title: Pharmacokinetic-pharmacodynamic model for the reversal of neuromuscular blockade by sugammadex.
abstract: BACKGROUND
  Sugammadex selectively binds steroidal neuromuscular blocking drugs, leading to reversal of neuromuscular blockade. The authors developed a pharmacokinetic-pharmacodynamic model for reversal of neuromuscular blockade by sugammadex, assuming that reversal results from a decrease of free drug in plasma and/or neuromuscular junction. The model was applied for predicting the interaction between sugammadex and rocuronium or vecuronium.
  
  
  METHODS
  Noninstantaneous equilibrium of rocuronium-sugammadex complex formation was assumed in the pharmacokinetic-pharmacodynamic interaction model. The pharmacokinetic parameters for the complex and sugammadex alone were assumed to be identical. After development of a pharmacokinetic-pharmacodynamic model for rocuronium alone, the interaction model was optimized using rocuronium and sugammadex concentration data after administration of 0.1-8 mg/kg sugammadex 3 min after administration of 0.6 mg/kg rocuronium. Subsequently, the predicted reversal of neuromuscular blockade by sugammadex was compared with data after administration of up to 8 mg/kg sugammadex at reappearance of second twitch of the train-of-four; or 3, 5, or 15 min after administration of 0.6 mg/kg rocuronium. Finally, the model was applied to predict reversal of vecuronium-induced neuromuscular blockade.
  
  
  RESULTS
  Using the in vitro dissociation constants for the binding of rocuronium and vecuronium to sugammadex, the pharmacokinetic-pharmacodynamic interaction model adequately predicted the increase in total rocuronium and vecuronium plasma concentrations and the time-course of reversal of neuromuscular blockade.
  
  
  CONCLUSIONS
  Model-based evaluation supports the hypothesis that reversal of rocuronium- and vecuronium-induced neuromuscular blockade by sugammadex results from a decrease in the free rocuronium and vecuronium concentration in plasma and neuromuscular junction. The model is useful for prediction of reversal of rocuronium and vecuronium-induced neuromuscular blockade with sugammadex.
authors.affiliation: LAP&P Consultants BV, Leiden, The Netherlands. b.ploeger@lapp.nl
authors.forename: Bart A
authors.initials: BA
authors.lastname: Ploeger
authors.forename: Jean
authors.initials: J
authors.lastname: Smeets
authors.forename: Ashley
authors.initials: A
authors.lastname: Strougo
authors.forename: Henk-Jan
authors.initials: HJ
authors.lastname: Drenth
authors.forename: Ge
authors.initials: G
authors.lastname: Ruigt
authors.forename: Natalie
authors.initials: N
authors.lastname: Houwing
authors.forename: Meindert
authors.initials: M
authors.lastname: Danhof
mesh_terms: D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions / Q000502:physiology; D005260:Female; D006801:Humans; D008297:Male; D008959:Models, Neurological; D019148:Neuromuscular Blockade / Q000379:methods*; D009469:Neuromuscular Junction / Q000187:drug effects / Q000378:metabolism; D016032:Randomized Controlled Trials as Topic / Q000379:methods; D000077122:Sugammadex; D013997:Time Factors; D047408:gamma-Cyclodextrins / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D047408:gamma-Cyclodextrins; D000077122:Sugammadex