Pharmacokinetic-Pharmacodynamic Model for the Reversal of Neuromuscular Blockade by Sugammadex

Abstract

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. 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. 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. 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.