Pharmacokinetic–Pharmacodynamic Model for the Reversal of Meeting Abstracts 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 pharmacokineticpharmacodynamic 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 rocuroniumand 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. IDEALLY, neuromuscular blocking agents should have a rapid onset and offset of neuromuscular blockade (NMB). Of the nondepolarizing neuromuscular blocking agents used in clinical practice, rocuronium shows the most rapid onset of NMB and has an intermediate to long duration of action. To decrease its duration of action, a cyclodextrin has been designed to specifically bind rocuronium, thereby reversing rocuronium-induced NMB. The effectiveness and safety of this cyclodextrin, sugammadex, for the reversal of rocuronium-induced NMB has been reported in several preclinical and clinical studies; these studies have investigated sugammadex administered at a variety of time points, including administration 3 min after a rocuronium dose and at reappearance of the second twitch (T2) of train-of-four (TOF) stimulation. Pharmacokinetic studies consistently show decreased rocuronium clearance and increased total rocuronium concentrations shortly after sugammadex administration. As discussed by others, rocuronium bound by sugammadex is eliminated by renal excretion with a total clearance that is approximately one-third that of unbound rocuronium. As a result, higher total rocuronium concentrations are observed after sugammadex administration, as compared with administration of rocuronium alone. However, it is hypothesized that the free rocuronium concentration decreases after sugammadex administration, resulting in decreased availability of rocuronium at the nicotinic receptors. As a result, a more rapid reversal of NMB is observed. Although consensus exists about the proposed mechanism of action for the reversal of rocuronium-induced NMB after sugammadex administration, this hypothesis has not been confirmed by measuring the actual free rocuronium concentration. The absence of an analytical method to separate free rocuronium from sugammadex-bound rocuronium prevents testing of this hypothesis. However, mechanism-based pharmacokinetic–pharmacodynamic (PK-PD) modeling and simulation can serve as an alternative method to evaluate the proposed mechanism of action of sugammadex. Mechanism-based PK-PD modeling involves the description of the processes in the causal path between drug administration and effect in a strictly quantitative manner. Adequate prediction of the observed data using a mechanismbased PK-PD model based on the proposed pharmacology and (patho) physiology should support the underlying hypotheses. The validity and accuracy of the model and its underlying mechanism can be improved if the model is based on prior knowledge from different sources (i.e., preclinical, in vitro bioassays) and is derived under different experimental circumstances. * Chief Scientific Officer, LAP&P Consultants BV, Leiden, The Netherlands, and Assistant Professor, Division of Pharmacology, Leiden/Amsterdam Center for Drug Research, Leiden University, Leiden, The Netherlands. † Pharmacometrician, ‡ Chief Executive Officer, LAP&P Consultants BV. # Professor of Pharmacology, Division of Pharmacology, Leiden/Amsterdam Center for Drug Research, Leiden University. § Director Clinical Research Neuroscience, N.V. Organon, a part of Schering-Plough Corporation, Oss, The Netherlands. Development Scientist, Pharmerit BV, Rotterdam, The Netherlands.