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
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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Associated Conditions
Contraindications & Blackbox Warnings
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Pharmacodynamics

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.

TargetActionsOrganism
AKappa-type opioid receptor
agonist
Humans
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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Toxicity

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

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Product Ingredients
IngredientUNIICASInChI Key
Difelikefalin acetate0P70AR5BYB1024829-44-4MZWHRPKAHCWTOI-KGURMGBCSA-N
International/Other Brands
Korsuva (Cara Therapeutics, Inc.)
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
KapruviaInjection, solution50 ?g/mlIntravenousVifor Fresenius Medical Care Renal Pharma France2022-05-04Not applicableEU flag
KapruviaInjection, solution50 ?g/mlIntravenousVifor Fresenius Medical Care Renal Pharma France2022-05-04Not applicableEU flag
KorsuvaInjection, solution50 ug/1mLIntravenousVifor (International) Inc.2021-01-11Not applicableUS flag

Categories

ATC Codes
V03AX04 — Difelikefalin
Drug Categories
Not Available
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
  1. 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]
  2. 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]
  3. 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]
  4. FDA Approved Drug Products: Korsuva (difelikefalin) for intravenous injection [Link]
  5. 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]
  6. EMA Approved Drug Products: Kapruvia (Difelikefalin) Intravenous Injection [Link]
  7. BioSpace News: Kapruvia® approved by European Commission for the treatment of moderate-to-severe pruritus in hemodialysis patients [Link]
PubChem Compound
24794466
PubChem Substance
347828265
ChemSpider
44208824
BindingDB
235785
RxNav
2569089
ChEMBL
CHEMBL3989915
Wikipedia
Difelikefalin
FDA label
Download (390 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3Active Not RecruitingTreatmentUremic Pruritus1
3CompletedTreatmentUremic Pruritus4
3Not Yet RecruitingTreatmentChronic Kidney Disease (CKD) / Pruritus1
3RecruitingTreatmentAtopic Dermatitis / Pruritus1
3RecruitingTreatmentChronic Kidney Disease (CKD) / Pruritus1
2CompletedTreatmentAcute Pain2
2CompletedTreatmentArticular inflammation / Joint Dysfunction / Musculoskeletal Disorders / Osteoarthritis in the Hip Joint / Osteoarthritis of the Knee / Rheumatic Diseases1
2CompletedTreatmentAtopic Dermatitis / Pruritus1
2CompletedTreatmentChronic Kidney Disease (CKD) / Pruritus1
2CompletedTreatmentNotalgia Paresthetica / Pruritus1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Injection, solutionIntravenous50 ?g/ml
Injection, solutionIntravenous50 ug/1mL
SolutionIntravenous50 mcg / mL
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US10793596No2020-10-062027-11-12US flag
US10138270No2018-11-272027-11-12US flag
US10017536No2018-07-102027-11-12US flag
US9359399No2016-06-072027-11-12US flag
US9334305No2016-05-102027-11-12US flag
US8536131No2013-09-172027-11-12US flag
US8486894No2013-07-162027-11-12US flag
US8236766No2012-08-072027-11-12US flag
US8217007No2012-07-102027-11-12US flag
US7727963No2010-06-012027-11-12US flag
US7713937No2010-05-112027-11-12US flag
US7402564No2008-07-222027-11-12US flag

Properties

State
Solid
Experimental Properties
PropertyValueSource
water solubilitySolublehttps://www.accessdata.fda.gov/drugsatfda_docs/label/2021/214916s000lbl.pdf
Predicted Properties
PropertyValueSource
Water Solubility0.0103 mg/mLALOGPS
logP-0.86ALOGPS
logP-1.7ChemAxon
logS-4.8ALOGPS
pKa (Strongest Acidic)1.92ChemAxon
pKa (Strongest Basic)10.26ChemAxon
Physiological Charge2ChemAxon
Hydrogen Acceptor Count9ChemAxon
Hydrogen Donor Count7ChemAxon
Polar Surface Area222.97 Å2ChemAxon
Rotatable Bond Count18ChemAxon
Refractivity185.74 m3·mol-1ChemAxon
Polarizability74.6 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Targets

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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
  1. 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]
  2. 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]
  3. 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