Assessment of the Potential for Displacement Interactions with Sugammadex
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ORIGINAL RESEARCH ARTICLE
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Assessment of the Potential for Displacement Interactions with Sugammadex A Pharmacokinetic-Pharmacodynamic Modelling Approach Alex Zwiers,1 Michiel van den Heuvel,1 Jean Smeets1 and Samantha Rutherford2 1 MSD, Oss, the Netherlands 2 Schering-Plough Research Institute, a Division of MSD, Newhouse, Scotland, UK
Abstract
Background: Sugammadex is a g-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-pharmacodynamic 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 concomitantly administered compound required to result in a train-of-four (TOF) ratio of
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