Difelikefalin Explained

Width:250
Tradename:Korsuva
Dailymedid:Difelikefalin
Pregnancy Au:B1
Pregnancy Au Comment:[1]
Routes Of Administration:Intravenous
Class:Kappa opioid receptor agonist
Atc Prefix:V03
Atc Suffix:AX04
Legal Au:S4
Legal Au Comment:[2] [3]
Legal Ca:Rx-only
Legal Ca Comment:[4] [5] [6]
Legal Us:Rx-only
Legal Us Comment:[7]
Legal Eu:Rx-only
Legal Eu Comment:[8]
Bioavailability:100% (IV)
Metabolism:Not metabolized
Elimination Half-Life:2 hours
Excretion:Excreted as unchanged
drug via bile and urine
Index2 Label:as salt
Cas Number:1024828-77-0
Cas Number2:1024829-44-4
Pubchem:24794466
Pubchem2:91864509
Drugbank:DB11938
Drugbank2:DBSALT003191
Chemspiderid:44208824
Unii:NA1U919MRO
Unii2:0P70AR5BYB
Kegg:D11111
Kegg2:D10890
Chembl:3989915
Synonyms:CR845, FE-202845, D-Phe-D-Phe-D-Leu-D-Lys-[γ-(4-N-piperidinyl)amino carboxylic acid][9]
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
C:36
H:53
N:7
O:6
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
Smiles2: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
Stdinchi: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
Stdinchi2:1S/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
Stdinchikey:FWMNVWWHGCHHJJ-SKKKGAJSSA-N
Stdinchikey2:MZWHRPKAHCWTOI-KGURMGBCSA-N

Difelikefalin, sold under the brand name Korsuva, is an opioid peptide used for the treatment of moderate to severe itch. It acts as a peripherally-restricted, highly selective agonist of the κ-opioid receptor (KOR).[10] [11] [12] [13]

Difelikefalin acts as an analgesic by activating KORs on peripheral nerve terminals and KORs expressed by certain immune system cells. 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).

Difelikefalin was approved for medical use in the United States in August 2021.[14] [15] The U.S. Food and Drug Administration considers it to be a first-in-class medication.[16]

Society and culture

Legal status

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. The applicant for this medicinal product is Vifor Fresenius Medical Care Renal Pharma France.[17] Difelikefalin was approved for medical use in the European Union in April 2022.[18]

Research

It is under development by Cara Therapeutics as an intravenous agent for the treatment of postoperative pain. An oral formulation has also been developed. 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. In addition to use as an analgesic, difelikefalin is also being investigated for the treatment of pruritus (itching). 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. It has also completed a phase III clinical trial for uremic pruritus in hemodialysis patients.[19]

Notes and References

  1. Web site: Updates to the Prescribing Medicines in Pregnancy database . Therapeutic Goods Administration (TGA) . 21 December 2022 . 2 January 2023 . 3 April 2022 . https://web.archive.org/web/20220403064059/https://www.tga.gov.au/updates-prescribing-medicines-pregnancy-database . live .
  2. Web site: Korsuva . Therapeutic Goods Administration (TGA) . 25 November 2022 . 7 April 2023 . 5 February 2023 . https://web.archive.org/web/20230205203429/https://www.tga.gov.au/resources/auspmd/korsuva . live .
  3. https://www.tga.gov.au/resources/auspar/auspar-korsuva
  4. Web site: Product monograph. 7 April 2023. Health Canada. 1 October 2022. https://web.archive.org/web/20221001060048/https://pdf.hres.ca/dpd_pm/00066996.PDF. live.
  5. Web site: Summary Basis of Decision - Korsuva . . 23 October 2014 . 24 January 2023 . 24 January 2023 . https://web.archive.org/web/20230124031805/https://hpr-rps.hres.ca/reg-content/summary-basis-decision-detailTwo.php?lang=en&linkID=SBD00615&lang=en . live .
  6. Web site: Details for: Korsuva . . 6 February 2023 . 3 March 2024 . 3 March 2024 . https://web.archive.org/web/20240303063930/https://dhpp.hpfb-dgpsa.ca/dhpp/resource/101892 . live .
  7. Web site: Korsuva- difelikefalin injection, solution . DailyMed . 12 September 2021 . 12 September 2021 . https://web.archive.org/web/20210912221530/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0c7b81f2-0fd3-47cb-8b0f-185e07f19c87 . live .
  8. Web site: Kapruvia EPAR . European Medicines Agency (EMA) . 22 February 2022 . 28 April 2022 . 6 May 2022 . https://web.archive.org/web/20220506032536/https://www.ema.europa.eu/en/medicines/human/EPAR/kapruvia . live . Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  9. Janecka A, Perlikowska R, Gach K, Wyrebska A, Fichna J . Development of opioid peptide analogs for pain relief . Current Pharmaceutical Design . 16 . 9 . 1126–1135 . 2010 . 20030621 . 10.2174/138161210790963869 .
  10. Book: Chalmers D . Peripheral kappa agonists. Sinatra RS, Jahr JS, Watkins-Pitchford JM . The Essence of Analgesia and Analgesics. https://books.google.com/books?id=ZwPIjKg0XukC&pg=PA490. 14 October 2010. Cambridge University Press. 978-1-139-49198-3. 490–491.
  11. Book: Apfelbaum J . Ambulatory Anesthesia, An Issue of Anesthesiology Clinics. 8 September 2014. Elsevier Health Sciences. 978-0-323-29934-3. 190–.
  12. Book: Leslie TA, Greavers MW, Yosipovitch G . Current Topical and Systemic Therapies for Itch . Cowan A, Yosipovitch G . Pharmacology of Itch. https://books.google.com/books?id=Jl0SCAAAQBAJ&pg=PA307. 10 April 2015. Springer. 978-3-662-44605-8. 307–.
  13. Book: Goli V, Pryde D, Omoto K . Oral Opioids. Allerton C . Pain Therapeutics: Current and Future Treatment Paradigms. https://books.google.com/books?id=zUINAgAAQBAJ&pg=PA56. 2013. Royal Society of Chemistry. 978-1-84973-645-9. 56–.
  14. Web site: Korsuva: FDA-Approved Drugs . U.S. Food and Drug Administration . 24 August 2021 . 25 August 2021 . https://web.archive.org/web/20210825050736/https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=214916 . live .
  15. Vifor Pharma and Cara Therapeutics announce U.S. FDA approval of Korsuva injection for the treatment of moderate-to-severe pruritus in hemodialysis patients . Vifor Pharma . Business Wire . 24 August 2021 . 24 August 2021 . 24 August 2021 . https://web.archive.org/web/20210824213538/https://www.businesswire.com/news/home/20210823005635/en/Vifor-Pharma-and-Cara-Therapeutics-announce-U.S.-FDA-approval-of-KORSUVA%E2%84%A2-injection-for-the-treatment-of-moderate-to-severe-pruritus-in-hemodialysis-patients . live .
  16. Advancing Health Through Innovation: New Drug Therapy Approvals 2021 . U.S. Food and Drug Administration (FDA) . 13 May 2022 . PDF . 22 January 2023 . 6 December 2022 . https://web.archive.org/web/20221206210020/https://www.fda.gov/media/155227/download . live .
  17. Web site: Kapruvia: Pending EC decision . European Medicines Agency . 24 February 2022 . 26 February 2022 . 27 October 2022 . https://web.archive.org/web/20221027142342/https://www.ema.europa.eu/en/medicines/human/EPAR/kapruvia . dead . Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  18. Web site: Kapruvia Product information . Union Register of medicinal products . 3 March 2023 . 4 March 2023 . https://web.archive.org/web/20230304072219/https://ec.europa.eu/health/documents/community-register/html/h1643.htm . live .
  19. Fishbane S, Jamal A, Munera C, Wen W, Menzaghi F . A Phase 3 Trial of Difelikefalin in Hemodialysis Patients with Pruritus . The New England Journal of Medicine . 382 . 3 . 222–232 . January 2020 . 31702883 . 10.1056/NEJMoa1912770 . free .

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