2-Hydroxypropyl-β-cyclodextrin, solubiliser in a novel dantrolene formulation: Its binding affinities to clinical compounds that may be used during anaesthesia or management of malignant hyperthermia

Abstract

2-Hydroxypropyl-β-cyclodextrin (HP-β-CD) is used as an excipient to improve the solubility of the highly lipophilic drug dantrolene in a novel formulation, NPJ5008. Dantrolene acts as an antidote for life-threatening anaesthesia-associated malignant hyperthermia (MH) crises and intervention speed is essential to minimise morbidity. NPJ5008 can be prepared and administered substantially faster than DANTRIUM IV in a smaller volume of fluid. Like other cyclodextrins in clinical use, HP-β-CD forms inclusion complexes with lipophilic molecules. The potential of HP-β-CD to unintentionally interact in vivo with other drugs administered during anaesthesia or an MH emergency was assessed. An in silico predictive model of HP-β-CD binding was built from published data using LigPrep/Glide and GROMACS for molecular dynamic simulations to generate data for binding free energy calculations, performed with the molecular mechanics Poisson–Boltzmann surface area method using a thermodynamic cycle. Docking of >70 anaesthesia-relevant compounds with HP-β-CD was evaluated and 10 compounds were predicted to bind HP-β-CD using a cut-off of −4 kcal mol⁻¹. In vitro isothermal titration calorimetry (37 °C, pH 7) was also used to determine the enthalpy of interaction of HP-β-CD with 18 of the most clinically relevant compounds, including rocuronium, vecuronium and remifentanyl (the strongest predicted binder from the in silico work). All had low injection heats with assay parameters of 1500 µM test compound and 50 µM HP-β-CD, i.e. there was no discernible binding to HP-β-CD. Thus, the HP-β-CD component of NPJ5008 is unlikely to interfere with other drugs clinically relevant in MH.