kappa opioid receptor (KOR)

Difelikefalin (CR-845; FE-202845) does not penetrate the blood-brain barrier. Difelikefalin does not bind to any receptors other than KORs, including mu opioid receptors[1].

Absorption, Distribution and Excretion
Difelikefalin is administered via bolus intravenous injection with each hemodialysis treatment - for this reason, each dose is effectively 100% bioavailable.
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.
The mean volume of distribution of difelikefalin is approximately 238 mL/kg.
One cycle of hemodialysis reduces difelikefalin plasma concentrations by 70-80% and no detectable drug remains after two cycles.

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Metabolism / Metabolites
Difelikefalin is not metabolized to any appreciable extent and is not a substrate for cytochrome P450 enzymes.

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Biological Half-Life
The half-life of difelikefalin in hemodialysis patients prior to dialysis ranges between 23 and 31 hours.

Protein Binding
Difelikefalin is approximately 23-28% protein-bound in plasma, although the specific proteins to which it binds are unclear.

[1]. Randomized Controlled Trial of Difelikefalin for Chronic Pruritus in Hemodialysis Patients. Kidney Int Rep. 2020 Jan 28;5(5):600-610.

[2]. A Phase 3 Trial of Difelikefalin in Hemodialysis Patients With Pruritus. N Engl J Med. 2020 Jan 16;382(3):222-232.

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. 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. 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. 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. Options for therapy are limited - with no FDA-approved treatments, off-label [gabapentin] was the most evidence-based and widely available treatment. 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. Difelikefalin was later approved by the EMA in April 2022 for the same indication.
Difelikefalin is a Kappa Opioid Receptor Agonist. The mechanism of action of difelikefalin is as an Opioid kappa Receptor Agonist.
See also: Difelikefalin Acetate (active moiety of).

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Drug 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.
FDA Label
Kapruvia is indicated for the treatment of moderate-to-severe pruritus associated with chronic kidney disease in adult patients on haemodialysis (see section 5. 1).
Treatment of chronic kidney disease associated pruritus

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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). 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. Although the specifics of the mechanism have yet to be elucidated, 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.

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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. 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.

C36H53N7O6

679.86

679.406

C, 63.60; H, 7.86; N, 14.42; O, 14.12

1024828-77-0

413256-25-2 (1HCl); 1024829-44-4 (acetate); 1024828-77-0; 2711717-77-8 (3HCl); 2742623-88-5 (TFA)

24794466

White to off-white solid powder

4.044

7

9

18

49

1080

4

O([H])C(C1(C([H])([H])C([H])([H])N(C([C@@]([H])(C([H])([H])C([H])([H])C([H])([H])C([H])([H])N([H])[H])N([H])C([C@@]([H])(C([H])([H])C([H])(C([H])([H])[H])C([H])([H])[H])N([H])C([C@@]([H])(C([H])([H])C2C([H])=C([H])C([H])=C([H])C=2[H])N([H])C([C@@]([H])(C([H])([H])C2C([H])=C([H])C([H])=C([H])C=2[H])N([H])[H])=O)=O)=O)=O)C([H])([H])C1([H])[H])N([H])[H])=O

FWMNVWWHGCHHJJ-SKKKGAJSSA-N

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

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

MR-13A9; CR-845; MR-13A-9; MR13A9; CR845; MR13A-9; trade name Korsuva

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO: ~100 mg/mL (~147.1 mM)
H2O: ≥ 100 mg/mL (~147.1 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (3.68 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (3.68 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (3.68 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)