Identification
- Summary
Difelikefalin is a kappa opioid receptor agonist used in the treatment of pruritus associated with chronic kidney disease in patients undergoing hemodialysis.
- Brand Names
- Korsuva
- Generic Name
- Difelikefalin
- DrugBank Accession Number
- DB11938
- Background
Difelikefalin (CR845) is an agonist of kappa opioid receptors (KORs) useful in the treatment of pruritus secondary to chronic kidney disease. KORs were first associated with itching in 1984.1 Further investigations revealed that dynorphins, endogenous agonists of KORs, work to inhibit the itching sensation at the spinal cord level, and scratching could be elicited in mouse models with the administration of KOR antagonists.1 These revelations led to the study of KOR agonists as a potential treatment option in patients suffering from pruritic conditions.
Pruritus associated with chronic kidney disease (also called uremic pruritus) affects 50-60% of all patients on dialysis and 25% of non-dialysis patients with chronic kidney disease.2,3 The clinical burden of uremic pruritus in this patient population is being increasingly recognized as contributing to a significant reduction in patient quality of life, poor outcomes, and even mortality.3 Options for therapy are limited - with no FDA-approved treatments, off-label gabapentin was the most evidence-based and widely available treatment.3
Difelikefalin received FDA approval in August 2021 (under the brand name Korsuva), becoming the first FDA-approved therapy for patients with chronic kidney disease suffering from uremic pruritus.5,4 Difelikefalin was later approved by the EMA in April 2022 for the same indication.7
- Type
- Small Molecule
- Groups
- Approved, Investigational
- Structure
Structure for Difelikefalin (DB11938)
- Weight
- Average: 679.863
Monoisotopic: 679.405732455 - Chemical Formula
- C36H53N7O6
- Synonyms
- Difelikefalin
- External IDs
- CR 845
- CR-845
- CR845
- FE202845
- MR-13A9
Pharmacology
- Indication
Difelikefalin is indicated for the treatment of moderate-to-severe pruritus associated with chronic kidney disease (CKD-aP; uremic pruritus) in adults undergoing hemodialysis.4,6
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Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Treatment of Moderate, severe chronic kidney disease-associated pruritus •••••••••••• ••••• •••••••••••• ••••••••• ••••••••• - Contraindications & Blackbox Warnings
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Difelikefalin is administered to patients undergoing hemodialysis for chronic kidney disease (CKD) to prevent and treat the pruritus often associated with CKD. It is administered via bolus intravenous injection at the end of each hemodialysis treatment.4 As it works on opioid receptors, difelikefalin can cause dizziness, somnolence, and other CNS depressant effects that may impair mental or physical abilities - as such, patients should be advised to avoid operating dangerous machinery until the effect of difelikefalin on that patient is known.4
- Mechanism of action
Difelikefalin is a synthetic peptide and agonist of kappa opioid receptors (KORs), which have long been known to be involved with the itching sensation (in addition to playing some role in addiction).1 Endogenous KOR agonists - called dynorphins - have a neuroinhibitory effect on the itching sensation at the spinal cord level and mouse models have shown KOR agonist antipruritic activity when used to treat itching induced by different pruritogens.1
Although the specifics of the mechanism have yet to be elucidated,4 the administration of KOR agonists, like difelikefalin, in patients with uremic pruritus has proven an effective means to suppress scratching and improve their quality of life.
Target Actions Organism AKappa-type opioid receptor agonistHumans - Absorption
Difelikefalin is administered via bolus intravenous injection with each hemodialysis treatment4 - for this reason, each dose is effectively 100% bioavailable.
- Volume of distribution
The mean volume of distribution of difelikefalin is approximately 238 mL/kg.4
- Protein binding
Difelikefalin is approximately 23-28% protein-bound in plasma, although the specific proteins to which it binds are unclear.4
- Metabolism
Difelikefalin is not metabolized to any appreciable extent and is not a substrate for cytochrome P450 enzymes.4
- Route of elimination
Following intravenous difelikefalin administration to hemodialysis patients, approximately 11% of the dose was excreted in the urine, 59% in the feces, and 20% in the dialysate.4
- Half-life
The half-life of difelikefalin in hemodialysis patients prior to dialysis ranges between 23 and 31 hours.4
- Clearance
One cycle of hemodialysis reduces difelikefalin plasma concentrations by 70-80% and no detectable drug remains after two cycles.4
- Adverse Effects
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In clinical studies, single doses of up to 12 times (and multiple doses of up to 5 times) the recommended dosage of difelikefalin were administered in subjects undergoing hemodialysis.4 These patients experienced a dose-dependent increase in adverse reactions, including gastrointestinal effects and CNS depressant effects. In the event of overdosage, difelikefalin is dialyzable - 4 hours of high-flux hemodialysis effectively clears approximately 70-80% of the drug from plasma, and levels are likely to be undetectable following a second cycle.4
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs
- Not Available
Interactions
- Drug Interactions
- This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.Not Available
- Food Interactions
- Avoid excessive or chronic alcohol consumption. Difelikefalin can cause dizziness and somnolence that may be exacerbated by the CNS depressant effects of alcohol.
Products
Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.- Product Ingredients
Ingredient UNII CAS InChI Key Difelikefalin acetate 0P70AR5BYB 1024829-44-4 MZWHRPKAHCWTOI-KGURMGBCSA-N - International/Other Brands
- Korsuva (Cara Therapeutics, Inc.)
- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Kapruvia Injection, solution 50 ?g/ml Intravenous Vifor Fresenius Medical Care Renal Pharma France 2022-05-04 Not applicable EU 
Kapruvia Injection, solution 50 ?g/ml Intravenous Vifor Fresenius Medical Care Renal Pharma France 2022-05-04 Not applicable EU Korsuva Solution 50 mcg / mL Intravenous Vifor Fresenius Medical Care Renal Pharma Ltd 2023-02-06 Not applicable Canada 
Korsuva Injection, solution 50 ug/1mL Intravenous Vifor (International) Inc. 2021-01-11 Not applicable US 
Categories
- ATC Codes
- V03AX04 — Difelikefalin
- Drug Categories
- Chemical TaxonomyProvided by Classyfire
- Description
- This compound belongs to the class of organic compounds known as oligopeptides. These are organic compounds containing a sequence of between three and ten alpha-amino acids joined by peptide bonds.
- Kingdom
- Organic compounds
- Super Class
- Organic acids and derivatives
- Class
- Carboxylic acids and derivatives
- Sub Class
- Amino acids, peptides, and analogues
- Direct Parent
- Oligopeptides
- Alternative Parents
- Phenylalanine and derivatives / Leucine and derivatives / N-acyl-alpha amino acids and derivatives / Alpha amino acid amides / Amphetamines and derivatives / D-alpha-amino acids / L-alpha-amino acids / Piperidinecarboxylic acids / N-acylpiperidines / Aralkylamines show 12 more
- Substituents
- 4-aminopiperidine / Alpha-amino acid / Alpha-amino acid amide / Alpha-amino acid or derivatives / Alpha-oligopeptide / Amine / Amino acid / Amino acid or derivatives / Amphetamine or derivatives / Aralkylamine show 31 more
- Molecular Framework
- Aromatic heteromonocyclic compounds
- External Descriptors
- Not Available
- Affected organisms
- Humans and other mammals
Chemical Identifiers
- UNII
- NA1U919MRO
- CAS number
- 1024828-77-0
- InChI Key
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N
- 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
- IUPAC Name
- 4-amino-1-[(2R)-6-amino-2-[(2R)-2-[(2R)-2-[(2R)-2-amino-3-phenylpropanamido]-3-phenylpropanamido]-4-methylpentanamido]hexanoyl]piperidine-4-carboxylic acid
- SMILES
- 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
References
- General References
- Inan S, Cowan A: Antipruritic Effects of Kappa Opioid Receptor Agonists: Evidence from Rodents to Humans. Handb Exp Pharmacol. 2020 Dec 10. doi: 10.1007/164_2020_420. [Article]
- Lipman ZM, Yosipovitch G: An evaluation of difelikefalin as a treatment option for moderate-to-severe pruritus in end stage renal disease. Expert Opin Pharmacother. 2021 Apr;22(5):549-555. doi: 10.1080/14656566.2020.1849142. Epub 2020 Dec 14. [Article]
- Trachtenberg AJ, Collister D, Rigatto C: Recent advances in the treatment of uremic pruritus. Curr Opin Nephrol Hypertens. 2020 Sep;29(5):465-470. doi: 10.1097/MNH.0000000000000625. [Article]
- FDA Approved Drug Products: Korsuva (difelikefalin) for intravenous injection [Link]
- GlobeNewswire: Cara Therapeutics and Vifor Pharma announce U.S. FDA approval of KORSUVA™ (difelikefalin) injection for the treatment of moderate-to-severe pruritus in hemodialysis patients [Link]
- EMA Approved Drug Products: Kapruvia (Difelikefalin) Intravenous Injection [Link]
- BioSpace News: Kapruvia® approved by European Commission for the treatment of moderate-to-severe pruritus in hemodialysis patients [Link]
- External Links
- PubChem Compound
- 24794466
- PubChem Substance
- 347828265
- ChemSpider
- 44208824
- BindingDB
- 235785
- 2569089
- ChEMBL
- CHEMBL3989915
- Wikipedia
- Difelikefalin
- FDA label
- Download (390 KB)
Clinical Trials
- Clinical Trials
Phase Status Purpose Conditions Count 3 Active Not Recruiting Treatment Uremic Pruritus 1 3 Completed Treatment Uremic Pruritus 5 3 Recruiting Treatment Chronic Kidney Disease (CKD) / Pruritus 2 3 Terminated Treatment Atopic Dermatitis / Pruritus 1 2 Completed Treatment Acute Pain 2
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Injection, solution Intravenous 50 ?g/ml Injection, solution Intravenous 50 g/mL Injection, solution Intravenous 50 ug/1mL Solution Intravenous 50 mcg / mL - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US10793596 No 2020-10-06 2027-11-12 US US10138270 No 2018-11-27 2027-11-12 US US10017536 No 2018-07-10 2027-11-12 US US9359399 No 2016-06-07 2027-11-12 US US9334305 No 2016-05-10 2027-11-12 US US8536131 No 2013-09-17 2027-11-12 US US8486894 No 2013-07-16 2027-11-12 US US8236766 No 2012-08-07 2027-11-12 US US8217007 No 2012-07-10 2027-11-12 US US7727963 No 2010-06-01 2027-11-12 US US7713937 No 2010-05-11 2027-11-12 US US7402564 No 2008-07-22 2027-11-12 US
Properties
- State
- Solid
- Experimental Properties
Property Value Source water solubility Soluble https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/214916s000lbl.pdf - Predicted Properties
Property Value Source Water Solubility 0.0103 mg/mL ALOGPS logP -0.86 ALOGPS logP -1.7 Chemaxon logS -4.8 ALOGPS pKa (Strongest Acidic) 1.92 Chemaxon pKa (Strongest Basic) 10.26 Chemaxon Physiological Charge 2 Chemaxon Hydrogen Acceptor Count 9 Chemaxon Hydrogen Donor Count 7 Chemaxon Polar Surface Area 222.97 Å2 Chemaxon Rotatable Bond Count 18 Chemaxon Refractivity 185.74 m3·mol-1 Chemaxon Polarizability 74.6 Å3 Chemaxon Number of Rings 3 Chemaxon Bioavailability 0 Chemaxon Rule of Five No Chemaxon Ghose Filter No Chemaxon Veber's Rule No Chemaxon MDDR-like Rule Yes Chemaxon - Predicted ADMET Features
- Not Available
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
- Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 259.59076 predictedDeepCCS 1.0 (2019) [M+H]+ 261.48618 predictedDeepCCS 1.0 (2019) [M+Na]+ 267.50784 predictedDeepCCS 1.0 (2019)
Targets
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Agonist
- General Function
- Opioid receptor activity
- Specific Function
- G-protein coupled opioid receptor that functions as receptor for endogenous alpha-neoendorphins and dynorphins, but has low affinity for beta-endorphins. Also functions as receptor for various synt...
- Gene Name
- OPRK1
- Uniprot ID
- P41145
- Uniprot Name
- Kappa-type opioid receptor
- Molecular Weight
- 42644.665 Da
References
- Fishbane S, Jamal A, Munera C, Wen W, Menzaghi F: A Phase 3 Trial of Difelikefalin in Hemodialysis Patients with Pruritus. N Engl J Med. 2020 Jan 16;382(3):222-232. doi: 10.1056/NEJMoa1912770. Epub 2019 Nov 8. [Article]
- Fishbane S, Mathur V, Germain MJ, Shirazian S, Bhaduri S, Munera C, Spencer RH, Menzaghi F: Randomized Controlled Trial of Difelikefalin for Chronic Pruritus in Hemodialysis Patients. Kidney Int Rep. 2020 Jan 28;5(5):600-610. doi: 10.1016/j.ekir.2020.01.006. eCollection 2020 May. [Article]
- FDA Approved Drug Products: Korsuva (difelikefalin) for intravenous injection [Link]
Drug created at October 20, 2016 21:02 / Updated at May 01, 2022 11:44