3362-71
90. Curigliano G, Spitaleri G, Fingert HJ, et al. Drug-induced QTc interval prolongation: a proposal towards an efficient and safe anticancer drug development. Eur J Cancer 2008; 44: 494-500
91. Darpo B, Sager P. Design of the "Thorough QT Study". Clin Pharmacol Ther 2008 Apr; 83 (4): 529; author reply 530
92. US Food and Drug Administration. Avelox (Moxifloxacin HCI) oral tablets. Application no. 21-334 & 21-085S10 [online]. Available from URL: http://www.fda.gov/cder/foi/nda/2001/21-085S010_Avelox_biopharmr.pdf [Accessed 2008 Jan 26]
93. Hartigan-Go K, Bateman DA, Nyberg G, et al. Concentration-related pharmacodynamic effects of thioridazine and its metabolites in humans. Clin Pharmacol Ther 1996; 60: 543-53
94. Hutmacher MM, Chapel S, Agin MA, et al. Performance characteristics for some typical QT study designs under the ICH E-14 guidance. J Clin Pharmacol 2008; 48: 215-24