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

• Published in: European journal of anaesthesiology Vol. 41; no. 5; p. 381
• Main Authors: Ng Kwet Shing, Richard H, Clayton, Lucy B, Smith, Samuel L, Watson, Marc J, McKenzie, Litza M, Chalmers, David P, Whitaker, Gareth, Bilmen, Jonathan G
• Format: Journal Article
• Language: English
• Published: England 01.05.2024
• Subjects: Administration, Oral; Adult; Area Under Curve; Biological Availability; Child; Cross-Over Studies; Dantrolene - adverse effects; Female; Healthy Volunteers; Humans; Male; Malignant Hyperthermia - diagnosis; Malignant Hyperthermia - drug therapy; Therapeutic Equivalency
• ISSN: 1365-2346
• DOI: 10.1097/EJA.0000000000001966

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 Dantrium®. The two formulations have been compared preclinically. Assess 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. 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. Single clinical centre in the UK, April to July 2021. Twenty-one healthy male and female individuals. Part 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. Overall 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. Adjusted 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®. NPJ5008 showed comparable pharmacokinetic and safety profiles to Dantrium®, while reducing dantrolene dose preparation/administration times, potentially reducing patient complications/healthcare resourcing in malignant hyperthermia. EudraCT Number: 2020-005719-35, MHRA approval.