福奈妥匹坦 | 1703748-89-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 中文名称: 福奈妥匹坦
• 英文名称: 4-(5-(2-(3,5-bis(trifluoromethyl)phenyl)-N,2-dimethylpropanamido)-4-(o-tolyl)pyridin-2-yl)-1-methyl-1-((phosphonooxy)methyl)piperazin-1-ium
• 英文别名: fosnetupitant；Fosnetupitant；[4-[5-[[2-[3,5-bis(trifluoromethyl)phenyl]-2-methylpropanoyl]-methylamino]-4-(2-methylphenyl)pyridin-2-yl]-1-methylpiperazin-1-ium-1-yl]methyl hydrogen phosphate
• CAS: 1703748-89-3
• 化学式: C₃₁H₃₅F₆N₄O₅P
• 分子量: 688.607
• InChiKey: HZIYEEMJNBKMJH-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5
• 重原子数：
  47
• 可旋转键数：
  8
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  106
• 氢给体数：
  1
• 氢受体数：
  13

ADMET

代谢

Fosnetupitant 是 [netupitant] 的前药。Netupitant 是 CYP3A4 的中等抑制剂和底物。在接受主要通过 CYP3A4 系统代谢的并发药物治疗的患者中应谨慎使用 Akynzeo。一剂量的 netupitant 300 mg 可显著抑制 CYP3A4 约 6 天。建议在 1 周内避免使用 CYP3A4 底物的药物。如果不可能，考虑减少 CYP3A4 底物的剂量。在人类、大鼠、狗、小型猪和卷尾猴的肝微粒体培养中，除了羟基化产物 (M3) 之外，还鉴定出两种主要代谢物，一种 _N-脱甲基产物 (M1)_ 和一种 _N-氧化产物 (M2)_，在所有物种中都有发现。发现 CYP3A4 负责将 netupitant 氧化为在人类肝微粒体培养中也观察到的相同代谢物。代谢是广泛的，代谢物通常在 24 小时内达到比母药更高的浓度。在大鼠中，M1 和 M2 的暴露与人类相似，但在狗中更高，然而 M3 在这两种物种中都低于人类。

Fosnetupitant is the prodrug of [netupitant]. Netupitant is a moderate inhibitor and substrate of CYP3A4. Akynzeo should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4 systems. One dose of netupitant 300 mg significantly inhibits CYP3A4 for about 6 days. It is avisable to avoid concomitant use of drugs that are CYP3A4 substrates for one week. If not possible, consider dose reduction of CYP3A4 substrates. In the human, rat, dog, minipig and marmoset liver microsomal incubations, two major metabolites, an _N-demethylation product (M1) _and an _N-oxidation product (M2)_, in addition to hydroxylation products (M3), were identified in all species. CYP3A4 was found to be responsible for the oxidation of netupitant to the same metabolites observed also in the incubations with human liver microsomes. Metabolism was extensive, with the metabolites generally achieving greater concentrations than parent drug witin 24 hours. M1 and M2 exposure was similar in rat to humans, but higher in dogs, however M3 was lower in both species than in humans.

来源:DrugBank

毒理性

• 毒性总结

阿克洋胶丸最常见的副作用（≥3%）包括头痛、乏力、消化不良、疲劳、便秘和红斑。阿克洋注射剂的安全性概况通常与阿克洋胶丸相似。目前，正在接受蒽环类药物加环磷酰胺治疗的患者中进行重复剂量安全性研究，以进一步建立这种情况下安全性概况。

Most common adverse reactions (≥3%) for AKYNZEO capsules are headache, asthenia, dyspepsia, fatigue, constipation and erythema. The safety profile of Akynzeo for injection is generally similar to that seen with Aynzeo capsules,. Currently a repeated dose safety study is ongoing in patients receiving anthracycline plus cyclophosphamide to further establish the safety profile in this setting.

来源:DrugBank

毒理性

• 蛋白质结合

Netupitant 在所有物种中的血浆蛋白结合率非常高（>99%）。

Netupitant is highly bound (>99%) to plasma proteins in all species.

来源:DrugBank

吸收、分配和排泄

• 吸收

在患者中静脉注射单剂量阿克佐约（235毫克福司妥皮坦和0.25毫克帕洛诺司琼，30分钟内输注）或健康受试者中静脉注射福司妥皮坦（235毫克福司妥皮坦，30分钟内输注），福司妥皮坦的最大浓度在30分钟输注结束时达到。在大鼠、狗和猴子中，每种动物的口服生物利用度差异很大，分别为42-105%，34-83%和37-62%。这种大的变异最可能是由于研究中使用的动物数量较少。

Following single intravenous doses of Akynzeo for injection in patients (235 mg fosnetupitant and 0.25 mg palonosetron infused in 30 minutes) or fosnetupitant in healthy subjects (235 mg fosnetupitant infused in 30 minutes), maximum concentration of fosnetupitant was achieved at the end of the 30-minute infusion. Oral bioavailability in each species varied substantially between animals, with 42-105%, 34-83% and 37-62% in rats, dogs, and monkeys. The large variation is most likely due to the low numbers of animals used in the studies.

来源:DrugBank

吸收、分配和排泄

• 消除途径

单次口服给予[14C]­netupitant后，约一半的放射性活性在给药后120小时内通过尿液和粪便排出。在336小时内收集的尿液和粪便中分别测量到总放射性剂量的3.95%和70.7%，口服netupitant剂量的平均不变部分在尿液中的排泄量不到1%，这意味着肾清除不是netupitant相关实体的重要消除途径。大约86.5%和4.7%的给予放射性活性估计在给药后30天内通过粪便和尿液排出。

After one oral dose of [14C]­netupitant, approximately one-half of the administered radioactivity was measured in the urine and feces within 120 hours of the dose. The total of 3.95% and 70.7% of the radioactive dose was measured in the urine and feces collected over 336 hours, respectively, and the average fraction of an oral dose of netupitant excreted unchanged in urine is under 1%, implying that renal clearance is not a significant route of elimination for the netupitant-related entities. About 86.5% and 4.7% of administered radioactivity was estimated to be excreted via the feces and urine within 30 days post-dose.

来源:DrugBank

吸收、分配和排泄

• 分布容积

健康受试者和患者中福司奈替坦的平均分布体积分别为124 +/- 76升和296 +/- 535升。

The mean SD volume of distribution of fosnetupitant in healthy subjects and in patients was 124 +/- 76 L and 296 +/- 535 L, respectively.

来源:DrugBank

吸收、分配和排泄

• 清除

Netupitant单次口服Akynzeo后，平均预估的系统清除率为0.3 ± 9.2 L/h（平均值 ± 标准差）。

Netupitant has a mean estimated systemic clearance of 0.3 ± 9.2 L/h (mean ± SD) after a single oral dose of Akynzeo.

来源:DrugBank

反应信息

• 作为反应物：
  描述：

  福奈妥匹坦 在 盐酸 作用下， 以 1,4-二氧六环 、 甲醇 、 二氯甲烷 为溶剂， 反应 3.0h， 生成 盐酸磷奈妥匹坦*
  参考文献：
  名称：

  JP2015/17121

  摘要：

  公开号：

文献信息

• Crystalline forms of fosnetupitant
  申请人：Helsinn Healthcare SA

  公开号：US10005803B2

  公开（公告）日：2018-06-26

  The present invention provides crystalline forms of the chloride monohydrochloride salt of fosnetupitant, methods of making the crystalline forms, and pharmaceutical dosage forms that make use of the crystalline forms.

  本发明提供了福斯硝普坦氯单盐酸盐的结晶形式、结晶形式的制造方法以及使用结晶形式的药物剂型。
• Pharmaceutical compositions and methods utilizing neostigmine and an NK-1 antagonist for treating myasthenia gravis
  申请人：DAS-MG, Inc.

  公开号：US11389420B2

  公开（公告）日：2022-07-19

  The present invention describes the use of a NK1-antagonist, in constant combination with neostigmine, to facilitate the treatment of a patient suffering from myasthenia gravis by providing a therapeutically effective neostigmine bromide or methylsulfate daily dose without the dose-limiting gastrointestinal adverse effects.

  本发明描述了一种 NK1-拮抗剂与新斯的明的恒定组合使用，通过提供治疗有效的溴化新斯的明或硫酸甲酯每日剂量而无剂量限制性胃肠道不良反应，从而促进对患有重症肌无力的患者的治疗。
• CRYSTALLINE FORMS OF FOSNETUPITANT
  申请人：Helsinn Healthcare SA

  公开号：EP3359547B1

  公开（公告）日：2020-07-22
• PHYSIOLOGICALLY BALANCED INJECTABLE FORMULATIONS OF FOSNETUPITANT
  申请人：Helsinn Healthcare SA

  公开号：EP3435980B1

  公开（公告）日：2019-11-13
• Crystalline Forms of Fosnetupitant
  申请人：Helsinn Healthcare SA

  公开号：US20170096442A1

  公开（公告）日：2017-04-06

  The present invention provides crystalline forms of the chloride monohydrochloride salt of fosnetupitant, methods of making the crystalline forms, and pharmaceutical dosage forms that make use of the crystalline forms.