The novel rapid formulation of intravenous dantrolene (NPJ5008) versus standard dantrolene (DantriumW) A clinical part-randomised phase 1 study in healthy volunteers

Abstract

BACKGROUND Delays 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 Dantrium1. The two formulations have been compared preclinically. OBJECTIVES Assess bioequivalence of overall dantrolene (free acid) exposure of NPJ5008 versus Dantrium1 and ascertain similarities in their pharmacokinetics and safety/tolerability profiles. Evaluate preparation/administration time savings for the new formulation. DESIGN Part 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. SETTING Single clinical centre in the UK, April to July 2021. PARTICIPANTS Twenty-one healthy male and female individuals. INTERVENTIONS Part 1: single intravenous 60 mg dose of NPJ5008 or Dantrium1, sequentially. Part 2: single intravenous 120 mg dose of NPJ5008. Simulation: five vials per formulation using paediatric and adult cannulas. MAIN OUTCOME MEASURES Overall drug exposure to last measurable concentration (AUC0 to last) and extrapolated to infinity (AUC0 to 1) were primary endpoints. Other pharmacokinetic, clinical and muscle-function parameters, and adverse events, were monitored. RESULTS Adjusted geometric mean ratios of NPJ5008 versus Dantrium1 were 90.24 and 90.44% for AUC0 to last and AUC0 to 1, 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 Dantrium1. CONCLUSION NPJ5008 showed comparable pharmacokinetic and safety profiles to Dantrium1, while reducing dantrolene dose preparation/administration times, potentially reducing patient complications/healthcare resourcing in malignant hyperthermia. TRIAL REGISTRATION EudraCT Number: 2020-005719-35, MHRA approval.