Electrocardiographic safety of cangrelor, a new intravenous antiplatelet agent: A randomized, double-blind, placebo- and moxifloxacin-controlled thorough QT study

Journal of Cardiovascular Pharmacology

Volumn 62, Issue 5, 2013, Pages 466-478

  Green, Cynthia L ^a,b   Whellan, David J ^c   Lambe, Lindsay ^b   Bellibas, S E ^d   Wijngaard, Peter ^d   Prats, Jayne ^d   Krucoff, Mitchell W ^a,b  

^a DUKE UNIVERSITY MEDICAL CENTER   (United States)

^b DUKE CLINICAL RESEARCH INSTITUTE   (United States)

^c THOMAS JEFFERSON UNIVERSITY   (United States)

^d MEDICINES COMPANY   (United States)

Author keywords

cangrelor; cardiac repolarization; electrocardiography; ICH E14; thorough QT study

Indexed keywords

CANGRELOR; MOXIFLOXACIN; PLACEBO;

ADULT; ARTICLE; CONTACT DERMATITIS; CONTROLLED STUDY; CROSSOVER PROCEDURE; DIZZINESS; DOUBLE BLIND PROCEDURE; DRUG BLOOD LEVEL; DRUG SAFETY; DRUG TOLERABILITY; ELECTROCARDIOGRAM; FAINTNESS; FEMALE; HEADACHE; HEART RATE; HEART REPOLARIZATION; HEART VENTRICLE FIBRILLATION; HEART VENTRICLE TACHYCARDIA; HUMAN; INFUSION RELATED REACTION; INJECTION SITE PAIN; INJECTION SITE REACTION; MAJOR CLINICAL STUDY; MALE; NEUROLOGIC DISEASE; NORMAL HUMAN; PRIORITY JOURNAL; QT INTERVAL; RANDOMIZED CONTROLLED TRIAL; SEIZURE; SKIN DISEASE; SKIN IRRITATION; VOLUNTEER;

ADENOSINE MONOPHOSPHATE; ADOLESCENT; ADULT; AZA COMPOUNDS; CROSS-OVER STUDIES; DOSE-RESPONSE RELATIONSHIP, DRUG; DOUBLE-BLIND METHOD; ELECTROCARDIOGRAPHY; FEMALE; FOLLOW-UP STUDIES; HUMANS; LONG QT SYNDROME; MALE; MIDDLE AGED; PLATELET AGGREGATION INHIBITORS; PURINERGIC P2Y RECEPTOR ANTAGONISTS; QUINOLINES; TIME FACTORS; YOUNG ADULT;

EID: 84888130993     PISSN: 01602446     EISSN: 15334023     Source Type: Journal    
DOI: 10.1097/FJC.0b013e3182a2630d     Document Type: Article

References (26)

1. Shah RR. Pharmacogenetic aspects of drug-induced torsade de pointes: potential tool for improving clinical drug development. Drug Saf. 2004; 27:145-172.
2. Gupta A, Lawrence AT, Krishnan K, et al. Current concepts in the mechanisms and management of drug-induced QT prolongation and torsade de pointes. Am Heart J. 2007;153:891-899.
3. Shah RR. Drug-induced prolongation of the QT interval: regulatory dilemmas and implications for approval and labeling of a new chemical entity. Fundam Clin Pharmacol. 2002;16:147-156.
4. Bass AS, Tomaselli G, Bullingham R III, et al. Drugs effects on ventricular repolarization: a critical evaluation of the strengths and weaknesses of current methodologies and regulatory practices. J Pharmacol Toxicol Methods. 2005;52:12-21.
5. US Food and Drug Administration. International Conference on Harmonisation; guidance on E14 clinical evaluation of QT/QTc interval prolongation and proarrhythmic potential for non-antiarrhythmic drugs; availability. Notice. Fed Regist. 2005;70:61134-61135.
6. ICH E14. Guidance for industry: E14 clinical evaluation of QT/QTc interval prolongation and proarrhythmic potential for non-antiarrhythmic drugs, October 2005. Issued by the U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER). Approved by the International Conference on Harmonisation (ICH). Available at: http://www.fda.gov/downloads/ RegulatoryInformation/Guidances/UCM129357.pdf. Accessed August 12, 2012.
7. Shah RR. Drugs, QTc interval prolongation and final ICH E14 guideline: an important milestone with challenges ahead. Drug Saf. 2005; 28: 1009-1028.
8. Darpo B. The thorough QT/QTc study 4 years after the implementation of the ICH E14 guidance. Br J Pharmacol. 2010;159:49-57.
9. Akers WS, Oh JJ, Oestreich JH, et al. Pharmacokinetics and pharmacodynamics of a bolus and infusion of cangrelor: a direct, parenteral P2Y12 receptor antagonist. J Clin Pharmacol. 2010;50:27-35.
10. Garcia R, Benet M, Arnau C, et al. Efficiency of the cross-over design: an empirical estimation. Stat Med. 2004;23:3773-3780.
11. Bloomfield DM, Kost JT, Ghosh K, et al. The effect of moxifloxacin on QTc and implications for the design of thorough QT studies. Clin Pharmacol Ther. 2008;84:475-480.
12. Avelox (Moxifloxacin Hydrochloride) Tablets; Avelox I.V. (Moxifloxacin Hydrochloride in Sodium Chloride Injection) [Package Insert]. Parsippany, NJ: The Medicines Company; 2007.
13. Malik M. Problems of heart rate correction in assessment of druginduced QT interval prolongation. J Cardiovasc Electrophysiol. 2001; 12:411-420.
14. Malik M, Farbom P, Batchvarov V, et al. Relation between QT and RR intervals is highly individual among healthy subjects: implications for heart rate correction of the QT interval. Heart. 2002;87:220-228.
15. Fridericia LS. Die Systolendauer im Elektrokardiogramm bei normalen Menchen und bei Herzkranken. Acta Med Scand. 1920;53:469-486.
16. Patterson S, Jones B, Zariffa N. Modeling and interpreting QTc prolongation in clinical pharmacology studies. Drug Inf J. 2005;39:437-445.
17. Verbeke G, Molenberghs G. Linear Mixed Models for Longitudinal Data. New York, NY: Springer Science + Business Media Inc; 2000.
18. Namboodiri NK. Experimental designs in which each subject is used repeatedly. Psychol Bull. 1972;77: 54-54.
19. Hulhoven R, Rosillon D, Bridson WE, et al. Effect of levetiracetam on cardiac repolarization in healthy subjects: a single-dose, randomized, placebo-and active-controlled, four-way crossover study. Clin Ther. 2008;30:260-270.
20. Stylianou A, Roger J, Stephens K. A statistical assessment of QT data following placebo and moxifloxacin dosing in thorough QT studies. J Biopharm Stat. 2008;18:502-516.
21. A Double Blind, Placebo Controlled, Multicenter Study to Assess the Safety and Tolerability of Intravenous AR C69931MX and Placebo in Unstable Angina Pectoris or Non Q Wave Myocardial Infarction. 1999. Final Study Report SC 931 5060.
22. Angiolillo DJ, Firstenberg MS, Price MJ, et al. Bridging antiplatelet therapy with cangrelor in patients undergoing cardiac surgery: a randomized controlled trial. JAMA. 2012; 307: 265-274.
23. Harrington RA, Stone GW, McNulty S, et al. Platelet inhibition with cangrelor in patients undergoing PCI. N Engl J Med. 2009;361:2318-2329.
24. Bhatt DL, Lincoff AM, Gibson CM, et al. Intravenous platelet blockade with cangrelor during PCI. N Engl J Med. 2009;361:2330-2341.
25. A placebo-controlled study of the electrophysiological effects of a single 80 mg prasugrel dose on the QT interval in healthy subjects. Available at: http://www.lillytrials.com/results/Effient.pdf. Accessed September 8, 2012.
26. Butler K, Wei C, Teng R. Single-dose ticagrelor does not prolong the QT interval in healthy subjects. Int J Clin Pharmacol Ther. 2010; 48: 643-651.