Arne Kristian Skulberg1,2, Anders Åsberg3,4, Hasse Zare Khiabani5, Hilde Røstad6, Ida Tylleskar1,7, Ola Dale1,8. 1. Department of Circulation and Medical Imaging, NTNU, Norwegian University of Science and Technology, Trondheim, Norway. 2. Division of Pre-hospital Services, Department of Air Ambulance, Oslo University Hospital, Oslo, Norway. 3. Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, Oslo, Norway. 4. Department of Transplantation Medicine, Oslo University Hospital-Rikshospitalet, Oslo, Norway. 5. Department of Pharmacology, Oslo University Hospital-Rikshospitalet, Oslo, Norway. 6. DNE PHARMA AS, Oslo, Norway. 7. Clinic of Emergency Medicine and Prehospital Care, St Olav's Hospital, Trondheim University Hospital, Trondheim, Norway. 8. Department of Research and Development, St Olav's Hospital, Trondheim University Hospital, Trondheim, Norway.
Abstract
BACKGROUND AND AIMS: Intranasal (i.n.) naloxone is an established treatment for opioid overdose. Anyone likely to witness an overdose should have access to the antidote. We aimed to determine whether an i.n. formulation delivering 1.4 mg naloxone hydrochloride would achieve systemic exposure comparable to that of 0.8 mg intramuscular (i.m.) naloxone. DESIGN: Open, randomized four-way cross-over trial. SETTING: Clinical Trials Units in St Olav's Hospital, Trondheim and Rikshospitalet, Oslo, Norway. PARTICIPANTS: Twenty-two healthy human volunteers, 10 women, median age = 25.8 years. INTERVENTION AND COMPARATOR: One and two doses of i.n. 1.4 mg naloxone compared with i.m. 0.8 mg and intravenous (i.v.) 0.4 mg naloxone. MEASUREMENTS: Quantification of plasma naloxone was performed by liquid chromatography tandem mass spectrometry. Pharmacokinetic non-compartment analyses were used for the main analyses. A non-parametric pharmacokinetic population model was developed for Monte Carlo simulations of different dosing scenarios. FINDINGS: Area under the curve from administration to last measured concentration (AUC0-last ) for i.n. 1.4 mg and i.m. 0.8 mg were 2.62 ± 0.94 and 3.09 ± 0.64 h × ng/ml, respectively (P = 0.33). Maximum concentration (Cmax ) was 2.36 ± 0.68 ng/ml for i.n. 1.4 mg and 3.73 ± 3.34 for i.m. 0.8 mg (P = 0.72). Two i.n. doses showed dose linearity and achieved a Cmax of 4.18 ± 1.53 ng/ml. Tmax was reached after 20.2 ± 9.4 minutes for i.n. 1.4 mg and 13.6 ± 15.4 minutes for i.m. 0.8 mg (P = 0.098). The absolute bioavailability for i.n. 1.4 mg was 0.49 (±0.24), while the relative i.n./i.m. bioavailability was 0.52 (±0.25). CONCLUSION: Intranasal 1.4 mg naloxone provides adequate systemic concentrations to treat opioid overdose compared with intramuscular 0.8 mg, without statistical difference on maximum plasma concentration, time to maximum plasma concentration or area under the curve. Simulations support its appropriateness both as peer administered antidote and for titration of treatment by professionals.
RCT Entities:
BACKGROUND AND AIMS: Intranasal (i.n.) naloxone is an established treatment for opioid overdose. Anyone likely to witness an overdose should have access to the antidote. We aimed to determine whether an i.n. formulation delivering 1.4 mg naloxone hydrochloride would achieve systemic exposure comparable to that of 0.8 mg intramuscular (i.m.) naloxone. DESIGN: Open, randomized four-way cross-over trial. SETTING: Clinical Trials Units in St Olav's Hospital, Trondheim and Rikshospitalet, Oslo, Norway. PARTICIPANTS: Twenty-two healthy human volunteers, 10 women, median age = 25.8 years. INTERVENTION AND COMPARATOR: One and two doses of i.n. 1.4 mg naloxone compared with i.m. 0.8 mg and intravenous (i.v.) 0.4 mg naloxone. MEASUREMENTS: Quantification of plasma naloxone was performed by liquid chromatography tandem mass spectrometry. Pharmacokinetic non-compartment analyses were used for the main analyses. A non-parametric pharmacokinetic population model was developed for Monte Carlo simulations of different dosing scenarios. FINDINGS: Area under the curve from administration to last measured concentration (AUC0-last ) for i.n. 1.4 mg and i.m. 0.8 mg were 2.62 ± 0.94 and 3.09 ± 0.64 h × ng/ml, respectively (P = 0.33). Maximum concentration (Cmax ) was 2.36 ± 0.68 ng/ml for i.n. 1.4 mg and 3.73 ± 3.34 for i.m. 0.8 mg (P = 0.72). Two i.n. doses showed dose linearity and achieved a Cmax of 4.18 ± 1.53 ng/ml. Tmax was reached after 20.2 ± 9.4 minutes for i.n. 1.4 mg and 13.6 ± 15.4 minutes for i.m. 0.8 mg (P = 0.098). The absolute bioavailability for i.n. 1.4 mg was 0.49 (±0.24), while the relative i.n./i.m. bioavailability was 0.52 (±0.25). CONCLUSION: Intranasal 1.4 mg naloxone provides adequate systemic concentrations to treat opioid overdose compared with intramuscular 0.8 mg, without statistical difference on maximum plasma concentration, time to maximum plasma concentration or area under the curve. Simulations support its appropriateness both as peer administered antidote and for titration of treatment by professionals.
Authors: Joanne Neale; Adrian Farrugia; Aimee N Campbell; Paul Dietze; Robyn Dwyer; Renae Fomiatti; Jermaine D Jones; Sandra D Comer; Suzanne Fraser; John Strang Journal: Drugs (Abingdon Engl) Date: 2021-02-22
Authors: Ida Tylleskar; Linn Gjersing; Lars Petter Bjørnsen; Anne-Cathrine Braarud; Fridtjof Heyerdahl; Ola Dale; Arne Kristian Skulberg Journal: BMC Emerg Med Date: 2020-09-05