Pharmacokinetics of concentrated naloxone nasal spray over first 30 minutes post-dosing: analysis of suitability for opioid overdose reversal

Abstract

Background and aims: Lack of non-injectable naloxone formulations has impeded widespread take-home provision for the prevention of heroin/opioid overdose deaths. For non-injectable formulations that are finally being investigated, rapid onset of action and sufficient bioavailability will be vital. We present analysis of data from a study of concentrated naloxone nasal spray formulations. Our aims are: to assess (1) pharmacokinetic properties and (2) suitability for overdose reversal in terms of naloxone absorption within 30 minutes post-dosing.

Design and interventions/comparator: Open-label, randomized, four-way cross-over Latin-square pharmacokinetic study of naloxone administration by three routes: intranasal at two doses (8 mg/0.4 ml, 16 mg/0.4 ml) versus sublingual (16 mg/ml) versus intravenous reference (1 mg/ml).

Setting: Clinical Pharmacology Unit at The Ohio State University (Columbus, OH, USA).

Participants: Twelve healthy volunteers (age 20-41; seven female).

Measurements: From blood plasma naloxone concentrations, (1) standard pharmacokinetic parameters, including maximum plasma concentration (C_max ) and mean absolute bioavailability (F%, relative to intravenous injection), were determined; as well as (2) partial area under the curve (AUC) values, t_max (time to maximum plasma concentration) and t_50% (time to 50% of maximum plasma concentration) as measures of early absorption.

Findings: (1) Bioavailability was F% = 25-28% for intranasal naloxone. Sublingual had low bioavailability (F% = 2%) and was not considered further. Mean C_max values for 8 mg (12.83 ng/ml) and 16 mg (18.25 ng/ml) intranasal exceeded 1 mg intravenous (9.64 ng/ml) naloxone. (2) Following intranasal administration, t_50% was reached within 8 minutes and t_max within 20 minutes. Mean naloxone absorption from dosing to 30 minutes (AUC₃₀ ) was greater following 8 mg (4.17 h × ng/ml) and 16 mg (5.91 h × ng/ml) intranasal than following 1 mg intravenous (1.70 h × ng/ml) administration.

Conclusions: Concentrated naloxone nasal spray has a promising pharmacokinetic profile, with substantial bioavailability. Its early absorption time-course suggests that concentrated nasal naloxone is suitable for emergency administration in the community, where rapid restoration of respiratory function is essential for opioid overdose reversal.

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