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

Abstract

Background and aims: Take-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.

Design: Open-label, randomized, five-way cross-over PK study.

Setting: Clinical trials facility (Croydon, UK).

Participants: Thirty-eight healthy volunteers (age 20-54 years; 11 female).

Intervention and comparator: Three 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.

Measurements: Regular 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.

Findings: Mean peak concentration (C_max ) 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 (T_max ). For comparison, the i.m. reference reached T_max 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.

Conclusions: Concentrated 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.

Keywords: Antidote; drug overdose; intranasal; naloxone; nasal; opiate; opioids; pharmacokinetics.

Figure 1

Mean plasma naloxone concentrations (observed values): dosing to 120 minutes (left) and dosing to 20 minutes (right)

Figure 2

Plots of plasma naloxone concentrations over time (left: 120 minutes; right: 20 minutes) for individual subjects after 2 mg intranasal (i.n.) dose

Figure 3

Scaled mean plasma naloxone concentrations after repeat administration at 3‐minute intervals (versus mean observed profiles of 0.4 mg intramuscular (i.m.) and 2 mg intranasal (i.n.) doses)

Figure 4

Scaled mean plasma naloxone concentrations after immediate administration of multiple doses at 0 minutes (versus mean observed profile of 4 mg intranasal (i.n.) dose)