Gill Mundin1, Rebecca McDonald2, Kevin Smith1, Stephen Harris3, John Strang2. 1. Mundipharma Research Limited, Cambridge, UK. 2. National Addiction Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK. 3. Department of Clinical Research, Purdue Pharma LP, Stamford, CT, USA.
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 (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.
RCT Entities:
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.
Authors: Jonathan E Freise; Elizabeth E McCarthy; Michelle Guy; Scott Steiger; Leslie Sheu Journal: J Gen Intern Med Date: 2018-06 Impact factor: 5.128
Authors: Rebecca McDonald; Ulrike Lorch; Jo Woodward; Björn Bosse; Helen Dooner; Gill Mundin; Kevin Smith; John Strang Journal: Addiction Date: 2017-11-16 Impact factor: 6.526