Difelikefalin
(Synonyms: CR-845; FE-202845) 目录号 : GC60137
A κ-opioid receptor agonist
Cas No.:1024828-77-0
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >99.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Difelikefalin is a κ-opioid receptor (KOR) agonist.1 It activates KOR in HEK293 cells expressing the human receptor (EC50 = 0.16 nM in a transactivation assay) and inhibits forskolin-induced cAMP production in R1.G1 mouse thyoma cells (EC50 = 0.048 nM). Difelikefalin is selective for KOR over the μ-opioid receptor (MOR; EC50 = >1 ?M in a transactivation assay). It reduces acetic acid-induced writhing, as well as scratching behavior induced by the KOR antagonist GNTI, in mice (ED50s = 0.07 and 0.05 mg/kg, respectively).
1.Schteingart, C.D., Menzaghi, F., Jiang, G., et al.Synthetic peptide amides(2008)
| Cas No. | 1024828-77-0 | SDF | |
| 别名 | CR-845; FE-202845 | ||
| Canonical SMILES | O=C(C1(N)CCN(C([C@@H](CCCCN)NC([C@@H](CC(C)C)NC([C@@H](CC2=CC=CC=C2)NC([C@@H](CC3=CC=CC=C3)N)=O)=O)=O)=O)CC1)O | ||
| 分子式 | C36H53N7O6 | 分子量 | 679.85 |
| 溶解度 | DMSO : 100 mg/mL (147.09 mM; Need ultrasonic); H2O : ≥ 100 mg/mL (147.09 mM) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 1.4709 mL | 7.3546 mL | 14.7091 mL |
| 5 mM | 0.2942 mL | 1.4709 mL | 2.9418 mL |
| 10 mM | 0.1471 mL | 0.7355 mL | 1.4709 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Difelikefalin: First Approval
Drugs 2021 Nov;81(16):1937-1944.PMID:34674115DOI:10.1007/s40265-021-01619-6.
Difelikefalin (Korsuva™) is a synthetic peptide agonist of the kappa opioid receptor being developed by Cara Therapeutics for the treatment of pruritus. In August 2021, intravenous Difelikefalin was approved in the USA for the treatment of moderate-to-severe pruritus associated with chronic kidney disease (CKD) in adults undergoing haemodialysis. Intravenous Difelikefalin has also been evaluated for CKD-associated pruritus in patients undergoing haemodialysis in various other countries, with Marketing Authorization Application under regulatory review in the EU and a phase III trial ongoing in Japan. Clinical studies of an oral formulation of Difelikefalin have also been completed or are underway in pruritus indications, including pruritus associated with atopic dermatitis, notalgia paraesthetica or primary biliary cholangitis. This article summarizes the milestones in the development of Difelikefalin leading to this first approval for CKD-associated pruritus in adults undergoing haemodialysis.
A Phase 3 Trial of Difelikefalin in Hemodialysis Patients with Pruritus
N Engl J Med 2020 Jan 16;382(3):222-232.PMID:31702883DOI:10.1056/NEJMoa1912770.
Background: Difelikefalin is a peripherally restricted and selective agonist of kappa opioid receptors that are considered to be important in modulating pruritus in conditions such as chronic kidney disease. Methods: In this double-blind, placebo-controlled, phase 3 trial, we randomly assigned patients undergoing hemodialysis who had moderate-to-severe pruritus to receive either intravenous Difelikefalin (at a dose of 0.5 μg per kilogram of body weight) or placebo three times per week for 12 weeks. The primary outcome was the percentage of patients with an improvement (decrease) of at least 3 points from baseline at week 12 in the weekly mean score on the 24-hour Worst Itching Intensity Numerical Rating Scale (WI-NRS; scores range from 0 to 10, with higher scores indicating greater itch intensity). The secondary outcomes included the change from baseline in itch-related quality-of-life measures, the percentage of patients with an improvement of at least 4 points in the WI-NRS score at week 12, and safety. Results: A total of 378 patients underwent randomization. A total of 82 of 158 patients (51.9%) in the Difelikefalin group had a decrease of at least 3 points in the WI-NRS score (primary outcome), as compared with 51 of 165 (30.9%) in the placebo group. The imputed percentage of patients with a decrease of at least 3 points in the WI-NRS score was 49.1% in the Difelikefalin group, as compared with 27.9% in the placebo group (P<0.001). Difelikefalin also resulted in a significant improvement from baseline to week 12 in itch-related quality of life as measured by the 5-D itch scale and the Skindex-10 scale. The imputed percentage of patients with a decrease of at least 4 points in the WI-NRS score at week 12 was significantly greater in the Difelikefalin group than in the placebo group (37.1% [observed data: 64 of 158 patients] vs. 17.9% [observed data: 35 of 165 patients], P<0.001). Diarrhea, dizziness, and vomiting were more common in the Difelikefalin group than in the placebo group. Conclusions: Patients treated with Difelikefalin had a significant reduction in itch intensity and improved itch-related quality of life as compared with those who received placebo. (Funded by Cara Therapeutics; KALM-1 ClinicalTrials.gov number, NCT03422653.).
Difelikefalin for pruritus associated with renal disease
Drugs Today (Barc) 2022 Sep;58(9):427-435.PMID:36102903DOI:10.1358/dot.2022.58.9.3425323.
Chronic kidney disease-associated pruritus (CKD-aP) has been recognized for over a century. The complex pathophysiology of CKD-aP makes it challenging to find an effective treatment; the proposed therapeutic options come from anecdotal reports and small clinical trials, which at best compare the test drug against placebo. Gabapentinoids have shown relevant efficacy but there are serious safety concerns about their possible central nervous system toxicity. Recently Difelikefalin, a κ-opioid receptor agonist, has been the first Food and Drug Administration (FDA)-approved drug for moderate-severe CKD-aP treatment. Approval from other regulatory agencies is expected in 2022. In this article, preclinical, pharmacokinetic and safety studies on Difelikefalin are reported, but a great part of the data derive from meeting abstracts and non-peer-review communications and this is a possible cause for concern regarding bias in publication. A review of published and unpublished studies about Difelikefalin in CKD-aP treatment is provided. Currently, two published large trials show that Difelikefalin offers a new therapeutic opportunity to treat CKD-aP, a condition that leads to both worse survival and quality of life in hemodialysis patients.
Efficacy and Safety of Difelikefalin in Japanese Patients With Moderate to Severe Pruritus Receiving Hemodialysis: A Randomized Clinical Trial
JAMA Netw Open 2022 May 2;5(5):e2210339.PMID:35511180DOI:10.1001/jamanetworkopen.2022.10339.
Importance: Patients with pruritus receiving hemodialysis frequently experience oppressive physical and psychiatric symptoms that directly affect their quality of life and increase mortality. However, treatment options are limited. Objective: To determine the clinically recommended dose of Difelikefalin, a κ-opioid receptor agonist, based on the efficacy, dose response, safety, and pharmacokinetics. Design, setting, and participants: This randomized, double-blind, placebo-controlled, 4-arm phase 2 trial was conducted from February 1, 2019, to October 22, 2019, at 94 sites in Japan. Patients with moderate to severe pruritus receiving hemodialysis were enrolled. Interventions: Difelikefalin (0.25, 0.5, and 1.0 μg/kg) and placebo were intravenously administered 3 times a week at the end of each hemodialysis session for 8 weeks. Main outcome and measures: The primary end point was the change from baseline in the weekly mean Worst Itching Intensity Numerical Rating Scale (NRS) score at week 8. Secondary outcomes measured changes in itch-related quality-of-life score using the Skindex-16 and 5-D itch scale. Safety was assessed according to adverse events, laboratory tests, vital signs, body weight, and 12-lead electrocardiogram. Results: A total of 247 Japanese patients (186 male [75%]; mean [SD] age, 64.5 [11.7] years) were randomized to placebo (n = 63), 0.25 μg/kg of Difelikefalin (n = 61), 0.5 μg/kg of Difelikefalin (n = 61), or 1.0 μg/kg of Difelikefalin (n = 62). The changes from baseline in the adjusted mean (SE) of the 24-hour Worst Itching Intensity NRS score at week 8 were -2.86 (0.29) in the placebo group, -2.97 (0.29) in the 0.25 μg/kg of Difelikefalin group, -3.65 (0.30) in the 0.5 μg/kg of Difelikefalin group, and -3.64 (0.30) in the 1.0 μg/kg of Difelikefalin group. Significant differences were found in the 0.5 μg/kg of Difelikefalin group (adjusted mean difference, -0.80; 95% CI, -1.55 to -0.04; P = .04) and the 1.0 μg/kg of Difelikefalin group (adjusted mean difference, -0.78; 95% CI, -1.54 to -0.03; P = .04) compared with placebo. The Skindex-16 overall score and 5-D itch scale total score indicated an improvement with treatment with 0.5 and 1.0 μg/kg of Difelikefalin (adjusted weekly mean [SE] Skindex-16 overall score at week 8, -27.79 [2.05]; 95% CI, -31.83 to -23.74 for 0.5 μg/kg of Difelikefalin and -22.69 [2.04]; 95% CI, -26.71 to -18.68 for 1.0 μg/kg of Difelikefalin; adjusted weekly mean [SE] 5-D itch scale total score at week 8, -6.5 [0.4]; 95% CI, -7.2 to -5.8 for 0.5 μg/kg of Difelikefalin and -6.8 [0.3]; 95% CI, -7.5 to -6.2 for 1.0 μg/kg of Difelikefalin). The incidence of adverse events was 67% (42 of 63 patients) in the placebo group, 72% (44 of 61 patients) in the 0.25 μg/kg of Difelikefalin group, 77% (47 of 61 patients) in the 0.5 μg/kg of Difelikefalin group, and 85% (53 of 62 patients) in the 1.0 μg/kg of Difelikefalin group. No dependency was reported. Conclusions and relevance: The findings of this phase 2 randomized clinical trial of Difelikefalin suggest that 0.5 μg/kg of Difelikefalin should be the clinically recommended dose as a new option for treating moderate to severe pruritus in patients undergoing hemodialysis because of its efficacy, acceptable tolerability, and manageable safety profile. Trial registration: ClinicalTrials.gov Identifier: NCT03802617.
Difelikefalin in the Treatment of Chronic Kidney Disease-Associated Pruritus: A Systematic Review
Pharmaceuticals (Basel) 2022 Jul 28;15(8):934.PMID:36015082DOI:10.3390/ph15080934.
Chronic kidney disease-associated pruritus (CKD-aP) is a chronic condition that significantly reduces the quality of life of patients with end-stage renal disease. The etiology is not fully understood, but imbalance in the activity of the opioid pathways, including downregulation of the kappa-opioid receptor, may contribute to itching sensation. Difelikefalin is a selective, peripherally acting kappa-opioid receptor (KOR) agonist. Recently, Difelikefalin has been approved as a first drug for the treatment of pruritus associated with chronic kidney disease (CKD) in adult hemodialysis patients. A systematic review of currently available clinical trials was performed to assess the efficacy and safety of Difelikefalin in patients with uremic pruritus. A literature review was conducted in May 2022 based on the PRISMA 2020 guidelines. The analyzed clinical trials showed that Difelikefalin was effective in reducing pruritus in patients as assessed by the Worst Itching Intensity Numerical Rating Scale. Improvement in quality of life assessed on the basis of the Skindex score and the 5-D itch scale was also noticed. The most commonly reported side effects were mild and included nausea, vomiting, dizziness, and diarrhea. Due to its proven efficacy and good safety profile, Difelikefalin is a promising drug for the treatment of pruritus in patients with chronic kidney disease.