Nasal naloxone - A pilot study of the pharmacokinetics of a concentrated formulation
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Introduction: Naloxone is the antidote against heroin and other opioids. As a measure to combat overdose deaths, nasal naloxone is wanted for bystander administration by lay people. The objective of this study was to investigate the pharmacokinetic profile of nasal naloxone delivered as in a high-concentration/low-volume formulation. The primary objective was to get a preliminary estimation of bioavailability of intranasal naloxone in human, healthy volunteers. Secondary objectives were a preliminary estimation of maximum serum concentration (Cmax) and time to maximum serum concentration (Tmax), and also to investigate the safety of the formulation. Materials and methods: This was a phase 1, single centre, open-label, randomised, two-way crossover trial in healthy male volunteers, n=5, age 18-45 years. 1.0 mg intravenous naloxone was compared to 2 mg intranasal naloxone given as 0.1 ml of 20 mg/ml nasal spray. Blood samples were drawn at predetermined intervals, and serum concentrations of naloxone was determined by a validated liquid chromatography-mass spectrometry method, and analysed by non-compartmental techniques. A 72-hour washout period was enforced between treatments. A post-study interview was performed. Results: Bioavailability (mean (95% confidence interval) were 47.1% (38.4-55.8) for the intranasal naloxone. Cmax were 4.24 (1.48-7.00). Tmax was reached after 16.0 min (5.80- 26.2). The mean half-lives varied from 80-90 min. No clinically significant adverse event was observed. Moreover, the spray provoked no unexpected adverse events. The only reported adverse drug reaction was taste of the nasal spray. Conclusions: The nasal sprayer resulted in a rapid systemic uptake, and a higher bioavailability than previously reported for low-concentration/high-volume formulations. The nasal spray provided serum concentration that surpassed the intravenous after 10 min, and stayed above until 240 min. The spray did not elicit worrying side effects in the exposed subjects. The results are promising and further development of the product is warranted. Based on these results we have chosen to study 8 and 16 mg/ml in the next study. Further trials comparing the nasal spray with clinically relevant doses of intramuscular naloxone, and studies investigating the pharmacodynamic properties of the product, is also needed.