Pharmacokinetic-pharmacodynamic model for the reversal of neuromuscular blockade by sugammadex.
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.
Ploeger
Bart A
BA
LAP&P Consultants BV, Leiden, The Netherlands. b.ploeger@lapp.nl
Smeets
Jean
J
Strougo
Ashley
A
Drenth
Henk-Jan
HJ
Ruigt
Ge
G
Houwing
Natalie
N
Danhof
Meindert
M
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*
D047408:gamma-Cyclodextrins; D000077122:Sugammadex