Assessment of the Potential for Displacement Interactions with Sugammadex
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Background: Sugammadex is a γ-cyclodextrin that binds with high affinity to the neuromuscular blocking agents (NMBAs) rocuronium (bromide) and vecuronium (bromide) by encapsulation. Cyclodextrins are known to form inclusion complexes with other compounds.
Objectives: We utilized a previously developed pharmacokinetic-pharmaco-dynamic model to identify potential clinically relevant displacement interactions with sugammadex. The potential for sugammadex to capture other drug molecules, thereby reducing their efficacy, is not discussed here.
Methods: Isothermal titration calorimetry (ITC) was used to determine the binding affinity (estimated by association rate constant [kass]) between sugammadex and 300 commonly prescribed drugs. The screening included drugs commonly used in or shortly after anaesthesia, commonly prescribed drugs such as antidepressants and cardiovascular drugs, drugs (both steroidal and nonsteroidal) acting on steroidal receptors (such as the corticosteroids hydrocortisone, prednisolone and dexamethasone), and the selective estrogen receptor modulator toremifene. The model took into account the population pharmacokinetic-pharmacodynamic relationships of sugammadex, rocuronium and vecuronium, the binding affinities of the NMBAs and other compounds as determined by ITC, and the relationship between the free concentration of NMBA with sugammadex in the presence of a third complexed compound. Using the model, the critical concentrations of a con-comitantly administered compound required to result in a train-of-four (TOF) ratio of <0.9, indicating reoccurrence of neuromuscular blockade, for each plasma concentration of sugammadex and NMBA were calculated. For compounds with a kass value of ≥2.5 ×104 mol/L likely to be administered during sugammadex reversal, the combinations of kass and maximum plasma drug concentration (Cmax) were entered into a graph, consisting of a critical line established using a conservative approach, and those compounds above this critical line potentially resulting in a TOF ratio <0.9 were subsequently identified. Clinical validation was performed in a post hoc analysis of data from ten sugammadex studies, in which the impact of various drugs administered perioperatively on neuromuscular recovery was assessed for up to 1 hour after sugammadex administration.
Results: ITC analysis demonstrated that the binding affinity of rocuronium and vecuronium for sugammadex was very high, with kass values of 1.79 × 107 mol/L and 5.72 × 106 mol/L, respectively. Only three compounds (flucloxacillin, fusidic acid and toremifene) were found to have critical combinations of kass and Cmax, and thus the potential for displacement. Sugammadex was administered to 600 patients for reversal of rocuronium- or vecuronium-induced blockade in the ten analysed studies, in which 21 co-administered drugs were selected for analysis. No reoccurrence of blockade occurred in any patient.
Conclusion: Of 300 drugs screened, only three (flucloxacillin, fusidic acid and toremifene) were found to have potential for a displacement interaction with sugammadex, which might potentially be noticed as a delay in recovery of the TOF ratio to 0.9. A clinical study found no evidence of a clinically relevant displacement interaction of flucloxacillin with sugammadex; these findings confirm the highly conservative nature of the modelling and simulation assumptions in the present study.
KeywordsVecuronium Rocuronium Isothermal Titration Calorimetry Critical Line Toremifene
This study was supported by MSD, Oss, the Netherlands. Alex Zwiers and Michiel van den Heuvel are employees of MSD, Oss, the Netherlands. Samantha Rutherford is an employee of Schering-Plough Research Institute, a division of MSD. Jean Smeets is a former employee of MSD, Oss, the Netherlands, and is currently employed by LAP&P Consultants BV, Leiden, the Netherlands.
The authors thank Ton Bom, MD for collecting and assimilating all of the study data into a database and Jan Huisman for performing SAS programming. Medical writing support was provided by Melanie More at Prime Medica Ltd (Knutsford, Cheshire, UK) during the preparation of this manuscript. Responsibility for the opinions, conclusions and interpretation of the data lies with the authors.
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