Casopitant mesylate
(Synonyms: GW679769B) 目录号 : GC62888
Casopitant mesylate (GW679769B) 是一种有效的，选择性的，脑通透性和口服活性神经激肽 1 (NK1) 受体拮抗剂。Casopitant mesylate 是第二类止吐药，可拮抗 substance P 的催吐作用。Casopitant mesylate 也是一种 CYP3A4 的底物和弱至中度抑制剂。Casopitant mesylate 可用于化疗引起的恶心和呕吐 (CINV) 和术后恶心和呕吐 (PONV)。
Cas No.:414910-30-8
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Casopitant mesylate (GW679769B) is a potent, selective, brain permeable and orally active neurokinin 1 (NK1) receptor antagonist. Casopitant mesylate is a second in the class of antiemetics that acts to antagonise the emetogenic effect of substance P. Casopitant mesylate is also a substrate and a weak-to-moderate inhibitor of CYP3A4. Casopitant mesylate can be used for chemotherapy-induced nausea and vomiting (CINV) and postoperative nausea and vomiting (PONV)[1][2].
In a ferret-model of Cisplatin- induced emesis, Casopitant (GW679769) inhibits retching and vomiting and reduced nausea-like behaviours in a dose-dependent manner. The pharmacokinetics and brain penetration of casopitant are studied in the ferret-model of cisplatin-induced emesis. Following a single intraperitoneal dose, radioactive labeled Casopitant ([14C]Casopitant) is rapidly absorbed, with plasma and brain concentrations being approximately equal at two hours post-dosing. [14C]Casopitant is found in the brain as the parent compound and two major oxidative metabolites (M1 and M2), accounting for approximately 76%, 19%, and 3% of the radioactivity, respectively; suggesting that the pharmacologic activity of Casopitant in the ferret is largely attributable to the parent compound. Casopitant possesses a high affinity for brain NK1 receptors in the ferret[2].
[1]. Ruhlmann C, et al. Casopitant: a novel NK(1)-receptor antagonist in the prevention of chemotherapy-induced nausea and vomiting. Ther Clin Risk Manag. 2009 Apr;5(2):375-84.
[2]. Minthorn E, et al. Pharmacokinetics and brain penetration of casopitant, a potent and selective neurokinin-1 receptor antagonist, in the ferret. Drug Metab Dispos. 2008 Sep;36(9):1846-52.
| Cas No. | 414910-30-8 | SDF | |
| 别名 | GW679769B | ||
| 分子式 | C31H39F7N4O5S | 分子量 | 712.72 |
| 溶解度 | 储存条件 | ||
| 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 | 1.4031 mL | 7.0154 mL | 14.0308 mL |
| 5 mM | 0.2806 mL | 1.4031 mL | 2.8062 mL |
| 10 mM | 0.1403 mL | 0.7015 mL | 1.4031 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。
Efficacy and safety of Casopitant mesylate, a neurokinin 1 (NK1)-receptor antagonist, in prevention of chemotherapy-induced nausea and vomiting in patients receiving cisplatin-based highly emetogenic chemotherapy: a randomised, double-blind, placebo-controlled trial
Lancet Oncol 2009 Jun;10(6):549-58.PMID:19428297DOI:10.1016/S1470-2045(09)70109-3.
Background: Chemotherapy-induced nausea and vomiting (CINV) remains a clinical management problem after treatment with highly emetogenic chemotherapy (HEC). We therefore designed and carried out a multicentre, randomised, double-blind, placebo-controlled trial to assess whether a three-drug antiemetic regimen of ondansetron, dexamethasone, and the neurokinin-1-receptor antagonist Casopitant mesylate was able to prevent acute and delayed CINV events in patients naive to chemotherapy with a malignant solid tumour who were scheduled to receive cisplatin-based HEC regimens. Methods: The study was done between Nov 6, 2006, and Oct 9, 2007, in 77 participating centres in 22 countries. All 810 patients enrolled in the trial received dexamethasone and ondansetron. Patients were randomly assigned to also receive placebo (n=269), single oral dose of Casopitant mesylate (150 mg oral, n=271), or 3-day intravenous plus oral Casopitant mesylate (90 mg intravenous on day 1 plus 50 mg oral on days 2 and 3, n=270). Randomisation was done using a central telephone system at the study level, because some centres were expected to recruit only a few patients during the study period. The primary endpoint was the proportion of patients achieving complete response (no vomiting, retching, or use of rescue medications) in the first 120 h after receiving HEC. Efficacy analysis was done on the modified intention-to-treat population (n=800), which included all patients who received placebo or study drug and HEC (n=265 control, n=266 single-dose oral Casopitant mesylate, n=269 3-day intravenous and oral Casopitant mesylate). Safety was reported in 802 patients who received either placebo or study medication. This study is registered with ClinicalTrials.gov, NCT00431236. Findings: Significantly more patients in each casopitant group achieved complete response in cycle 1 of HEC treatment than did those in the control group (175 [66%] patients in the control group, 228 [86%] in the single-dose oral Casopitant mesylate group [p<0.0001 vs control], and 214 [80%] in the 3-day intravenous plus oral Casopitant mesylate group (p=0.0004 vs control]). This improvement was sustained over multiple cycles of HEC. Adverse events occurred in 205 (77%) patients in the single-dose oral Casopitant mesylate group and 203 (75%) patients in the 3-day intravenous and oral Casopitant mesylate group compared with 194 (73%) of patients in the control group. The most common serious adverse events were neutropenia (n=5 [3%] in the control group, n=3 [1%] in the single-dose oral Casopitant mesylate group, and n=11 [4%] in the 3-day intravenous plus oral Casopitant mesylate group), febrile neutropenia (n=1 [<1%] in the control group, n=4 [1%] in the single-dose oral Casopitant mesylate group, and n=6 [2%] in the 3-day intravenous plus oral Casopitant mesylate group), and dehydration (n=4 [2%] in the control group, n=2 [<1%] in the single-dose oral Casopitant mesylate group, and n=1 [<1%] in the 3-day intravenous plus oral Casopitant mesylate group). Interpretation: A three-drug regimen including a single oral dose or 3-day intravenous plus oral regimen of Casopitant mesylate plus dexamethasone and ondansetron significantly reduced CINV events in patients receiving HEC compared with a two-drug regimen of dexamethasone and ondansetron. Funding: GlaxoSmithKline.
Casopitant and ondansetron for postoperative nausea and vomiting prevention in women at high risk for emesis: a phase 3 study
Arch Surg 2011 Feb;146(2):201-6.PMID:21339433DOI:10.1001/archsurg.2010.327.
Hypothesis: Postoperative nausea and vomiting (PONV) are associated with a variety of complications. Neurokinin subtype 1 receptor antagonists have antiemetic activity in the postoperative setting, and the neurokinin subtype 1 receptor antagonist Casopitant mesylate (GW679769) was well tolerated and effective at reducing the incidence of PONV in phase 1 and phase 2 trials. Design: A multicenter, randomized, double-blind, parallel-group, phase 3 analysis was designed to evaluate the safety and efficacy of casopitant in combination with a single intravenous dose of the serotonin subtype 3 receptor antagonist ondansetron hydrochloride for the prevention of PONV in the perioperative setting. Setting: Forty-three centers in 11 countries. Patients: We studied 484 women at high risk for developing PONV scheduled to undergo operations associated with high emetogenic risk. Interventions: The women were randomized to receive a single dose of intravenous ondansetron, 4 mg, or oral casopitant, 50 mg, in combination with intravenous ondansetron, 4 mg. Main outcome measures: The primary end point was the proportion of patients who achieved a complete response, defined as no vomiting, retching, or rescue therapy. Patients received a balanced anesthetic regimen. Results: Between March 20 and August 31, 2006, 484 patients were enrolled in the study. Patients in the casopitant plus ondansetron group had a 68.7% rate of complete response during the first 24 hours after surgery compared with 58.7% in the ondansetron-only group (P = .03). The difference between groups in complete response from 24 to 48 hours (63.4% with ondansetron only vs 70.0% with ondansetron plus casopitant) was not significant. No vomiting for 0 to 24 hours was observed in 89.7% of the casopitant plus ondansetron group compared with 74.9% of the ondansetron-only group (P < .001). Oral casopitant administered in combination with ondansetron was well tolerated. Conclusions: The results of this pivotal phase 3 study demonstrate that the combination of casopitant and ondansetron was superior to ondansetron only in patients at high risk for PONV. Trial Registration clinicaltrials.gov Identifier: NCT00326248.
Randomized, double-blind, dose-ranging trial of the oral neurokinin-1 receptor antagonist Casopitant mesylate for the prevention of cisplatin-induced nausea and vomiting
Ann Oncol 2009 Nov;20(11):1867-73.PMID:19541792DOI:10.1093/annonc/mdp194.
Background: Casopitant mesylate is a novel, oral neurokinin-1 receptor antagonist with demonstrated antiemetic efficacy. We conducted a randomized, double-blind, controlled phase II trial to evaluate three casopitant doses as part of a triple-therapy regimen for the prevention of nausea and vomiting associated with high-dose cisplatin. The aim of the study was to detect a dose response. Patients and methods: A total of 493 patients with solid tumors receiving a first cycle of cisplatin > or =70 mg/m(2) were randomly assigned among six treatment arms. The primary analysis compared a control arm [ondansetron/dexamethasone (Ond/Dex)] with three investigational treatments (Ond/Dex plus oral casopitant 50, 100, or 150 mg administered daily for 3 days). Two exploratory arms were included: one evaluating a single oral casopitant dose of 150 mg added to standard Ond/Dex and another with 3-day oral aprepitant-based therapy (Ond/Dex plus aprepitant 125 mg day 1, 80 mg days 2-3). Results: The complete response (CR) rate (defined as no vomiting, retching, rescue therapy, or premature discontinuation) was significantly increased in each casopitant arm relative to control over the 120-h evaluation period: 76% (50 mg), 86% (100 mg), 77% (150 mg), and 60% with control (P = 0.0036). The CR rate for the single oral dose regimen was similar to the CR rate reported for the 3-day regimens. No differences were observed in the incidence of nausea or significant nausea among groups in the primary analysis. The most common adverse events related to treatment included headache (n = 10) and hiccups (n = 14). Conclusion: All doses of oral casopitant as a 3-day regimen (and likely as a 150-mg single oral dose) in combination with Ond/Dex provided significant improvement in the prevention of cisplatin-induced emesis.
Quantitation of a de-fluorinated analogue of Casopitant mesylate by normal-phase liquid chromatography/mass spectrometry
Rapid Commun Mass Spectrom 2010 Sep 15;24(17):2650-4.PMID:20740542DOI:10.1002/rcm.4688.
The introduction of Quality by Design (QbD) in Drug Development has resulted in a greater emphasis on chemical process understanding, in particular on the origin and fate of impurities. Therefore, the identification and quantitation of low level impurities in new Active Pharmaceutical Ingredients (APIs) play a crucial role in project progression and this has created a greater need for sensitive and selective analytical methodology. Consequently, scientists are constantly challenged to look for new applications of traditional analytical techniques. In this context a normal-phase liquid chromatography/electrospray ionization mass spectrometry (LC/ESI-MS) method was developed to determine the amount of a de-fluorinated analogue impurity in Casopitant mesylate, a new API under development in GlaxoSmithKline, Verona. Normal-phase LC provided the selectivity needed between our target analyte and Casopitant, while a single quadrupole mass spectrometer was used to ensure the sensitivity needed to detect the impurity at <0.05%w/w. Standard solutions and samples were prepared in heptane/ethanol (50:50, v/v) containing 1% of 2 M NH(3) in ethanol; the mobile phase consisted of heptane/ethanol (95:5, v/v) with isocratic elution (flow rate: 1.0 mL/min, total run time: 23 min). To allow the formation of ions in solutions under normal-phase (apolar) conditions, a post-column infusion of a solution of 0.1% v/v of formic acid in methanol was applied (flow rate: 200 microL/min). The analysis was carried out in positive ion mode, monitoring the impurity by single ion monitoring (SIM). The method was fully validated and its applicability was demonstrated by the analysis of real-life samples. This work is an example of the need for selective and accurate methodology during the development of a new chemical entity in order to develop an appropriate control strategy for impurities to ultimately ensure patient safety.
Phase 2 trial results with the novel neurokinin-1 receptor antagonist casopitant in combination with ondansetron and dexamethasone for the prevention of chemotherapy-induced nausea and vomiting in cancer patients receiving moderately emetogenic chemotherapy
Cancer 2009 Dec 15;115(24):5807-16.PMID:19834961DOI:10.1002/cncr.24630.
Background: This randomized, double-blind, dose-ranging, placebo-controlled, phase 2 trial evaluated the neurokinin-1 receptor antagonist Casopitant mesylate in combination with ondansetron/dexamethasone (ond/dex) for the prevention of chemotherapy-induced nausea and vomiting (CINV) related to moderately emetogenic chemotherapy (MEC). Methods: Chemotherapy-naive patients who were receiving MEC (N=723) were randomized to receive either oral placebo or casopitant at doses of 50 mg, 100 mg, or 150 mg daily (on Days 1-3) plus ondansetron (on Days 1-3) and dexamethasone (Day 1). Two exploratory arms evaluated single-dose casopitant (150 mg) plus ond/dex and a 3-day casopitant regimen with once-daily ondansetron and dexamethasone. Primary endpoints were rates of complete response (CR) (no vomiting, retching, rescue therapy, or premature discontinuation) and significant nausea (SN) (>or=25 mm on a visual analog scale) over the first 120 hours after Cycle 1 of MEC. Secondary endpoints included acute and delayed CR and SN rates, rates of nausea, vomiting, and safety. Results: All casopitant doses that were tested significantly increased the proportion of patients with CR: The CR rates were 80.8% with casopitant 50 mg, 78.5% with casopitant 100 mg, and 84.2% with casopitant 150 mg compared with 69.4% in the control group (P=.0127); casopitant 150 mg was identified as the minimally effective dose. In exploratory analyses, single-dose casopitant demonstrated a 79.2% CR rate, and once-daily ondansetron plus casopitant produced an 83.5% CR rate. Vomiting rates in the first 5 days after MEC were reduced with casopitant-containing regimens (from 23% to 10%-16%). Rates of SN did not differ among treatment arms (range, 28%-29%). Casopitant appeared to be well tolerated with no notable differences in overall adverse event frequency. Conclusions: Casopitant plus ond/dex was more effective than ond/dex alone for the prevention of CINV.