Sugammadex: Clinical Pharmacokinetics and Pharmacodynamics

  • Jennifer Nguyen-Lee
  • Natalie Moreland
  • Alireza Sadoughi
  • Reza Borna
  • Ali Salehi
  • Jonathan S. Jahr
Neuromuscular Blockade (GS Murphy, Section Editor)
  • 24 Downloads
Part of the following topical collections:
  1. Neuromuscular Blockade

Abstract

Purpose of Review

The purpose of this chapter is to provide an evidence based understanding of the pharmacokinetics and pharmacodynamics of sugammadex.

Recent Findings

Sugammadex is a c-cyclodextrin that rapidly reverses the effect of aminosteroid nondepolarizing neuromuscular blocking agents (NMBAs) rocuronium and vecuronium by forming an inactive 1:1 complex. It is only available in an intravenous form with a bioavailabilty of 100%. It does not bind to plasma proteins and is eliminated unchanged by the kidneys. The type of NMBA used and the degree of the residual neuromuscular blockade at the time of administration determine the dose of sugammadex needed and the speed of reversal. Plasma levels of exogenous compounds with similar steroidal structure, such as some hormones, hormonal contraceptives, and pheromones may also be reduced following administration of sugammadex. While the package insert does not indicate dosage adjustments in elderly patients, or those with hepatic, cardiac, pulmonary comorbidities (not approved in pediatric patients less than 18 years or patients with a creatinine clearance less than 30 ml/min), sugammadex dosing possibly should be adjusted based upon the patient’s age and comorbidities, including liver or kidney failure and morbid obesity.

Summary

Sugammadex has been shown to be an effective agent in reversing the effects of NMBAs with an acceptable safety and efficacy profile.

Keywords

Sugammadex Pharmacokinetics Pharmacodynamics Clinical therapeutics 

Notes

Acknowledgments

The authors wish to thank Nathaniel Bailey, MD, and Chrisana Grande, PhD, of Merck, for providing editorial support and references for the Bleeding section and for sharing insight and information on Drug Interactions and Affinity. The section on Sugammadex and Bleeding was adapted and modified from an unpublished, limited distribution monograph provided by Merck.

Compliance with Ethical Standards

Conflict of Interest

Jennifer Nguyen-Lee declares that she has no conflict of interest.

Natalie Moreland declares that she has no conflict of interest.

Alireza Sadoughi declares that he has no conflict of interest.

Reza Borna declares that he has no conflict of interest.

Ali Salehi declares that he has no conflict of interest.

Jonathan S. Jahr has received compensation for service on a speaker’s bureau from Merck, the manufacturer of sugammadex.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Goodman LS, Hardman JG, Limbird LE, Gilman AG. Goodman and Gilman’s The Pharmacological Basis of Therapeutics, vol. 10; 2011.  https://doi.org/10.1001/jama.288.16.2052.Google Scholar
  2. 2.
    Bom A, Bradley M, Cameron K, et al. A novel concept of reversing neuromuscular block: chemical encapsulation of rocuronium bromide by a cyclodextrin-based synthetic host. Angew Chem Int Ed Engl. 2002;41(2):266–70. http://www.ncbi.nlm.nih.gov/pubmed/12491405. Accessed 12 Dec 2017CrossRefPubMedGoogle Scholar
  3. 3.
    Naguib M. Sugammadex: another milestone in clinical neuromuscular pharmacology. Anesth Analg. 2007;104(3):575–81.  https://doi.org/10.1213/01.ane.0000244594.63318.fc.CrossRefPubMedGoogle Scholar
  4. 4.
    Gijsenbergh F, Ramael S, Houwing N, van Iersel T. First human exposure of Org 25969, a novel agent to reverse the action of rocuronium bromide. Anesthesiology. 2005;103(4):695–703. http://www.ncbi.nlm.nih.gov/pubmed/16192761. Accessed 20 Nov 2017CrossRefPubMedGoogle Scholar
  5. 5.
    White PF, Tufanogullari B, Sacan O, et al. The effect of residual neuromuscular blockade on the speed of reversal with Sugammadex. Anesth Analg. 2009;108(3):846–51.  https://doi.org/10.1213/ane.0b013e31818a9932.CrossRefPubMedGoogle Scholar
  6. 6.
    Vanacker BF, Vermeyen KM, Struys MMRF, Rietbergen H, Vandermeersch E, Saldien V, et al. Reversal of rocuronium-induced neuromuscular block with the novel drug sugammadex is equally effective under maintenance anesthesia with propofol or sevoflurane. Anesth Analg. 2007;104(3):563–8.  https://doi.org/10.1213/01.ane.0000231829.29177.8e.CrossRefPubMedGoogle Scholar
  7. 7.
    Rex C, Wagner S, Spies C, Scholz J, Rietbergen H, Heeringa M, et al. Reversal of neuromuscular blockade by sugammadex after continuous infusion of rocuronium in patients randomized to sevoflurane or propofol maintenance anesthesia. Anesthesiology. 2009;111(1):30–5.  https://doi.org/10.1097/ALN.0b013e3181a51cb0.CrossRefPubMedGoogle Scholar
  8. 8.
    Pühringer FK, Gordon M, Demeyer I, Sparr HJ, Ingimarsson J, Klarin B, et al. Sugammadex rapidly reverses moderate rocuronium- or vecuronium-induced neuromuscular block during sevoflurane anaesthesia: a dose-response relationship. Br J Anaesth. 2010;105(5):610–9.  https://doi.org/10.1093/bja/aeq226.CrossRefPubMedGoogle Scholar
  9. 9.
    Groudine SB, Soto R, Lien C, Drover D, Roberts K. A randomized, dose-finding, phase II study of the selective relaxant binding drug, Sugammadex, capable of safely reversing profound rocuronium-induced neuromuscular block. Anesth Analg. 2007;104(3):555–62.  https://doi.org/10.1213/01.ane.0000260135.46070.c3.CrossRefPubMedGoogle Scholar
  10. 10.
    Zwiers A, van den Heuvel M, Smeets J, Rutherford S. Assessment of the potential for displacement interactions with sugammadex. Clin Drug Investig. 2010;31(2):1.  https://doi.org/10.2165/11584730-000000000-00000.CrossRefGoogle Scholar
  11. 11.
    Merck & Co. Bridion (sugammadex) injection, for intravenous use: US prescribing information. 2015. http://www.accessdata.fda.gov/. Accessed 8 Jun 2016.
  12. 12.
    •• Schaller SJ, Lewald H. Clinical pharmacology and efficacy of sugammadex in the reversal of neuromuscular blockade. Expert Opin Drug Metab Toxicol. 2016;12(9):1097–108.  https://doi.org/10.1080/17425255.2016.1215426. This article provides a very detailed and comprehensive discussion of the pharmacodynamics of sugammadex. CrossRefPubMedGoogle Scholar
  13. 13.
    Pongrácz A, Szatmári S, Nemes R, Fülesdi B, Tassonyi E. Reversal of neuromuscular blockade with sugammadex at the reappearance of four twitches to train-of-four stimulation. Anesthesiology. 2013;119(1):36–42.  https://doi.org/10.1097/ALN.0b013e318297ce95.CrossRefPubMedGoogle Scholar
  14. 14.
    •• Kaufhold N, Schaller SJ, Stäuble CG, et al. Sugammadex and neostigmine dose-finding study for reversal of residual neuromuscular block at a train-of-four ratio of 0.2 (SUNDRO20). Asai T ed. Br J Anaesth. 2016;116(2):233–240.  https://doi.org/10.1093/bja/aev437. This article is the most useful dose-finding study for sugammadex and the updated review on its use.
  15. 15.
    Schaller SJ, Fink H, Ulm K, Blobner M. Sugammadex and neostigmine dose-finding study for reversal of shallow residual neuromuscular block. Anesthesiology. 2010;113(5):1054–60.  https://doi.org/10.1097/ALN.0b013e3181f4182a.CrossRefPubMedGoogle Scholar
  16. 16.
    McDonagh DL, Benedict PE, Kovac AL, et al. Efficacy, safety, and pharmacokinetics of sugammadex for the reversal of rocuronium-induced neuromuscular blockade in elderly patients. Anesthesiology. 2011;114(2):318–29.  https://doi.org/10.1097/ALN.0b013e3182065c36.CrossRefPubMedGoogle Scholar
  17. 17.
    Llauradó S, Sabaté A, Ferreres E, Camprubí I, Cabrera A. Sugammadex ideal body weight dose adjusted by level of neuromuscular blockade in laparoscopic bariatric surgery. Anesthesiology. 2012;117(1):93–8.  https://doi.org/10.1097/ALN.0b013e3182580409.CrossRefPubMedGoogle Scholar
  18. 18.
    • Badaoui R, Cabaret A, Alami Y, Zogheib E, Popov I, Lorne E, et al. Reversal of neuromuscular blockade by sugammadex in laparoscopic bariatric surgery: in support of dose reduction. Anaesth Crit Care Pain Med. 2016;35(1):25–9.  https://doi.org/10.1016/j.accpm.2015.09.003. This article documents the use of sugammadex in bariatric surgery and provides an indication of dosage adjustments based on ideal versus actual body weight with sugammadex in obese patients. CrossRefPubMedGoogle Scholar
  19. 19.
    •• Loupec T, Frasca D, Rousseau N, Faure J-P, Mimoz O, Debaene B. Appropriate dosing of sugammadex to reverse deep rocuronium-induced neuromuscular blockade in morbidly obese patients. Anaesthesia. 2016;71(3):265–72.  https://doi.org/10.1111/anae.13344. This article is the premier source for discussing the use and dosage of sugammadex in mordibly obese patients. CrossRefPubMedGoogle Scholar
  20. 20.
    Fujita A, Ishibe N, Yoshihara T, Ohashi J, Makino H, Ikeda M, et al. Rapid reversal of neuromuscular blockade by sugammadex after continuous infusion of rocuronium in patients with liver dysfunction undergoing hepatic surgery. Acta Anaesthesiol Taiwanica. 2014;52(2):54–8.  https://doi.org/10.1016/j.aat.2014.04.007.CrossRefGoogle Scholar
  21. 21.
    Cammu G, Van Vlem B, Van Den Heuvel M, et al. Dialysability of sugammadex and its complex with rocuronium in intensive care patients with severe renal impairment. Br J Anaesth. 2012;109:382–90.  https://doi.org/10.1093/bja/aes207.CrossRefPubMedGoogle Scholar
  22. 22.
    Staals LM, Snoeck MMJ, Driessen JJ, et al. Reduced clearance of rocuronium and sugammadex in patients with severe to end-stage renal failure: a pharmacokinetic study. Br J Anaesth. 2010;104:31–9.  https://doi.org/10.1093/bja/aep340.CrossRefPubMedGoogle Scholar
  23. 23.
    Geldner G, Niskanen M, Laurila P, Mizikov V, Hübler M, Beck G, et al. A randomised controlled trial comparing sugammadex and neostigmine at different depths of neuromuscular blockade in patients undergoing laparoscopic surgery. Anaesthesia. 2012;67(9):991–8.  https://doi.org/10.1111/j.1365-2044.2012.07197.x.CrossRefPubMedGoogle Scholar
  24. 24.
    Wu X, Oerding H, Liu J, Vanacker B, Yao S, Dahl V, et al. Rocuronium blockade reversal with sugammadex vs. neostigmine: randomized study in Chinese and Caucasian subjects. BMC Anesthesiol. 2014;14(1):53.  https://doi.org/10.1186/1471-2253-14-53.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Grosse-Sundrup M, Henneman JP, Sandberg WS, et al. Intermediate acting non-depolarizing neuromuscular blocking agents and risk of postoperative respiratory complications: prospective propensity score matched cohort study. BMJ. 2012;345:e6329. http://www.ncbi.nlm.nih.gov/pubmed/23077290. Accessed 12 Dec 2017CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Sasaki N, Meyer MJ, Malviya SA, Stanislaus AB, MacDonald T, Doran ME, et al. Effects of neostigmine reversal of nondepolarizing neuromuscular blocking agents on postoperative respiratory outcomes. Anesthesiology. 2014;121(5):959–68.  https://doi.org/10.1097/ALN.0000000000000440.CrossRefPubMedGoogle Scholar
  27. 27.
    Herbstreit F, Zigrahn D, Ochterbeck C, Peters J, Eikermann M. Neostigmine/glycopyrrolate administered after recovery from neuromuscular block increases upper airway collapsibility by decreasing genioglossus muscle activity in response to negative pharyngeal pressure. Anesthesiology. 2010;113(6):1280–8.  https://doi.org/10.1097/ALN.0b013e3181f70f3d.CrossRefPubMedGoogle Scholar
  28. 28.
    Amao R, Zornow MH, Cowan RM, Cheng DC, Morte JB, Allard MW. Use of sugammadex in patients with a history of pulmonary disease. J Clin Anesth. 2012;24(4):289–97.  https://doi.org/10.1016/j.jclinane.2011.09.006.CrossRefPubMedGoogle Scholar
  29. 29.
    Saarnivaara L, Simola M. Effects of four anticholinesterase-anticholinergic combinations and tracheal extubation on QTc interval of the ECG, heart rate and arterial pressure. Acta Anaesthesiol Scand. 1998;42(4):460–3. http://www.ncbi.nlm.nih.gov/pubmed/9563867. Accessed 12 Dec 2017CrossRefPubMedGoogle Scholar
  30. 30.
    Dahl V, Pendeville PE, Hollmann MW, Heier T, Abels EA, Blobner M. Safety and efficacy of sugammadex for the reversal of rocuronium-induced neuromuscular blockade in cardiac patients undergoing noncardiac surgery. Eur J Anaesthesiol. 2009;26(10):874–84.  https://doi.org/10.1097/EJA.0b013e32832c605b.CrossRefPubMedGoogle Scholar
  31. 31.
    de Kam P-J, van den Heuvel MW, Grobara P, Zwiers A, Jadoul JL, de Clerck E, et al. Flucloxacillin and diclofenac do not cause recurrence of neuromuscular blockade after reversal with sugammadex. Clin Drug Investig. 2012;32(3):203–12.  https://doi.org/10.2165/11598980-000000000-00000.CrossRefPubMedGoogle Scholar
  32. 32.
    Min K, Bondiskey P, Schulz V, Al E. Evaluation of hypersensitivity incidence following repeated single-dose sugammadex administration in healthy subjects [abstract no.1AP15–9]. Eur J Anaesthesiol. 2015;32(Suppl 53):57.Google Scholar
  33. 33.
    Food and Drug Administration. Sugammadex medical review: application number 022225Orig1s000. 2015. http://www.accessdata.fda.gov/. Accessed 8 Jun 2016.
  34. 34.
    De Kam P-J, Grobara P, Prohn M, et al. Effects of sugammadex on activated partial thromboplastin time and prothrombin time in healthy subjects. Int J Clin Pharmacol Ther. 2014;52(3):227–36.  https://doi.org/10.5414/CP201976.CrossRefPubMedGoogle Scholar
  35. 35.
    Rahe-Meyer N, Fennema H, Schulman S, Klimscha W, Przemeck M, Blobner M, et al. Effect of reversal of neuromuscular blockade with sugammadex versus usual care on bleeding risk in a randomized study of surgical patients. Anesthesiology. 2014;121(5):969–77.  https://doi.org/10.1097/ALN.0000000000000424.CrossRefPubMedGoogle Scholar
  36. 36.
    De Kam P-J, Kruithof AC, van Lierop M-J, et al. Lack of a clinically relevant effect of sugammadex on anti-Xa activity or activated partial thromboplastin time following pretreatment with either unfractionated or low-molecular-weight heparin in healthy subjects. Int J Clin Pharmacol Ther. 2014;52(8):631–41.  https://doi.org/10.5414/CP202091.CrossRefPubMedGoogle Scholar
  37. 37.
    • Taş N, Korkmaz H, Yağan Ö, Korkmaz M. Effect of sugammadex on postoperative bleeding and coagulation parameters after septoplasty: a randomized prospective study. Med Sci Monit. 2015;21:2382–6.  https://doi.org/10.12659/MSM.894971. This article discusses the coagulation and bleeding parameters with sugammadex in patients at high risk for complications. CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    de Kam P-J, El Galta R, Kruithof AC, et al. No clinically relevant interaction between sugammadex and aspirin on platelet aggregation and coagulation parameters. Int J Clin Pharmacol Ther. 2013;51(12):976–85.  https://doi.org/10.5414/CP201970.CrossRefPubMedGoogle Scholar
  39. 39.
    de Kam P-J, Hou J, Wang Z, Lin WH, van den Heuvel M. Pharmacokinetics of sugammadex 16 mg/kg in healthy Chinese volunteers. Int J Clin Pharmacol Ther. 2015;53(6):456–61.  https://doi.org/10.5414/CP202234.CrossRefPubMedGoogle Scholar
  40. 40.
    Bom A, Hope F, Rutherford S, Thomson K. Preclinical pharmacology of sugammadex. J Crit Care. 2009;24:29–35.  https://doi.org/10.1016/j.jcrc.2008.10.010.CrossRefPubMedGoogle Scholar
  41. 41.
    Donati F, Donati FÇO. Expert opinion on pharmacotherapy Sugammadex: a cyclodextrin to reverse neuromuscular blockade in anaesthesia Sugammadex: a cyclodextrin to reverse neuromuscular blockade in anaesthesia. Expert Opin Pharmacother. 2008;9(8):1375–86.  https://doi.org/10.1517/14656560802046211.CrossRefPubMedGoogle Scholar
  42. 42.
    Eleveld DJ, Kuizenga K, Proost JH, Wierda JMKH. A temporary decrease in twitch response during reversal of rocuronium-induced muscle relaxation with a small dose of sugammadex. Anesth Analg. 2007;104(3):582–4.  https://doi.org/10.1213/01.ane.0000250617.79166.7f.CrossRefPubMedGoogle Scholar
  43. 43.
    Peeters PAM, van den Heuvel MW, van Heumen E, Passier PCCM, Smeets JMW, van Iersel T, et al. Safety, tolerability and pharmacokinetics of sugammadex using single high doses (up to 96 mg/kg) in healthy adult subjects. Clin Drug Investig. 2010;30(12):1.  https://doi.org/10.2165/11538920-000000000-00000.CrossRefGoogle Scholar
  44. 44.
    Peeters P, Passier P, Smeets J, Zwiers A, de Zwart M, van de Wetering-Krebbers S, et al. Sugammadex is cleared rapidly and primarily unchanged via renal excretion. Biopharm Drug Dispos. 2011;32(3):159–67.  https://doi.org/10.1002/bdd.747.CrossRefPubMedGoogle Scholar
  45. 45.
    • Panhuizen IF, SJA G, Buerkle C, et al. Efficacy, safety and pharmacokinetics of sugammadex 4 mg kg-1 for reversal of deep neuromuscular blockade in patients with severe renal impairment. Br J Anaesth. 2015;114(5):777–84.  https://doi.org/10.1093/bja/aet586. Compared the efficacy and safety of sugammadex 4 mg kg -1 between patients with severe renal disease (creatinine clearance < 30 ml min -1 ) and controls (creatinine clearance ≥ 80 ml min -1 ). They showed efficacy in patients with ESRD; however, the authors could not recommend use due to potential risks. CrossRefPubMedGoogle Scholar
  46. 46.
    Momeni A, Rouhi H, Kiani G, Amiri M. Effects of high-flux versus low-flux membranes on pulmonary function tests in hemodialysis patients. Tanaffos. 2013;12(1):31–5. http://www.ncbi.nlm.nih.gov/pubmed/25191447. Accessed 20 Nov 2017PubMedPubMedCentralGoogle Scholar
  47. 47.
    • Li X, Xu H, Xiao XC, Deng SL, Wang W, Tang R. Prognostic effect of high-flux hemodialysis in patients with chronic kidney disease. Brazilian J Med Biol Res = Rev Bras Pesqui medicas e Biol. 2016;49(1):e4708.  https://doi.org/10.1590/1414-431X20154708. Discussion of high-flux hemodialysis with sugammadex and its implications. Google Scholar
  48. 48.
    Hemmerling TM, Zaouter C, Geldner G, Nauheimer D. Sugammadex—a short review and clinical recommendations for the cardiac anesthesiologist. Ann Card Anaesth. 2010;13(3):206–16.  https://doi.org/10.4103/0971-9784.69052.CrossRefPubMedGoogle Scholar
  49. 49.
    Staals LM, Snoeck MMJ, Driessen JJ, Flockton EA, Heeringa M, Hunter JM. Multicentre, parallel-group, comparative trial evaluating the efficacy and safety of sugammadex in patients with end-stage renal failure or normal renal function. Br J Anaesth. 2008;101(4):492–7.  https://doi.org/10.1093/bja/aen216.CrossRefPubMedGoogle Scholar
  50. 50.
    • Min KC, Lasseter KC, Marbury TC, Wrishko RE, Hanley WD, Wolford DG, et al. Pharmacokinetics of sugammadex in subjects with moderate and severe renal impairment. Int J Clin Pharmacol Ther. 2017;55(9):746–52.  https://doi.org/10.5414/CP203025. This article discusses the use of sugammadex in patients with moderate to severe renal impairment. PubMedGoogle Scholar
  51. 51.
    Staals LM, Snoeck MMJ, Hunter JM, Heeringa M, Driessen JJ. Pharmacokinetics of rocuronium and sugammadex in patients with normal and impaired renal function. Present 13th World Congr Anesth (WCA) Cape Town, South Africa. 2008:2-7.Google Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Jennifer Nguyen-Lee
    • 1
  • Natalie Moreland
    • 1
  • Alireza Sadoughi
    • 1
  • Reza Borna
    • 1
  • Ali Salehi
    • 1
  • Jonathan S. Jahr
    • 1
    • 2
  1. 1.Anesthesiology and Perioperative MedicineDavid Geffen School of Medicine at UCLA, UCLA HealthLos AngelesUSA
  2. 2.David Geffen School of Medicine at UCLA, UCLA HealthLos AngelesUSA

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