I am a
Home I AM A Search Login

Papers of the Week

Papers: 8 May 2021 - 14 May 2021

Human Studies, Pharmacology/Drug Development

2021 May 13

Clin Transl Sci

Effect of Difelikefalin, a Selective Kappa Opioid Receptor Agonist, on Respiratory Depression: A Randomized, Double-Blind, Placebo-Controlled Trial.


Viscusi ER, Torjman MC, Munera CL, Stauffer JW, Setnik BS, Bagal SN
Clin Transl Sci. 2021 May 13.
PMID: 33982405.


Difelikefalin, a selective kappa opioid receptor agonist designed to limit central nervous system (CNS) penetration, is under development for the treatment of pruritus. Its hydrophilic, small-peptidic structure limits CNS entry, minimizing potential CNS-mediated adverse events (AEs). This study assessed the effect of difelikefalin on key relevant measures of respiratory depression in healthy volunteers. This single-center, randomized, double-blind, placebo-controlled, 3-way crossover study enrolled healthy, nonsmoking volunteers. Subjects were randomized to 1 of 3 treatment sequences of difelikefalin (1.0 or 5.0 mcg/kg intravenously [IV]) or placebo on sequential days with an intervening 24 (±2) hour washout period. The primary endpoints included incidence of increased end-tidal carbon dioxide (ETCO ) ≥10 mm Hg versus baseline or a level >50 mm Hg sustained ≥30 seconds, and incidence of reduction in saturation of peripheral oxygen (SpO ) to <92% sustained ≥30 seconds. Secondary endpoints included incidence of reduced respiratory rate and other safety assessments. Fifteen subjects were randomized and completed the study. No subject on placebo or difelikefalin met the increased ETCO or reduced SpO primary endpoint criteria for respiratory depression. All respiratory measures in each group remained near baseline values during 4-hour postdose observations. No subject met the reduced respiratory rate criterion or experienced clinically significant changes in ETCO , SpO , or respiratory rate. The most commonly reported treatment-emergent AEs (TEAEs; ≥20% of subjects) were paresthesia, hypoesthesia, and somnolence in the difelikefalin arms. All TEAEs were mild and resolved without intervention. Difelikefalin 1.0 and 5.0 mcg/kg IV did not produce respiratory depression.