Citation

Krieter P, Gyaw S, Crystal R, Skolnick P. J. Pharmacol. Exp. Ther. 2019; ePub(ePub): ePub.

Affiliation

Opiant Pharmaceuticals, Inc. pskolnick@opiant.com.

Copyright

(Copyright © 2019, American Society for Pharmacology and Experimental Therapeutics)

DOI

10.1124/jpet.118.256115

PMID

30940694

Abstract

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 (IM) injection in a cohort of healthy volunteers. Nalmefene was absorbed slowly following IN administration, with a median T_max of 2 h. Addition of the absorption enhancer dodecyl maltoside (Intravail®) reduced T_max to 0.25 h and increased C _max by ~2.2-fold. The pharmacokinetic properties of IN nalmefene (3 mg) formulated with dodecyl maltose has characteristics consistent with an effective rescue medication: its onset of action is comparable to an IM injection of nalmefene (1.5 mg) previously approved to treat opioid overdose. Furthermore, the C_max following IN administration is ~3-fold higher than following IM dosing, comparable to previously reported plasma concentrations of nalmefene observed 5 min. following a 1 mg IV dose. The high affinity, very rapid onset, and long half-life (>7 h) of IN nalmefene present distinct advantages as a rescue medication, particularly against longer-lived synthetic opioids.

The American Society for Pharmacology and Experimental Therapeutics.

Language: en

Keywords

opioid receptors; opioids; pharmacokinetics