Assessment of the potential for displacement interactions with sugammadex: a pharmacokinetic-pharmacodynamic modelling approach.
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.


OBJECTIVE
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 [k(ass)]) 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 <0.9, indicating reoccurrence of neuromuscular blockade, for each plasma concentration of sugammadex and NMBA were calculated. For compounds with a k(ass) value of ≥ 2.5 × 104 mol/L likely to be administered during sugammadex reversal, the combinations of k(ass) and maximum plasma drug concentration (C(max)) 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 k(ass) 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 k(ass) and C(max), 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.


CONCLUSIONS
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.
Schering-Plough Research Institute, a Division of MSD, Newhouse, Scotland, UK. alex.zwier@merk.com
Alex
A
Zwiers
Michiel
M
van den Heuvel
Jean
J
Smeets
Samantha
S
Rutherford
D000732:Androstanols / Q000037:antagonists & inhibitors / Q000494:pharmacology; D002151:Calorimetry; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006801:Humans; D008954:Models, Biological; D019148:Neuromuscular Blockade / Q000379:methods; D003473:Neuromuscular Nondepolarizing Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000077123:Rocuronium; D000077122:Sugammadex; D014673:Vecuronium Bromide / Q000037:antagonists & inhibitors / Q000494:pharmacology; D047408:gamma-Cyclodextrins / Q000493:pharmacokinetics / Q000494:pharmacology*
D000732:Androstanols; D003473:Neuromuscular Nondepolarizing Agents; D047408:gamma-Cyclodextrins; D000077122:Sugammadex; D014673:Vecuronium Bromide; D000077123:Rocuronium