Pharmacokinetics of concentrated naloxone nasal spray for opioid overdose reversal: Phase I healthy volunteer study

Abstract

Background and AimsTake‐home naloxone can prevent death from heroin/opioid overdose, but pre‐provision is difficult because naloxone is usually given by injection. Non‐injectable alternatives, including naloxone nasal sprays, are currently being developed. To be effective, the intranasal (i.n.) spray dose must be adequate but not excessive, and early absorption must be comparable to intramuscular (i.m.) injection. We report on the pharmacokinetics (PK) of a specially produced concentrated novel nasal spray. The specific aims were to: (1) estimate PK profiles of i.n. naloxone, (2) compare early systemic exposure with i.n. versus i.m. naloxone and (3) estimate i.n. bioavailability.DesignOpen‐label, randomized, five‐way cross‐over PK study.SettingClinical trials facility (Croydon, UK).ParticipantsThirty‐eight healthy volunteers (age 20–54 years; 11 female).Intervention and comparatorThree doses of i.n. (1 mg/0.1 ml, 2 mg/0.1 ml, 4 mg/0.2 ml) versus 0.4 mg i.m. (reference) and 0.4 mg intravenous (i.v.) naloxone.MeasurementsRegular blood samples were taken, with high‐frequency sampling during the first 15 minutes to capture early systemic exposure. PK parameters were determined from plasma naloxone concentrations. Exploratory analyses involved simulation of repeat administration.FindingsMean peak concentration (Cmax) values for 1 mg (1.51 ng/ml), 2 mg (2.87 ng/ml) and 4 mg (6.02 ng/ml) i.n. exceeded 0.4 mg i.m. (1.27 ng/ml) naloxone. All three i.n. doses rapidly achieved plasma levels > 50% of peak concentrations (T50%) by 10 minutes, peaking at 15–30 minutes (Tmax). For comparison, the i.m. reference reached Tmax at 10 minutes. Mean bioavailability was 47–51% for i.n. relative to i.m. naloxone. Simulation of repeat dosing (2 × 2 mg i.n. versus 5 × 0.4 mg i.m. doses) at 3‐minute intervals showed that comparable plasma naloxone concentrations would be anticipated.ConclusionsConcentrated 2 mg intranasal naloxone is well‐absorbed and provides early exposure comparable to 0.4 mg intramuscular naloxone, following the 0.4 mg intramuscular curve closely in the first 10 minutes post‐dosing and maintaining blood levels above twice the intramuscular reference for the next 2 hours.

18th Latest Advances in Psychiatry Symposium

“…The standard mode of administration for naloxone is intravenously (IV) but, in an effort to make it more accessible, Sir John Strang worked with a team to produce an intranasal version that was compared with iv and intramuscular (IM) versions. 2 Results showed that IV administration of naloxone (0.4mg) produces a 'big spike' in mean plasma concentration, throwing the patient immediately into withdrawal symptoms, which is why ambulance crews now administer IM naloxone (0.4mg) to avoid an aggressive spike but ensure similar recovery. The onset of action of intranasal naloxone at a 1mg dose was not immediate enough for use in the emergency care setting, while the 4mg intranasal dose produced a 'big spike' in mean plasma concentration that resulted in withdrawal symptoms.…”

Commentary on McDonald et al. (2018): Intranasal naloxone—from the laboratory to the real world

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Commentary on McDonald et al (2018): Intranasal naloxone-from the laboratory to the real world It is timely that research and technology combine to develop products addressing barriers to naloxone administration in community and prison settings. Addressing potential implementation barriers and understanding outcomes with real-world use will maximize the opportunities to prevent opioid overdose deaths.

The work by McDonald and colleagues [1] is a welcome addition to what is known about naloxone bioavailability and pharmacokinetics, combined with the promise of a fit-for-purpose naloxone product for lay-person administration.

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“…Addressing potential implementation barriers and understanding outcomes with real-world use will maximize the opportunities to prevent opioid overdose deaths.The work by McDonald and colleagues [1] is a welcome addition to what is known about naloxone bioavailability and pharmacokinetics, combined with the promise of a fit-for-purpose naloxone product for lay-person administration. Intranasal and other non-injectable naloxone formulations have clear benefits for community supply to carers and family members.…”

“…Commentary on McDonald et al (2018): Intranasal naloxone-from the laboratory to the real world It is timely that research and technology combine to develop products addressing barriers to naloxone administration in community and prison settings. Addressing potential implementation barriers and understanding outcomes with real-world use will maximize the opportunities to prevent opioid overdose deaths.…”

“…Macdonald et al [1] highlight concerns with 'over-antagonism', which may pertain to higher doses. A dose-dependent reversal of fentanylinduced respiratory depression was demonstrated in a small study of anaesthetized patients [4], suggesting that dose is important.…”