Difelikefalin

Difelikefalin, sold under the brand name Korsuva, is an analgesic opioid peptide used for the treatment of moderate to severe itching. It acts as a peripherally specific, highly selective agonist of the κ-opioid receptor (KOR).[5][6][7][8]

Difelikefalin
Clinical data
Trade namesKorsuva
Other namesCR845, FE-202845, D-Phe-D-Phe-D-Leu-D-Lys-[γ-(4-N-piperidinyl)amino carboxylic acid][1]
License data
Routes of
administration		Intravenous
Drug classKappa opioid receptor agonist
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability100% (IV)[5]
MetabolismNot metabolized[5]
Elimination half-life2 hours[5]
ExcretionExcreted as unchanged
drug via bile and urine[5]
Identifiers
IUPAC name
  • 4-amino-1-[(2R)-6-amino-2-[[(2R)-2-[[(2R)-2-[[(2R)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
Chemical and physical data
FormulaC36H53N7O6
Molar mass679.863 g·mol−1
3D model (JSmol)
SMILES
  • CC(C)C[C@H](C(=O)N[C@H](CCCCN)C(=O)N1CCC(CC1)(C(=O)O)N)NC(=O)[C@@H](CC2=CC=CC=C2)NC(=O)[C@@H](CC3=CC=CC=C3)N

  • as salt: CC(O)=O.CC(C)C[C@@H](NC(=O)[C@@H](CC1=CC=CC=C1)NC(=O)[C@H](N)CC1=CC=CC=C1)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O
InChI
  • InChI=1S/C36H53N7O6/c1-24(2)21-29(32(45)40-28(15-9-10-18-37)34(47)43-19-16-36(39,17-20-43)35(48)49)42-33(46)30(23-26-13-7-4-8-14-26)41-31(44)27(38)22-25-11-5-3-6-12-25/h3-8,11-14,24,27-30H,9-10,15-23,37-39H2,1-2H3,(H,40,45)(H,41,44)(H,42,46)(H,48,49)/t27-,28-,29-,30-/m1/s1
  • Key:FWMNVWWHGCHHJJ-SKKKGAJSSA-N

  • as salt: InChI=1S/C36H53N7O6.C2H4O2/c1-24(2)21-29(32(45)40-28(15-9-10-18-37)34(47)43-19-16-36(39,17-20-43)35(48)49)42-33(46)30(23-26-13-7-4-8-14-26)41-31(44)27(38)22-25-11-5-3-6-12-25;1-2(3)4/h3-8,11-14,24,27-30H,9-10,15-23,37-39H2,1-2H3,(H,40,45)(H,41,44)(H,42,46)(H,48,49);1H3,(H,3,4)/t27-,28-,29-,30-;/m1./s1
  • Key:MZWHRPKAHCWTOI-KGURMGBCSA-N

Difelikefalin was approved for medical use in the United States in August 2021.[3][9][10]

Difelikefalin acts as an analgesic by activating KORs on peripheral nerve terminals and KORs expressed by certain immune system cells.[5] Activation of KORs on peripheral nerve terminals results in the inhibition of ion channels responsible for afferent nerve activity, causing reduced transmission of pain signals, while activation of KORs expressed by immune system cells results in reduced release of proinflammatory, nerve-sensitizing mediators (e.g., prostaglandins).[5]

Society and culture

On 24 February 2022, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Kapruvia, intended for treatment of moderate-to-severe pruritus associated with chronic kidney disease.[11] The applicant for this medicinal product is Vifor Fresenius Medical Care Renal Pharma France.[11] Difelikefalin was approved for medical use in the European Union in April 2022.[4]

Research

It is under development by Cara Therapeutics as an intravenous agent for the treatment of postoperative pain.[5][6][8] An oral formulation has also been developed.[8] Due to its peripheral selectivity, difelikefalin lacks the central side effects like sedation, dysphoria, and hallucinations of previous KOR-acting analgesics such as pentazocine and phenazocine.[5][6] In addition to use as an analgesic, difelikefalin is also being investigated for the treatment of pruritus (itching).[5][6][7] Difelikefalin has completed phase II clinical trials for postoperative pain and has demonstrated significant and "robust" clinical efficacy, along with being safe and well tolerated.[6][8] It has also completed a phase III clinical trial for uremic pruritus in hemodialysis patients.[12]

References
  1. Janecka A, Perlikowska R, Gach K, Wyrebska A, Fichna J (2010). "Development of opioid peptide analogs for pain relief". Curr. Pharm. Des. 16 (9): 1126–35. doi:10.2174/138161210790963869. PMID 20030621.
  2. https://pdf.hres.ca/dpd_pm/00066996.PDF
  3. "Korsuva- difelikefalin injection, solution". DailyMed. Retrieved 12 September 2021.
  4. "Kapruvia EPAR". European Medicines Agency (EMA). 22 February 2022. Retrieved 28 April 2022. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  5. Raymond S. Sinatra; Jonathan S. Jahr; J. Michael Watkins-Pitchford (14 October 2010). The Essence of Analgesia and Analgesics. Cambridge University Press. pp. 490–491. ISBN 978-1-139-49198-3.
  6. Jeffrey Apfelbaum (8 September 2014). Ambulatory Anesthesia, An Issue of Anesthesiology Clinics. Elsevier Health Sciences. pp. 190–. ISBN 978-0-323-29934-3.
  7. Alan Cowan; Gil Yosipovitch (10 April 2015). Pharmacology of Itch. Springer. pp. 307–. ISBN 978-3-662-44605-8.
  8. Charlotte Allerton (2013). Pain Therapeutics: Current and Future Treatment Paradigms. Royal Society of Chemistry. pp. 56–. ISBN 978-1-84973-645-9.
  9. "Korsuva: FDA-Approved Drugs". U.S. Food and Drug Administration. Retrieved 24 August 2021.
  10. "Vifor Pharma and Cara Therapeutics announce U.S. FDA approval of Korsuva injection for the treatment of moderate-to-severe pruritus in hemodialysis patients" (Press release). Vifor Pharma. 24 August 2021. Retrieved 24 August 2021 – via Business Wire.
  11. "Kapruvia: Pending EC decision". European Medicines Agency. 24 February 2022. Retrieved 26 February 2022. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  12. Fishbane S, Jamal A, Munera C, Wen W, Menzaghi F (2020). "A phase 3 trial of difelikefalin in hemodialysis patients with pruritus". N Engl J Med. 382 (3): 222–232. doi:10.1056/NEJMoa1912770. PMID 31702883.
  • "Difelikefalin". Drug Information Portal. U.S. National Library of Medicine.
  • Clinical trial number NCT03422653 for "A Study to Evaluate the Safety and Efficacy of CR845 in Hemodialysis Patients With Moderate-to-Severe Pruritus (KALM-1)" at ClinicalTrials.gov
  • Clinical trial number NCT03636269 for "CR845-CLIN3103: A Global Study to Evaluate the Safety and Efficacy of CR845 in Hemodialysis Patients With Moderate-to-Severe Pruritus (KALM-2)" at ClinicalTrials.gov


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