Fighting Fire with Fire: Development of Intranasal Nalmefene to Treat Synthetic Opioid Overdose

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 371; no. 2; pp. 409 - 415
• Main Authors: Krieter, Philip, Gyaw, Shwe, Crystal, Roger, Skolnick, Phil
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.11.2019; The American Society for Pharmacology and Experimental Therapeutics
• Subjects: Administration, Intranasal; Adolescent; Adult; Analgesics, Opioid - adverse effects; Analgesics, Opioid - blood; Cross-Over Studies; Double-Blind Method; Drug Development - methods; Drug Overdose - blood; Drug Overdose - drug therapy; Female; Humans; Injections, Intramuscular; Male; Middle Aged; Naltrexone - administration & dosage; Naltrexone - analogs & derivatives; Naltrexone - blood; Narcotic Antagonists - administration & dosage; Narcotic Antagonists - blood; Special Section on The Opioid Crisis; Synthetic Drugs - adverse effects; Synthetic Drugs - metabolism; Treatment Outcome; Young Adult; LC-MS/MS; FDA; AE; IN; t1/2; CI; Tmax; AUC0–t; DDM
• ISSN: 0022-3565; 1521-0103; 1521-0103
• DOI: 10.1124/jpet.118.256115

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 μ 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 Cmax (Tmax) of 2 hours. Addition of the absorption enhancer dodecyl maltoside (Intravail, Neurelis, Inc., Encinitas, CA) reduced Tmax to 0.25 hour and increased Cmax 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 Cmax 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.