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

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, 4-way crossover 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, Ohio, USA).

PARTICIPANTS: 12 healthy volunteers (age 20-41; 7 female).

MEASUREMENTS: From blood plasma naloxone concentrations, 1) standard pharmacokinetic parameters, including maximum plasma concentration (Cmax) and mean absolute bioavailability (F%, relative to intravenous injection), were determined; as well as 2) partial area under the curve (AUC) values, tmax (time to maximum plasma concentration), and T50% (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 Cmax 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, T50% was reached within 8 minutes and tmax 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.