Difelikefalin

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

Clinical data
Trade names	Korsuva
Other names	CR845, FE-202845, D-Phe-D-Phe-D-Leu-D-Lys-[γ-(4-N-piperidinyl)amino carboxylic acid][1]
License data	US DailyMed: Difelikefalin
Pregnancy category	AU: B1[2][3]
Routes of administration	Intravenous
Drug class	Kappa opioid receptor agonist
ATC code	V03AX04 (WHO)
Legal status
Legal status	AU: S4 (Prescription only)[2][4] CA: ℞-only[5][6][7] US: ℞-only[8] EU: Rx-only[9]
Pharmacokinetic data
Bioavailability	100% (IV)[10]
Metabolism	Not metabolized[10]
Elimination half-life	2 hours[10]
Excretion	Excreted as unchanged drug via bile and urine[10]
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	1024828-77-0 as salt: 1024829-44-4
PubChem CID	24794466 as salt: 91864509
DrugBank	DB11938 as salt: DBSALT003191
ChemSpider	44208824
UNII	NA1U919MRO as salt: 0P70AR5BYB
KEGG	D11111 as salt: D10890
ChEMBL	ChEMBL3989915
CompTox Dashboard (EPA)	DTXSID401032896
Chemical and physical data
Formula	C36H53N7O6
Molar mass	679.863 g·mol−1
3D model (JSmol)	Interactive image as salt: Interactive image
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 acts as an analgesic by activating KORs on peripheral nerve terminals and KORs expressed by certain immune system cells.^[10] 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).^[10]

Difelikefalin was approved for medical use in the United States in August 2021.^[8][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.^[17] 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.^[9][18]

Research

It is under development by Cara Therapeutics as an intravenous agent for the treatment of postoperative pain.^[10][11][13] An oral formulation has also been developed.^[13] 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.^[10][11] In addition to use as an analgesic, difelikefalin is also being investigated for the treatment of pruritus (itching).^[10][11][12] 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.^[11][13] It has also completed a phase III clinical trial for uremic pruritus in hemodialysis patients.^[19]

References

1. Janecka A, Perlikowska R, Gach K, Wyrebska A, Fichna J (2010). "Development of opioid peptide analogs for pain relief". Current Pharmaceutical Design. 16 (9): 1126–1135. doi:10.2174/138161210790963869. PMID 20030621.
2. "Korsuva". Therapeutic Goods Administration (TGA). 25 November 2022. Archived from the original on 5 February 2023. Retrieved 7 April 2023.
3. "Updates to the Prescribing Medicines in Pregnancy database". Therapeutic Goods Administration (TGA). 21 December 2022. Archived from the original on 3 April 2022. Retrieved 2 January 2023.
4. https://www.tga.gov.au/resources/auspar/auspar-korsuva ^{[bare URL]}
5. "Product monograph" (PDF). Health Canada. Archived (PDF) from the original on 1 October 2022. Retrieved 7 April 2023.
6. "Summary Basis of Decision - Korsuva". Health Canada. 23 October 2014. Archived from the original on 24 January 2023. Retrieved 24 January 2023.
7. "Details for: Korsuva". Health Canada. 6 February 2023. Archived from the original on 3 March 2024. Retrieved 3 March 2024.
8. "Korsuva- difelikefalin injection, solution". DailyMed. Archived from the original on 12 September 2021. Retrieved 12 September 2021.
9. "Kapruvia EPAR". European Medicines Agency (EMA). 22 February 2022. Archived from the original on 6 May 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.
10. Chalmers D (14 October 2010). "Peripheral kappa agonists". In Sinatra RS, Jahr JS, Watkins-Pitchford JM (eds.). The Essence of Analgesia and Analgesics. Cambridge University Press. pp. 490–491. ISBN 978-1-139-49198-3.
11. Apfelbaum J (8 September 2014). Ambulatory Anesthesia, An Issue of Anesthesiology Clinics. Elsevier Health Sciences. pp. 190–. ISBN 978-0-323-29934-3.
12. Leslie TA, Greavers MW, Yosipovitch G (10 April 2015). "Current Topical and Systemic Therapies for Itch". In Cowan A, Yosipovitch G (eds.). Pharmacology of Itch. Springer. pp. 307–. ISBN 978-3-662-44605-8.
13. Goli V, Pryde D, Omoto K (2013). "Oral Opioids". In Allerton C (ed.). Pain Therapeutics: Current and Future Treatment Paradigms. Royal Society of Chemistry. pp. 56–. ISBN 978-1-84973-645-9.
14. "Korsuva: FDA-Approved Drugs". U.S. Food and Drug Administration. Archived from the original on 25 August 2021. Retrieved 24 August 2021.
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" (Press release). Vifor Pharma. 24 August 2021. Archived from the original on 24 August 2021. Retrieved 24 August 2021 – via Business Wire.
16. Advancing Health Through Innovation: New Drug Therapy Approvals 2021 (PDF). U.S. Food and Drug Administration (FDA) (Report). 13 May 2022. Archived from the original on 6 December 2022. Retrieved 22 January 2023. This article incorporates text from this source, which is in the public domain.
17. "Kapruvia: Pending EC decision". European Medicines Agency. 24 February 2022. Archived from the original on 27 October 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.
18. "Kapruvia Product information". Union Register of medicinal products. Archived from the original on 4 March 2023. Retrieved 3 March 2023.
19. Fishbane S, Jamal A, Munera C, Wen W, Menzaghi F (January 2020). "A Phase 3 Trial of Difelikefalin in Hemodialysis Patients with Pruritus". The New England Journal of Medicine. 382 (3): 222–232. doi:10.1056/NEJMoa1912770. PMID 31702883.

External links

• 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