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Effect of Sugammadex on QT/QTc Interval Prolongation when Combined with QTc-Prolonging Sevoflurane or Propofol Anaesthesia

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Abstract

Background

We evaluated the potential for QT/corrected QT (QTc) interval prolongation after sugammadex given with propofol or sevoflurane anaesthesia.

Methods

This was a two-factorial, randomized, parallel-group study in 132 healthy subjects. Anaesthesia was maintained with sevoflurane or propofol. At ~20 min following sevoflurane/propofol initiation, sugammadex 4 mg/kg or placebo was administered. Neuromuscular blocking agents were not administered. Electrocardiograms were recorded regularly. The primary variable was the time-matched mean difference in the Fridericia-corrected QT interval (QTcF) change from baseline for sugammadex versus placebo when combined with propofol or sevoflurane. No relevant QTcF prolongation was concluded if the upper one-sided 95 % confidence interval (CI) was below the 10 ms margin of regulatory non-inferiority, up to 30 min post-study drug. Blood samples were taken for pharmacokinetic analysis. An exploratory analysis evaluated potential QT/QTc effects of neostigmine 50 μg/kg/glycopyrrolate 10 μg/kg in combination with propofol.

Results

The estimated mean QTcF differences between sugammadex and placebo ranged from −2.4 to 0.6 ms when combined with either anaesthetic. The largest upper one-sided 95 % CI for the mean QTcF difference between sugammadex and placebo was 2 ms, occurring 2 min post-dosing. Propofol and sevoflurane resulted in mean QTcF increases exceeding 10 and 30 ms, respectively. On top of these prolongations, the effect of sugammadex was negligible at all timepoints. The mean peak sugammadex concentration was 66.5 μg/mL, with exposure similar in the sevoflurane/propofol groups. The mean QTcF changes from baseline following neostigmine/glycopyrrolate in 10 healthy subjects ranged between −1.4 and 3.6 ms.

Conclusion

Sugammadex 4 mg/kg does not cause clinically relevant QTc interval prolongation versus placebo when combined with propofol or sevoflurane.

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Acknowledgments

Pieter-Jan de Kam and Justin Dennie are employees of Merck Sharp & Dohme Corp. (Whitehouse Station, NJ, USA). Peter Grobara, Marjan LF Jagt-Smook and Michiel W van den Heuvel are employees of MSD (Oss, The Netherlands). Employees of Merck Sharp & Dohme Corp. and MSD may potentially own stock and/or hold stock options in the company. Pierre AM Peeters and Rob JW Berg were formerly employees of MSD. Guy Cammu has received lecture fees from MSD and research grants for funded work on sugammadex from MSD. Pierre Peeters received stocks from MSD during his time of employment by them. Steven Ramael is an employee of SGS Life Science Services (Antwerp, Belgium), and his institution received funding for the current study from MSD. Medical writing support was provided by Melanie More of Prime Medica Ltd (Knutsford, Cheshire, UK). This assistance was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. (Whitehouse Station, NJ, USA). This study was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. (Whitehouse Station, NJ, USA). Support with ECG analysis was provided by Biomedical Systems [BMS] (St Louis, MO, USA), with logistical support from BMS in Brussels, Belgium. The design and conduct of the study, as well as the analysis of the study data and opinions, conclusions, and interpretation of the data, were the responsibility of the authors.

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Correspondence to Pieter-Jan de Kam.

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de Kam, PJ., Grobara, P., Dennie, J. et al. Effect of Sugammadex on QT/QTc Interval Prolongation when Combined with QTc-Prolonging Sevoflurane or Propofol Anaesthesia. Clin Drug Investig 33, 545–551 (2013). https://doi.org/10.1007/s40261-013-0095-8

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