Prolonged QTc interval in cancer therapeutic drug development: Defining arrhythmic risk in malignancy

Progress in Cardiovascular Diseases

Volumn 53, Issue 2, 2010, Pages 164-172

  Brell, Joanna M ^a  

^a NATIONAL CANCER INSTITUTE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANTIBIOTIC AGENT; ANTIDEPRESSANT AGENT; ANTIEMETIC AGENT; ANTIFUNGAL AGENT; ANTIHISTAMINIC AGENT; ANTINEOPLASTIC AGENT; ARSENIC TRIOXIDE; CISAPRIDE; COMBRETASTATIN; CYCLOPHOSPHAMIDE; DASATINIB; DIURETIC AGENT; ELECTROLYTE; ENZASTAURIN; EPOTHILONE DERIVATIVE; INTERFERON; INTERLEUKIN 2; ISTODAX; METHADONE; NEUROLEPTIC AGENT; PROTEIN TYROSINE KINASE INHIBITOR; ROMIDEPSIN; SUNITINIB; TAXANE DERIVATIVE; THALIDOMIDE; TIPIFARNIB; UNCLASSIFIED DRUG; VANDETANIB;

ADVANCED CANCER; ARTICLE; CANCER CHEMOTHERAPY; CANCER PATIENT; CARDIOTOXICITY; CARDIOVASCULAR RISK; CLINICAL TRIAL; CUTANEOUS T CELL LYMPHOMA; DRUG SAFETY; DRUG SCREENING; DRUG SYNTHESIS; DRUG TOLERABILITY; GENETIC SUSCEPTIBILITY; HEART ARRHYTHMIA; HEART VENTRICLE FIBRILLATION; HUMAN; INCIDENCE; LONG QT SYNDROME; MALIGNANT NEOPLASTIC DISEASE; MELANOMA; PANCREAS CARCINOMA; PATIENT MONITORING; POSTMARKETING SURVEILLANCE; PRACTICE GUIDELINE; PROMYELOCYTIC LEUKEMIA; QT INTERVAL; QT PROLONGATION; RISK ASSESSMENT; SIDE EFFECT; SUDDEN DEATH; TORSADE DES POINTES; ACTION POTENTIAL; ANIMAL; ARRHYTHMIAS, CARDIAC; CHEMICALLY INDUCED; CHEMISTRY; DRUG APPROVAL; DRUG DESIGN; DRUG EFFECTS; HEART MUSCLE CONDUCTION SYSTEM; NEOPLASMS; PATHOPHYSIOLOGY; RISK FACTOR; STRUCTURE ACTIVITY RELATION; TIME; UNITED STATES;

ACTION POTENTIALS; ANIMALS; ANTINEOPLASTIC AGENTS; ARRHYTHMIAS, CARDIAC; DRUG APPROVAL; DRUG DESIGN; HEART CONDUCTION SYSTEM; HUMANS; NEOPLASMS; PRACTICE GUIDELINES AS TOPIC; RISK ASSESSMENT; RISK FACTORS; STRUCTURE-ACTIVITY RELATIONSHIP; TIME FACTORS; TORSADES DE POINTES; UNITED STATES;

EID: 77955936651     PISSN: 00330620     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.pcad.2010.05.005     Document Type: Article

References (36)

1. Vertex Pharmaceuticals press releases available at: , 2008 and , 2007. Last accessed July 22, 2010. http://investors.vrtx.com/releasedetail.cfm?ReleaseID=276543.
2. International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use The clinical evaluation of QT/QTc prolongation and pro-arrhythmic potential for non-antiarrhythmic drugs: E14 2005, International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use, Geneva, Switzerland, Available at:, Last accessed July 22, 2010. http://www.ich.org/LOB/media/MEDIA1476.pdf.
3. Darpo B. Spectrum of drugs prolonging QT interval and the incidence of torsades de pointes. Eur Heart J Suppl 2003, 3K:K70-K80.
4. Whellan D.J., Green C.L., Piccini J.P., et al. QT as a safety biomarker in drug development. Clin Pharmacol Ther 2009, 86:101-104.
5. HaverKamp W., Breithardt G., Camm J.A., et al. Potential for QT prolongation and pro-arrhythmia by non-anti-arrhythmic drugs: clinical and regulatory implications report on a Policy Conference of the European Society of Cardiology. Cardiovasc Res 2000, 47:219-223.
6. Moss A.J. QT interval and torsades de pointes. Drug Saf 1999, 21(Suppl):5-10.
7. Vitola J., Vukanovic J., Roden D.M. Cisapride-induced torsades de pointes. J Cardiovasc Electrophysiol 1998, 9:1109-1113.
8. Strevel E.L., Ing D.J., Su L.L. Molecularly targeted oncology therapeutics and prolongation of the QT interval. J Clin Oncol 2007, 25:3262-3371.
9. Fingert H., Varterasain M. Safety biomarkers and the clinical development of oncology therapeutics: considerations for cardiovascular risk and safety management. AAPS J 2006, 8(article 10):E89-E94.
10. Bednar M.M., Harrigan E.P., Anziano R.J., et al. The QT interval. Prog Cardiovasc Dis 2001, 43(No 5 suppl):1-45.
11. Zehender M., Hohnloser S., Just H. QT-interval prolonging drugs: mechanisms and clinical relevance of their arrhythmic hazards. Cardiovasc Drugs Ther 1991, 5:515-530.
12. Molnar J., Zhang F., Weiss J., et al. Diurnal pattern of QTc interval: how long is prolonged? Possible relation to circadian triggers of cardiovascular events. J Am Coll Cardiol 1996, 27:76-83.
13. Agin M.A., Kazierad D.J., Abel R., et al. Assessing QT variability in normal volunteers. Proc Am Coll Clin Pathol 2003.
14. Priori S.G., Schwartz P.J., Napolitano C., et al. Risk stratification in the long-QT syndrome. N Engl J Med 2003, 348:1866-1874.
15. Andersom M.E., Al-Khatib S.M., Roden D.M., et al. Cardiac repolarization: current knowledge, critical gaps, and new approaches to drug development and patient management. Am Heart J 2002, 144:769-781.
16. Redfern W.S., Carlsson L., Davis A.S., et al. Relationships between preclinical cardiac electrophysiology, clinical QT interval prolongation and torsades de pointes for a broad range of drugs: evidence for a provisional safety margin in drug development. Cardiovasc Res 2003, 58:32-45.
17. Roden D.M. Drug-induced prolongation of the QT interval. N Engl J Med 2004, 350:1013-1022.
18. Kr: model systems and relevance to human arrhythmias. J Cardiovasc Pharmacol 2001, 38:737-744.
19. Barbey J.T., Pezzullo J.C., Saignet S.L. Effect of arsenic trioxide on QT interval in patients with advanced malignancies. J Clin Oncol 2003, 21:3609-3615.
20. Varterasian M., Meyer M., Fingert H., et al. Baseline heart rate-corrected QT and eligibility for clinical trials in oncology. J Clin Oncol 2003, 21:3378-3379.
21. Ahmad K., Dorian P. Drug-induced QT prolongation and proarrhythmia: an inevitable link?. Europace-Eur Soc Cardiol 2007, iv16-iv22.
22. Floyd J.D., Nguyen D.T., Lobins R.L., et al. Cardiotoxicity of cancer therapy. J Clin Oncol 2005, 23:7685-7696.
23. DePonti F., Poluzzi E., Montanaro N. QT-interval prolongation by non-cardiac drugs: lessons to be learned from recent experience. Eur J Clin Pharmacol 2000, 56:1-18.
24. Sarapa N., Britto M.R. Challenges of characterizing proarrhythmic risk due to QTc prolongation induced by nonadjuvant anticancer agents. Expert Opin Drug Saf 2008, 7:305-318.
25. 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 2005, International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use, Geneva, Switzerland, Available at:, Last accessed July 22, 2010. http://www.ich.org/LOB/media/MEDIA2192.pdf.
26. Rock E.P., Finkle J., Fingert H.J., et al. Assessing proarrhythmic potential of drugs when optimal studies are infeasible. Am Heart J 2009, 157:827-836.
27. Shah R.R. If a drug deemed "safe" in nonclinical tests subsequently prolongs QT in phase 1 studies, how can its sponsor convince regulators to allow development to proceed?. Pharmacol Ther 2008, 119:215-221.
28. Garnett C.E., Beasley N., Bhattaram V.A., et al. Concentration-QT relationships play a key role in evaluation of proarrhythmic risk during regulatory review. J Clin Pharmacol 2008, 48:13-18.
29. Kummar S., Kinders R., Rubinstein L., et al. Compressing drug development timelines in oncology using phase "0" trials. Nat Rev Cancer 2007, 7:131-139.
30. Arsenic trioxide prescribing information available at: Last accessed July 22, 2010. http://www.trisenox.com/490-Trisenox-Prescibing-Info.aspx.
31. Agrawal M., Grady C., Fairclough D.L., et al. Patients' decision-making process regarding participation in phase I oncology research. J Clin Oncol 2006, 24:4479-4484.
32. QTc prolonging agents available at: Last accessed July 22, 2010. http://www.qtdrugs.org.
33. Romidepsin prescribing information available at: Last accessed July 22, 2010. http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/022393lbl.pdf.
34. Bates S.E., Rosing D.R., Fofo T., et al. Challenges of evaluating cardiac effects of anticancer agents. Clin Cancer Res 2006, 12:3871-3873.
35. Piekarz R.L., Frye A.R., Wright J.J., et al. Cardiac studies in patients treated with depsipeptide, FK228, in a phase II trial for T-cell lymphoma. Clin Cancer Res 2006, 12:3762-3773.
36. Fitzgerald P.T., Ackerman M.J. Drug-induced torsades de pointes: evolving role of pharmacogenomics. Heart Rhythm 2005, 2:S30-S37.