Effects of Sugammadex Doses up to 32 mg/kg Alone or in Combination with Rocuronium or Vecuronium on QTc Prolongation
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Sugammadex reverses the effects of rocuronium- and vecuronium-induced neuromuscular blockade, which are achieved by encapsulation. It is known that some non-antiarrhythmic drugs have the potential to delay cardiac repolarization and it is therefore recommended that the effects of all new drugs on the QT interval are assessed.
This thorough corrected QT (QTc) study evaluated the effect of sugammadex alone and in combination with rocuronium or vecuronium on the individually corrected QTc interval (QTcI).
This was a randomized, double-blind, six-period crossover, placebo-controlled study, with an open-label active-controlled component (moxifloxacin). The study was designed according to International Conference on Harmonization (ICH) E14 guidelines. The study was conducted in a clinical research unit from November 2006 to April 2007. Healthy male and female subjects (n = 84) were enrolled in the study. Subjects were randomized to six treatment sequences comprising single intravenous doses of placebo, moxifloxacin 400 mg (positive control), sugammadex 4 mg/kg, sugammadex 32 mg/kg, sugammadex 32 mg/kg with rocuronium 1.2 mg/kg and sugammadex 32 mg/kg with vecuronium 0.1 mg/kg. Triplicate ECGs were recorded at 13 timepoints up to 23.5 hours after study drug administration and QT intervals were evaluated manually under blinded conditions. The primary outcome was the largest time-matched mean difference in QTcI change from baseline compared with placebo across the 13 timepoints up to 23.5 hours after study drug administration. Blood samples were also collected for pharmacokinetic analysis.
Of the 84 randomized healthy subjects, 80 completed the study. After moxifloxacin, QTcI prolongations were observed compared with placebo; the lower limit of the one-sided 95% confidence interval (CI) for the largest time-matched mean difference in QTcI change compared with placebo was 20.8 msec (90% CI 18.5, 23.1), thus exceeding the ICH E14 safety margin of 5 msec and demonstrating assay sensitivity. In contrast, the largest time-matched mean difference in QTcI (msec) from placebo with sugammadex treatments ranged from 2.1 (sugammadex 4 mg/kg alone) to 4.3 (sugammadex 32 mg/kg with vecuronium 0.1 mg/kg). For the largest time-matched mean difference in QTcI change compared with placebo the corresponding upper limit of the one-sided 95% CI was well below the 10 msec margin for both sugammadex doses. Telemetry results revealed that one subject experienced a non-sustained ventricular tachycardia 4 hours after sugammadex 32 mg/kg, which was self-terminating after 20 beats and considered unlikely to be drug related. Pharmacokinetic-QTc analysis showed a statistically significant (p<0.01) relationship between sugammadex plasma concentration and QTcI; however, at mean maximum plasma concentrations of the therapeutic and supratherapeutic sugammadex dose, the predicted one-sided upper 95% CI for the largest time-matched QTcI difference from placebo was below 10 msec. Rocuronium or vecuronium co-administration did not affect the relationship between sugammadex concentrations and QTc.
Based on the results of this study of healthy subjects, it can be concluded that sugammadex alone or in combination with rocuronium or vecuronium is not associated with QTc prolongation.
Funding for the study and preparation of this manuscript was provided by MSD, Oss, the Netherlands. Ganimed GmbH ECG laboratory performed the manual evaluation of the ECG interval data, and CRS Clinical Research Services GmbH, Mönchengladbach, Germany conducted the study. Medical writing support was provided by Melanie More at Prime Medica (Knutsford, Cheshire, UK) during the preparation of this manuscript. Emiel van Heumen, an employee of MSD, Oss, the Netherlands, provided his safety input into the manuscript. The design and conduct of the study, as well as the analysis of the study data and the opinions, conclusions and interpretation of the data are the responsibility of the authors.
Pieter-Jan de Kam is a consultant of MSD, Oss, the Netherlands. Jacqueline van Kuijk, Marita Prohn and Pierre Peeters are employees of MSD, Oss, the Netherlands.
This work was presented at the European Society of Anaesthesiology Annual Meeting, Copenhagen, Denmark, 31 May–3 June 2008.
- 1.Guidance for industry E14 clinical evaluation of QT/QTc interval prolongation and proarrhythmic potential for non-antiarrhythmic drugs: 2005 [online]. Available from URL: http://www.fda.gov/CbER/gdlns/iche14qtc.htm [Accessed 2008 Jun 11]Google Scholar
- 14.Yildirsim H, Adanir T, Atay A. The effects of sevoflurane, isoflurane and desflurane on QT interval of the ECG. Eur J Anaesthesiol 2004 Jul; 21(7): 566–70Google Scholar
- 16.Jones B, Kenward MG. Design and analysis of cross-over trials. 2nd ed. London: Chapman and Hall, 2003Google Scholar
- 18.Beal SL, Sheiner LB, Boeckmann AJ, editors. NONMEM users guides. Ellicott City (MD): Icon Development Solutions}, 1989–2006Google Scholar
- 21.Peeters PAM, van den Heuvel M, van Heumen E, et al. Evaluating the safety and pharmacokinetics of sugammadex using single high doses (up to 96 mg/kg) in healthy adult subjects. Clin Drug Investig. In pressGoogle Scholar
- 25.de Kam PJ, van Kuijk J, Smeets J, et al. Single IV sugammadex doses up to 32 mg/kg are not associated with QT/QTc prolongation. In: The Annual Meeting of the American Society of Anesthesiologist; 2007 October 13–17; San Francisco (CA). Anesthesiology 2007; 107: A1580Google Scholar
- 26.Dahl V, Pendeville E, Hollmann MW, et al. Reversal of rocuronium-induced neuromuscular blockade by sugammadex in cardiac patients. In: The Annual Meeting of the American Society of Anesthesiologist; 2007 October 13–17; San Francisco (CA). Anesthesiology 2007; 107: A1581Google Scholar
- 28.Van lymen M, Parlow JL. The effects of reversal of neuromuscular blockade on autonomic control in the perioperative period. Anesth Analg 1997 Jan; 84(1): 148–54Google Scholar