• Richard H Ng Kwet Shing, Lucy B Clayton, Samuel L Smith, Marc J Watson, Litza M McKenzie, David P Chalmers, Gareth Whitaker, and Jonathan G Bilmen.
• From the Norgine, Harefield (RHNKS, LBC, SLS, MJW), Quotient Sciences, Ruddington (LMM, DPC, GW) and University of Leeds, Leeds, UK (JGB).
• Eur J Anaesthesiol. 2024 May 1; 41 (5): 381390381-390.

BackgroundDelays in treating anaesthesia-induced malignant hyperthermia increase risks of complications and death. NPJ5008 is a novel formulation of the indicated treatment, dantrolene sodium, developed to shorten preparation and administration times compared with the reference formulation Dantrium®. The two formulations have been compared preclinically.ObjectivesAssess bioequivalence of overall dantrolene (free acid) exposure of NPJ5008 versus Dantrium® and ascertain similarities in their pharmacokinetics and safety/tolerability profiles. Evaluate preparation/administration time savings for the new formulation.DesignPart 1 of this open-label trial in humans was a 1 : 1 randomised crossover study; part 2 was a single-arm study. Trial pharmacy data and laboratory simulations assessed preparation/administration step timings.SettingSingle clinical centre in the UK, April to July 2021.ParticipantsTwenty-one healthy male and female individuals.InterventionsPart 1: single intravenous 60 mg dose of NPJ5008 or Dantrium®, sequentially. Part 2: single intravenous 120 mg dose of NPJ5008. Simulation: five vials per formulation using paediatric and adult cannulas.Main Outcome MeasuresOverall drug exposure to last measurable concentration (AUC 0 to last ) and extrapolated to infinity (AUC 0 to ∞ ) were primary endpoints. Other pharmacokinetic, clinical and muscle-function parameters, and adverse events, were monitored.ResultsAdjusted geometric mean ratios of NPJ5008 versus Dantrium® were 90.24 and 90.44% for AUC 0 to last and AUC 0 to ∞ , respectively, with the 90% confidence intervals (CI) within the 80 to 125% acceptance interval, establishing bioequivalence. No new safety issues emerged: any adverse events were of a similar magnitude across treatments and related to pharmacological properties of dantrolene. Pharmacy and simulation data revealed that every step in preparation and administration was 26 to 69% faster for NPJ5008 than Dantrium®.ConclusionNPJ5008 showed comparable pharmacokinetic and safety profiles to Dantrium®, while reducing dantrolene dose preparation/administration times, potentially reducing patient complications/healthcare resourcing in malignant hyperthermia.Trial RegistrationEudraCT Number: 2020-005719-35, MHRA approval.Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Society of Anaesthesiology.

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