Pharmacokinetics of a novel, approved, 1.4‐mg intranasal naloxone formulation for reversal of opioid overdose—a randomized controlled trial

Abstract

BACKGROUND AND AIMS\nIntranasal (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\xa0mg naloxone hydrochloride would achieve systemic exposure comparable to that of 0.8\xa0mg intramuscular (i.m.) naloxone.\n\n\nDESIGN\nOpen, randomized four-way cross-over trial.\n\n\nSETTING\nClinical Trials Units in St Olav s Hospital, Trondheim and Rikshospitalet, Oslo, Norway.\n\n\nPARTICIPANTS\nTwenty-two healthy human volunteers, 10 women, median age\xa0=\xa025.8\xa0years.\n\n\nINTERVENTION AND COMPARATOR\nOne and two doses of i.n. 1.4\xa0mg naloxone compared with i.m. 0.8\xa0mg and intravenous (i.v.) 0.4\xa0mg naloxone.\n\n\nMEASUREMENTS\nQuantification 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.\n\n\nFINDINGS\nArea under the curve from administration to last measured concentration (AUC0-last ) for i.n. 1.4\xa0mg and i.m. 0.8\xa0mg were 2.62\xa0±\xa00.94 and 3.09\xa0±\xa00.64\xa0h\xa0×\xa0ng/ml, respectively (P\xa0=\xa00.33). Maximum concentration (Cmax ) was 2.36\xa0±\xa00.68\xa0ng/ml for i.n. 1.4\xa0mg and 3.73\xa0±\xa03.34 for i.m. 0.8\xa0mg (P\xa0=\xa00.72). Two i.n. doses showed dose linearity and achieved a Cmax of 4.18\xa0±\xa01.53\xa0ng/ml. Tmax was reached after 20.2\xa0±\xa09.4\xa0minutes for i.n. 1.4\xa0mg and 13.6\xa0±\xa015.4\xa0minutes for i.m. 0.8 mg (P\xa0=\xa00.098). The absolute bioavailability for i.n. 1.4\xa0mg was 0.49 (±0.24), while the relative i.n./i.m. bioavailability was 0.52 (±0.25).\n\n\nCONCLUSION\nIntranasal 1.4\xa0mg naloxone provides adequate systemic concentrations to treat opioid overdose compared with intramuscular 0.8\xa0mg, 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.