Department of Circulation and Medical Imaging, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.
Division of Pre-hospital Services, Department of Air Ambulance, Oslo University Hospital, Oslo, Norway.
Addiction. 2019 May;114(5):859-867. doi: 10.1111/add.14552. Epub 2019 Feb 15.
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.
Open, randomized four-way cross-over trial.
Clinical Trials Units in St Olav's Hospital, Trondheim and Rikshospitalet, Oslo, Norway.
Twenty-two healthy human volunteers, 10 women, median age = 25.8 years.
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.
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.
Area under the curve from administration to last measured concentration (AUC ) 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 (C ) 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 C of 4.18 ± 1.53 ng/ml. T 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).
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.
鼻内（i.n.）纳洛酮是治疗阿片类药物过量的既定治疗方法。任何可能目睹过量的人都应该能够获得解毒剂。我们旨在确定 1.4mg 盐酸纳洛酮的 i.n. 制剂是否能达到与 0.8mg 肌肉内（i.m.）纳洛酮相当的全身暴露。
开放、随机四交叉试验。
挪威特隆赫姆圣奥拉夫医院和奥斯陆里克斯医院的临床试验单位。
22 名健康的人类志愿者，10 名女性，中位年龄=25.8 岁。
与 i.m. 0.8mg 和 i.v. 0.4mg 纳洛酮相比，1 剂和 2 剂 i.n. 1.4mg 纳洛酮。
通过液相色谱串联质谱法对血浆纳洛酮进行定量。使用非房室药代动力学分析进行主要分析。为不同给药方案的蒙特卡罗模拟开发了非参数药代动力学群体模型。
i.n. 1.4mg 和 i.m. 0.8mg 的给药至最后测量浓度的曲线下面积（AUC）分别为 2.62±0.94 和 3.09±0.64 h×ng/ml（P=0.33）。C 最大值分别为 i.n. 1.4mg 的 2.36±0.68ng/ml 和 i.m. 0.8mg 的 3.73±3.34ng/ml（P=0.72）。两剂 i.n. 显示出剂量线性，并达到 4.18±1.53ng/ml 的 C。i.n. 1.4mg 的 T 为 20.2±9.4 分钟，i.m. 0.8mg 的 T 为 13.6±15.4 分钟（P=0.098）。i.n. 1.4mg 的绝对生物利用度为 0.49（±0.24），而 i.n./i.m. 的相对生物利用度为 0.52（±0.25）。
与肌肉内 0.8mg 相比，鼻内 1.4mg 纳洛酮提供足够的全身浓度来治疗阿片类药物过量，在最大血浆浓度、达到最大血浆浓度的时间或曲线下面积方面没有统计学差异。模拟支持其作为同行管理的解毒剂和专业人员治疗滴定的适当性。
