The novel rapid formulation of intravenous dantrolene (NPJ5008) versus standard dantrolene (DANTRIUM IV): A clinical part-randomised phase 1 study in healthy volunteers.
Journal
European journal of anaesthesiology
ISSN: 1365-2346
Titre abrégé: Eur J Anaesthesiol
Pays: England
ID NLM: 8411711
Informations de publication
Date de publication:
29 Feb 2024
29 Feb 2024
Historique:
medline:
6
3
2024
pubmed:
6
3
2024
entrez:
6
3
2024
Statut:
aheadofprint
Résumé
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 IV. The two formulations have been compared preclinically. Assess bioequivalence of overall dantrolene (free acid) exposure of NPJ5008 versus DANTRIUM IV 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 IV, 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 (AUC0 to last) and extrapolated to infinity (AUC0 to ∞) were primary endpoints. Other pharmacokinetic, clinical and muscle-function parameters, and adverse events, were monitored. Adjusted geometric mean ratios of NPJ5008 versus DANTRIUM IV were 90.24 and 90.44% for AUC0 to last and AUC0 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 IV. NPJ5008 showed comparable pharmacokinetic and safety profiles to DANTRIUM IV, while reducing dantrolene dose preparation/administration times, potentially reducing patient complications/healthcare resourcing in malignant hyperthermia. EudraCT Number: 2020-005719-35, MHRA approval.
Sections du résumé
BACKGROUND
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 IV. The two formulations have been compared preclinically.
OBJECTIVES
OBJECTIVE
Assess bioequivalence of overall dantrolene (free acid) exposure of NPJ5008 versus DANTRIUM IV and ascertain similarities in their pharmacokinetics and safety/tolerability profiles. Evaluate preparation/administration time savings for the new formulation.
DESIGN
METHODS
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
METHODS
Single clinical centre in the UK, April to July 2021.
PARTICIPANTS
METHODS
Twenty-one healthy male and female individuals.
INTERVENTIONS
METHODS
Part 1: single intravenous 60 mg dose of NPJ5008 or DANTRIUM IV, sequentially. Part 2: single intravenous 120 mg dose of NPJ5008. Simulation: five vials per formulation using paediatric and adult cannulas.
MAIN OUTCOME MEASURES
METHODS
Overall drug exposure to last measurable concentration (AUC0 to last) and extrapolated to infinity (AUC0 to ∞) were primary endpoints. Other pharmacokinetic, clinical and muscle-function parameters, and adverse events, were monitored.
RESULTS
RESULTS
Adjusted geometric mean ratios of NPJ5008 versus DANTRIUM IV were 90.24 and 90.44% for AUC0 to last and AUC0 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 IV.
CONCLUSION
CONCLUSIONS
NPJ5008 showed comparable pharmacokinetic and safety profiles to DANTRIUM IV, while reducing dantrolene dose preparation/administration times, potentially reducing patient complications/healthcare resourcing in malignant hyperthermia.
TRIAL REGISTRATION
BACKGROUND
EudraCT Number: 2020-005719-35, MHRA approval.
Identifiants
pubmed: 38445365
doi: 10.1097/EJA.0000000000001966
pii: 00003643-990000000-00174
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Society of Anaesthesiology and Intensive Care.
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