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, 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 (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.