The novel rapid formulation of intravenous dantrolene (NPJ5008) versus standard dantrolene (Dantrium®): A clinical part-randomised phase 1 study in healthy volunteers.
Eur J Anaesthesiol
; 41(5): 381-390, 2024 May 01.
Article
en En
| MEDLINE
| ID: mdl-38445365
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 Dantrium®. The two formulations have been compared preclinically.OBJECTIVES:
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.DESIGN:
Part 1 of this open-label trial in humans was a 1ââ1 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 60âmg dose of NPJ5008 or Dantrium®, sequentially. Part 2 single intravenous 120âmg dose of NPJ5008. Simulation five vials per formulation using paediatric and adult cannulas. MAIN OUTCOMEMEASURES:
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.RESULTS:
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®.CONCLUSION:
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. TRIAL REGISTRATION EudraCT Number 2020-005719-35, MHRA approval.
Texto completo:
1
Base de datos:
MEDLINE
Asunto principal:
Dantroleno
/
Hipertermia Maligna
Límite:
Adult
/
Child
/
Female
/
Humans
/
Male
Idioma:
En
Revista:
Eur J Anaesthesiol
Asunto de la revista:
ANESTESIOLOGIA
Año:
2024
Tipo del documento:
Article