• Gill Mundin, Rebecca McDonald, Kevin Smith, Stephen Harris, and John Strang.
• Mundipharma Research Limited, Cambridge, UK.
• Addiction. 2017 Sep 1; 112 (9): 1647-1652.

Background And AimsLack 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/ComparatorOpen-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).SettingClinical Pharmacology Unit at The Ohio State University (Columbus, OH, USA).ParticipantsTwelve healthy volunteers (age 20-41; seven female).MeasurementsFrom 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.ConclusionsConcentrated 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.© 2017 Society for the Study of Addiction.

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