title: Safety, tolerability and pharmacokinetics of sugammadex using single high doses (up to 96 mg/kg) in healthy adult subjects: a randomized, double-blind, crossover, placebo-controlled, single-centre study.
abstract: OBJECTIVE
  Sugammadex facilitates rapid reversal of rocuronium- and vecuronium-induced neuromuscular blockade. This study aimed to evaluate the safety, tolerability and pharmacokinetics of high doses of sugammadex (up to 96 mg/kg) in healthy subjects.
  
  
  METHODS
  In this randomized, double-blind, crossover, placebo-controlled, single-centre study, 13 healthy adults were scheduled to receive three single intravenous doses of sugammadex in ascending order (32, 64 and 96 mg/kg) and placebo (interspersed between sugammadex doses), each separated by a 1-week washout period. Subjects were randomized to one of four treatment sequences, receiving doses as constant rate infusions over 5 minutes. Safety was assessed by adverse events, 12-lead ECGs, vital signs, and blood and urine laboratory parameters; pharmacokinetics were evaluated from blood and urine sugammadex concentrations.
  
  
  RESULTS
  Sugammadex was well tolerated in 12 of the 13 subjects, with adverse events being generally mild, of limited duration and more frequent at higher doses. The most common adverse event was dysgeusia; there were no serious adverse events. One subject was withdrawn from the study after experiencing several adverse events following first exposure to sugammadex, related to a probable hypersensitivity reaction to sugammadex. Pharmacokinetics were dose linear over the dose range studied (32-96 mg/kg), and 90-93% of the sugammadex dose was excreted unchanged in urine within 48 hours.
  
  
  CONCLUSIONS
  High doses of sugammadex (up to 96 mg/kg) were well tolerated in 12 of the 13 subjects. One male subject experienced several adverse events associated with a probable hypersensitivity reaction to sugammadex. Pharmacokinetics were dose linear over the range 32-96 mg/kg, with elimination predominantly via the renal route.
authors.affiliation: Early Stage Development, MSD, Oss, the Netherlands. pierre.peeters2@merck.com
authors.forename: Pierre A M
authors.initials: PA
authors.lastname: Peeters
authors.forename: Michiel W
authors.initials: MW
authors.lastname: van den Heuvel
authors.forename: Emiel
authors.initials: E
authors.lastname: van Heumen
authors.forename: Paul C C M
authors.initials: PC
authors.lastname: Passier
authors.forename: Jean M W
authors.initials: JM
authors.lastname: Smeets
authors.forename: Thijs
authors.initials: T
authors.lastname: van Iersel
authors.forename: Alex
authors.initials: A
authors.lastname: Zwiers
mesh_terms: D000328:Adult; D018592:Cross-Over Studies; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009426:Netherlands; D009465:Neuromuscular Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D015990:Placebo Effect; D000077122:Sugammadex; D016896:Treatment Outcome; D047408:gamma-Cyclodextrins / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*
chemical_list: D009465:Neuromuscular Agents; D047408:gamma-Cyclodextrins; D000077122:Sugammadex
references.citation: Anesth Analg. 2007 Mar;104(3):563-8
references.pmid: 17312209
references.citation: Anesthesiology. 2003 Sep;99(3):632-7; discussion 6A
references.pmid: 12960547
references.citation: Clin Drug Investig. 2010;30(9):599-611
references.pmid: 20568829
references.citation: Br J Anaesth. 2006 Jan;96(1):36-43
references.pmid: 16357116
references.citation: Minerva Anestesiol. 2006 Mar;72(3):97-109
references.pmid: 16493386
references.citation: Anesth Analg. 2007 Mar;104(3):555-62
references.pmid: 17312208
references.citation: Anesthesiology. 2007 Aug;107(2):239-44
references.pmid: 17667567
references.citation: Anesthesiology. 2007 May;106(5):935-43
references.pmid: 17457124
references.citation: Anesthesiology. 2007 Feb;106(2):283-8
references.pmid: 17264722
references.citation: Anesthesiology. 2006 Apr;104(4):718-23
references.pmid: 16571967
references.citation: Anesthesiology. 2005 Oct;103(4):695-703
references.pmid: 16192761
references.citation: Toxicol Pathol. 2008 Jan;36(1):30-42
references.pmid: 18337219
references.citation: Br J Anaesth. 2008 Mar;100(3):373-9
references.pmid: 18238834
references.citation: Anesthesiology. 2006 Apr;104(4):667-74
references.pmid: 16571960
references.citation: Anesth Analg. 2007 Mar;104(3):569-74
references.pmid: 17312210
references.citation: Br J Anaesth. 2007 May;98(5):624-7
references.pmid: 17347184
references.citation: Angew Chem Int Ed Engl. 2002 Jan 18;41(2):266-70
references.pmid: 12491405