Pharmacokinetics of a novel, approved, 1.4 mg intranasal naloxone formulation for reversal of opioid overdose- a randomised controlled trial.

BACKGROUND AND AIMS: Intranasal (IN) naloxone is an established treatment for opioid overdose. Anyone likely to witness an overdose should have access to the antidote. We aimed to determine whether an IN formulation delivering 1.4 mg naloxone hydrochloride would achieve systemic exposure comparable to that of 0.8 mg intramuscular naloxone.

DESIGN: Open, randomised four-way crossover trial SETTING: Clinical Trials Units in St. Olav´s Hospital, Trondheim, and Rikshospitalet, Oslo, Norway PARTICIPANTS: 22 healthy human volunteers, ten women. Median age 25.8 years.

INTERVENTION AND COMPARATOR: One and two doses of IN 1.4 mg naloxone compared with intramuscular (IM) 0.8 mg and intravenous (IV) 0.4 mg naloxone MEASUREMENTS: Quantification of plasma naloxone was performed by liquid chromatography tandem mass spectrometry. Pharmacokinetic non-compartment analyses were used for the main analyses. A non-parametric pharmacokinetic population model was developed for Monte Carlo simulations of different dosing scenarios.

FINDINGS: AUC0-last for IN 1.4 mg and IM 0.8 mg were 2.62 ±0.94 and 3.09 ±0.64 h*ng/mL, respectively (p=0.33). Cmax was 2.36 ±0.68 ng/mL for IN 1.4 mg, and 3.73 ±3.34 for IM 0.8 mg (p=0.72). Two IN doses showed dose linearity and achieved a Cmax of 4.18 ±1.53 ng/mL. Tmax was reached after 20.2 ±9.4 min for IN 1.4 mg and 13.6 ±15.4 min for IM (p=0.098). The absolute bioavailability for IN 1.4 mg was 0.49 (±0.24), while the relative IN/IM bioavailability was 0.52 (±0.25).

CONCLUSION: Intranasal 1.4 mg naloxone provides adequate systemic concentrations to treat opioid overdose, compared with intramuscular 0.8 mg, without statistical difference on maximum plasma concentration, time to maximum plasma concentration or area under the curve. Simulations support its appropriateness both as peer administered antidote and for titration of treatment by professionals.