Pharmacokinetics of a new, nasal formulation of naloxone
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Nasal naloxone is wanted for bystander administration in opioid overdose and as a needle-free alternative for emergency medical personnel. Epidemiologic studies have indicated a therapeutic effect of bystander administration of low-concentration/high-volume formulations. The objective for this study was to describe the nasal pharmacokinetics of a new high-concentration/low-volume nasal formulation of naloxone.
This was an open, randomized triple crossover trial in healthy, human volunteers (n = 12) where two doses of nasal naloxone (0.8 and 1.6 mg) and one intravenous dose (1.0 mg) were compared. Fifteen serum samples were collected before and until 6 h after naloxone administration. Quantification of naloxone was performed by a validated liquid chromatography-tandem mass spectrometry method.
Bioavailability was 0.54 (0.45–0.63) for the 0.8 mg and 0.52 (0.37–0.67) for the 1.6 mg nasal naloxone formulation. Maximum concentration levels (C max) were 1.45 ng/ml (1.07–1.84) for 0.8 mg and 2.57 ng/ml (1.49–3.66) for the 1.6 mg. Time to maximum concentrations (T max) were reached at 17.9 min (11.4–24.5) and 18.6 min (14.4–22.9) for the 0.8 mg and the 1.6 mg doses, respectively.
This nasal naloxone formulation had a rapid, systemic uptake and higher bioavailability than naloxone formulations not designed for IN use. This indicates that an optimized high-concentration/low-volume nasal spray formulation may deliver a therapeutic dose. The 1.6 mg nasal dose provided serum concentrations that surpassed those of 1.0 mg IV after 15–20 min and stayed above for the rest of the study period.
KeywordsNasal Intranasal Naloxone Pharmacokinetics Bioavailability Overdose
Thanks to the Unit for Applied Clinical Research, NTNU, for the assistance with GCP monitoring and providing the internet-based randomization, to the Clinical Research Facility, St. Olav’s University Hospital, for conducting the study, and to the Proteomics and Metabolomics Core Facility, PROMEC, NTNU, for conducting the naloxone analysis. These infrastructures are all funded by the Faculty of Medicine, NTNU and the Central Norway Regional Health Authority. We also wish to acknowledge professor Thorsteinn Loftsson, University of Iceland, Reykjavík, Iceland for his valuable advises regarding the formulation. Thanks also to Richard Poulsson, Azanta, Denmark for valuable guidance and genuine interest in the project, and to Inge Christoffer Olsen at ICOStatistics for his aid with the statistical modeling. This study was funded by grants from the Laerdal Foundation for Acute Medicine, Unimed Innovation/St. Olav’s University Hospital and Felles Forskningsutvalg, NTNU/St. Olav’s University Hospital, Norway.
Compliance with ethical standards
Ethical approval and informed consent
All procedures performed in the studies involving human participants were in accordance with the ethical standards of the Helsinki declaration, the principles of the International Conference on Harmonisation, and Good Clinical Practice guidelines. It was approved by the Regional Committee of Medical and Health Research Ethics (2013/1519/REK sør-øst A) and the Norwegian Medicines Agency (EudraCT number: 2013–000050-22) and registered in clinicaltrials.gov (NCT02158117). Informed written consent was obtained from all subjects prior to inclusion. Participants were insured trough the Drug Liability Association, Norway, and compensated for each treatment visit with 1500 NOK (160 Euro/ 175 USD).
Declarations of interest
Ola Dale’s (OD) employer Norwegian University of Science and Technology (NTNU) have recently signed cooperation and licensing contracts with Den norske Eterfabrikk (DnE) to seek commercialization of the nasal naloxone formulation developed by OD. The latter regulates potential royalties for OD through NTNU. OD is engaged by DnE as Principle Investigator in a pharmacokinetic study of naloxone for which OD receives no personal honorarium. DnE has compensated OD for one travel from Trondheim to Oslo.
Arne Kristian Skulberg (AKS) has signed a non-compete contract with DnE lasting the duration of his PhD program at NTNU (estimated 2018). This does not limit AKS right to publish results. AKS will receive no financial benefit from the license agreement between DnE and NTNU. Other authors declare that they have no conflicts of interest.
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