New concentrated naloxone nasal spray for opioid overdose reversal

First published: March 29, 2019 | Last updated: May 20th, 2019

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Professor John Strang

Professor of Addictions & Head of Department

Professor Sir John Strang

Professor of Addictions & Head of Department

Professor Sir John Strang is an academic and a medic with over 30 years’ experience in addictions psychiatry. He is the Director of the National Addiction Centre and Head of the Addictions Department at King’s College London (KCL). He is Leader of the Addictions Clinical Academic Group at King’s Health Partners. Professor Strang has published over 400 scientific papers in the addiction field and contributed to national and international policy, having worked with a range of governmental and non-governmental organisations and having chaired policy-informing committees and expert groups for Department of Health, NICE and Public Health England.

JS has also worked with pharmaceutical companies to seek to identify new or improved treatments (including naloxone products and including with Mundipharma). KCL (JS’s employer) has separately registered intellectual property on a novel buccal naloxone formulation with which JS is involved. For a fuller bio of JS and his declarations of interest see: https://kclpure.kcl.ac.uk/portal/john.strang.html

http://www.addiction-ssa.org/symposium/presentation/pre-provision-of-emergency-naloxone-major-achievements-but-substantial-chal



Background:

Take-home naloxone can prevent fatal outcome from heroin/opioid overdose[1] but pre-provision is difficult because naloxone is given by injection. Following off-label use of untested improvised nasal naloxone kits, FDA approved a first nasal spray in the US in late 2015[2]. For nasal sprays, the dose must be adequate, rapid-acting, but not excessive with risk of ‘over-antagonism’[3-5]. We report on the pharmacokinetics (PK) of a concentrated nasal spray currently in development.

Aims:

Primary objectives:

To assess PK profiles of intranasal (IN) naloxone
To compare early partial systemic exposure with IN vs intramuscular (IM) and intravenous (IV) naloxone.

Secondary objective:

To determine IN bioavailability relative to IM naloxone.

Methods:

A PK study (open-label, randomised, 5-way crossover; EudraCT: 2015-004493-15) in healthy volunteers compared highly-concentrated IN naloxone (10mg/ml, 20mg/ml) at three doses (1mg/2mg/4mg) versus 0.4mg IM (primary reference) and 0.4mg IV naloxone; special interest in early uptake, with intense blood sampling over the first 15 minutes.

Results:

(a) Subjects: 32 healthy volunteers (age 20-54; 10 female).

(b) PK profiles: IN naloxone had mean bioavailability of approximately 50% relative to IM naloxone (average 47-51% across three doses). During the first 10 minutes post-dosing, the 2mg IN dose closely followed the 0.4mg IM curve, reached blood levels at twice the 0.4mg IM dose by 15 minutes and maintained blood levels at more than twice the 0.4mg IM dose for the next couple of hours. All three IN naloxone doses were characterised by rapid achievement of plasma levels >50% of peak concentrations (T50%) by 10 minutes and then by maximum plasma levels at 15 minutes.

Conclusions and Discussion:

Concentrated nasal naloxone appears well-absorbed (approx. 50% relative bioavailability).

The 2mg IN dose provides an interesting new PK-profile, giving speed of onset and early exposure comparable to 0.4mg IM dose, but with effective maintenance of plasma levels for the next couple of hours at twice the level maintained by the IM dose. Clinicians may see different merits of the various time-course profiles (and speed of onset and duration of effect). Furthermore, clinicians and policymakers may see implementation advantages with IN naloxone for take-home naloxone programs.

References:

[1] WHO (2014). Community Management of Opioid Overdose. Available at: www.who.int/substance_abuse/publications/management_opioid_overdose/en

[2] FDA (2015). FDA Moves Quickly to Approve Easy-to-use Nasal Spray to Treat Opioid Overdose. Available at: www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm473505.htm

[3] Hertz, S. (2012). Naloxone for Outpatient Use: Data Required to Support an NDA.  Available at: www.fda.gov/downloads/Drugs/NewsEvents/UCM300874.pdf

[4] UKMi (2016). Naloxone Products for Emergency Opiate Overdose Reversal in Non-medical Settings. Available at: www.ukmi.nhs.uk/filestore/ukmiaps/Naloxone%20product%20safety%20review_FINAL.pdf

[5] Neale, J., & Strang, J. (2015). Naloxone – does over‐antagonism matter? Evidence of iatrogenic harm after emergency treatment of heroin/opioid overdose. Addiction, 110(10), 1644-1652.

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Professor John Strang