PMID- 33982405
OWN - NLM
STAT- MEDLINE
DCOM- 20220215
LR  - 20240403
IS  - 1752-8062 (Electronic)
IS  - 1752-8054 (Print)
IS  - 1752-8054 (Linking)
VI  - 14
IP  - 5
DP  - 2021 Sep
TI  - Effect of difelikefalin, a selective kappa opioid receptor agonist, on 
      respiratory depression: A randomized, double-blind, placebo-controlled trial.
PG  - 1886-1893
LID - 10.1111/cts.13042 [doi]
AB  - 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, three-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 i.v.) or placebo on sequential days with an 
      intervening 24 (+/-2) h washout period. The primary end points included incidence 
      of increased end-tidal carbon dioxide (ETCO(2) ) greater than or equal to 10 mm 
      Hg versus baseline or a level greater than 50 mm Hg sustained greater than or 
      equal to 30 seconds, and incidence of reduction in saturation of peripheral 
      oxygen (SpO(2) ) to less than 92% sustained greater than or equal to 30 seconds. 
      Secondary end points 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(2) or reduced SpO(2) 
      primary end point criteria for respiratory depression. All respiratory measures 
      in each group remained near baseline values during 4-h postdose observations. No 
      subject met the reduced respiratory rate criterion or experienced clinically 
      significant changes in ETCO(2) , SpO(2) , 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 i.v. did not 
      produce respiratory depression.
CI  - (c) 2021 The Authors. Clinical and Translational Science published by Wiley 
      Periodicals LLC on behalf of the American Society for Clinical Pharmacology and 
      Therapeutics.
FAU - Viscusi, Eugene R
AU  - Viscusi ER
AD  - Department of Anesthesiology, Sidney Kimmel Medical College at Thomas Jefferson 
      University, Philadelphia, Pennsylvania, USA.
FAU - Torjman, Marc C
AU  - Torjman MC
AD  - Department of Anesthesiology, Sidney Kimmel Medical College at Thomas Jefferson 
      University, Philadelphia, Pennsylvania, USA.
FAU - Munera, Catherine L
AU  - Munera CL
AD  - Cara Therapeutics, Stamford, Connecticut, USA.
FAU - Stauffer, Joseph W
AU  - Stauffer JW
AD  - Cara Therapeutics, Stamford, Connecticut, USA.
FAU - Setnik, Beatrice S
AU  - Setnik BS
AD  - Department of Pharmacology and Toxicology, University of Toronto, Toronto, 
      Ontario, Canada.
AD  - Altasciences, Montreal, Quebec, Canada.
FAU - Bagal, Sukirti N
AU  - Bagal SN
AD  - Cara Therapeutics, Stamford, Connecticut, USA.
LA  - eng
GR  - Cara Therapeutics/
PT  - Journal Article
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
DEP - 20210721
PL  - United States
TA  - Clin Transl Sci
JT  - Clinical and translational science
JID - 101474067
RN  - 0 (Piperidines)
RN  - 0 (Placebos)
RN  - 0 (Receptors, Opioid, kappa)
RN  - 142M471B3J (Carbon Dioxide)
RN  - NA1U919MRO (difelikefalin)
SB  - IM
MH  - Adolescent
MH  - Adult
MH  - Carbon Dioxide/analysis
MH  - Cross-Over Studies
MH  - Double-Blind Method
MH  - Female
MH  - Healthy Volunteers
MH  - Humans
MH  - Incidence
MH  - Male
MH  - Middle Aged
MH  - Oxygen Saturation/drug effects
MH  - Piperidines/administration & dosage/*adverse effects
MH  - Placebos/administration & dosage/adverse effects
MH  - Pruritus/drug therapy
MH  - Receptors, Opioid, kappa/*agonists
MH  - Respiratory Insufficiency/chemically induced/diagnosis/*epidemiology
MH  - Respiratory Rate/drug effects
MH  - Young Adult
PMC - PMC8504812
COIS- C.L.M. and S.N.B. are employees of Cara Therapeutics and had input into the 
      content of the report. E.R.V. is a scientific consultant for Cara Therapeutics. 
      M.C.T. is a scientific consultant for Cara Therapeutics. B.S.S. was an employee 
      of Syneos Health, Toronto, Ontario, Canada, at the time of this study and had 
      input on the design, conduct, and data analysis of this study. J.W.S. was an 
      employee of and held stock in Cara Therapeutics at the time of this study, and 
      had input on the design, execution, and analysis of this trial. He is currently 
      employed by Antibe Therapeutics, Toronto, Ontario, Canada.
EDAT- 2021/05/14 06:00
MHDA- 2022/02/16 06:00
PMCR- 2021/09/01
CRDT- 2021/05/13 06:50
PHST- 2021/03/02 00:00 [revised]
PHST- 2020/11/25 00:00 [received]
PHST- 2021/03/06 00:00 [accepted]
PHST- 2021/05/14 06:00 [pubmed]
PHST- 2022/02/16 06:00 [medline]
PHST- 2021/05/13 06:50 [entrez]
PHST- 2021/09/01 00:00 [pmc-release]
AID - CTS13042 [pii]
AID - 10.1111/cts.13042 [doi]
PST - ppublish
SO  - Clin Transl Sci. 2021 Sep;14(5):1886-1893. doi: 10.1111/cts.13042. Epub 2021 Jul 
      21.