National Institute on Drug Abuse, National Institutes of Health, Bethesda, Maryland (P.K., S.G.) and Opiant Pharmaceuticals, Santa Monica, California (R.C., P.S.).
National Institute on Drug Abuse, National Institutes of Health, Bethesda, Maryland (P.K., S.G.) and Opiant Pharmaceuticals, Santa Monica, California (R.C., P.S.)
J Pharmacol Exp Ther. 2019 Nov;371(2):409-415. doi: 10.1124/jpet.118.256115. Epub 2019 Apr 2.
The dramatic rise in overdose deaths linked to synthetic opioids (e.g., fentanyl, carfentanil) may require more potent, longer-duration opiate antagonists than naloxone. Both the high affinity of nalmefene at opiate receptors and its long half-life led us to examine the feasibility of developing an intranasal (IN) formulation as a rescue medication that could be especially useful in treating synthetic opioid overdose. In this study, the pharmacokinetic properties of IN nalmefene were compared with an intramuscular (i.m.) injection in a cohort of healthy volunteers. Nalmefene was absorbed slowly following IN administration, with a median time to reach C (T) of 2 hours. Addition of the absorption enhancer dodecyl maltoside (Intravail, Neurelis, Inc., Encinitas, CA) reduced T to 0.25 hour and increased C by ∼2.2-fold. The pharmacokinetic properties of IN nalmefene (3 mg) formulated with dodecyl maltoside has characteristics consistent with an effective rescue medication: its onset of action is comparable to an i.m. injection of nalmefene (1.5 mg) previously approved to treat opioid overdose. Furthermore, the C following IN administration was ∼3-fold higher than following i.m. dosing, comparable to previously reported plasma concentrations of nalmefene observed 5 minutes following a 1-mg i.v. dose. The high affinity, very rapid onset, and long half-life (>7 hours) of IN nalmefene present distinct advantages as a rescue medication, particularly against longer-lived synthetic opioids.
与合成阿片类药物（如芬太尼、卡芬太尼）相关的过量死亡急剧上升，可能需要比纳洛酮更有效、持续时间更长的阿片类拮抗剂。纳美芬在阿片受体上的高亲和力及其长半衰期促使我们研究开发一种鼻腔内（IN）制剂作为救援药物的可行性，这种药物在治疗合成阿片类药物过量方面可能特别有用。在这项研究中，我们比较了 IN 纳美芬在一组健康志愿者中的药代动力学特性与肌内（IM）注射。IN 给药后纳美芬吸收缓慢，达到 C（T）的中位数时间为 2 小时。添加吸收增强剂十二烷基麦芽糖苷（Intravail，Neurelis，Inc.，Encinitas，CA）将 T 缩短至 0.25 小时，并将 C 增加约 2.2 倍。用十二烷基麦芽糖苷配制的 IN 纳美芬（3 毫克）的药代动力学特性具有有效的救援药物的特征：其作用开始时间与先前批准用于治疗阿片类药物过量的肌内注射纳美芬（1.5 毫克）相当。此外，IN 给药后的 C 约为肌内给药后的 3 倍，与先前报告的静脉内 1 毫克剂量后 5 分钟观察到的纳美芬血浆浓度相当。IN 纳美芬具有高亲和力、非常快速的作用开始和长半衰期（>7 小时），作为救援药物具有明显优势，特别是针对半衰期较长的合成阿片类药物。
