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2010年11月,美国FDA批准了治疗转移性乳腺癌新药甲磺酸艾日布林(eribulin mesylate)。本品是软海绵素B经结构优化后的大环酮类似物,适用人群为至少接受过2种化疗方案(含蒽环类和紫杉类化疗药物)的转移性乳腺癌患者。《抗转移性乳腺癌新药甲磺酸艾日布林》     

甲磺酸艾日布林(Halaven)注射液

由Eisai公司研发的甲磺酸艾日布林注射液于2010年11月15日获得FDA批准在美国上市。该注射液用于治疗已经接受过至少2种化疗方案治疗的转移性乳腺癌患者[1]。Halaven的主要成分是甲磺酸艾日布林(eribulin me-sylate)。化学名称:2-(3-amino-2-hydroxypropyl)hexacosa-hydro-3-methoxy-26-methyl-20,27-bis(methylene)-11,15-     

甲磺酸艾日布林注射液

由Eisai公司研发的甲磺酸艾日布林注射液于 2010年11月15 日获得 FDA 批准在美国上市。该注射液用于治疗已经接受过至少2种化疗方案治疗的转移性乳腺癌患者。Halaven 的主要成分是甲磺酸艾日布林(Eribulin mesylate)。化学名称：2-(3-amino-2- hydroxypropyl)hexacosahydro-3-methoxy-26-methyl-20,27-bis(methylene)-11,15-18,21-24,28-triepoxy-7,9-ethano-12,15-methano-9H,15H-furo[3,2-i]furo[2′,3′-5,6]pyrano[4,3-b][1,4]dioxacyclopentacosin-5(4H)-one, methanesulfonate(salt)；分子式：C₄₀H₅₉NO_11·CH₄O₃S；分子量：826.0(游离碱分子量：729.9)；CAS 登记号：441045-17-6，253128-41-5(游离碱)。     

世界海洋药物现状与发展趋势

近年来,美国食品药品管理局(FDA)/欧洲医药管理局(EMA)连续批准了5个海洋药物(齐考诺肽,Ω-3-脂肪酸乙酯,曲贝替定,甲磺酸艾日布林和阿特赛曲斯)上市,预示着海洋药物的发展迎来了新的机遇。本文就国内外海洋药物的现状和发展趋势进行归纳和梳理,并对我国海洋药物发展和产业化中存在的问题进行探讨。     

乳腺癌治疗药甲磺酸艾日布林

Eisai公司研发的非紫衫烷类微管抑制剂甲磺酸艾日布林注射剂（商品名：Halven）于2010年11月获美国FDA批准用于治疗曾接受至少2种抗癌药物,包括蒽环类和紫衫烷类药物治疗的转移性乳腺癌患者。其可基于微管蛋白的抗有丝分裂机制,使细胞周期停滞于G2／M期,破坏有丝分裂纺锤体,最终诱导肿瘤细胞凋亡。     

新的化疗药Halaven获FDA批准用于治疗脂肪肉瘤

美国FDA于2016年1月28日批准一种化疗药Halaven(eribulin mesylate,甲磺酸艾瑞布林),治疗脂肪肉瘤(STS,软组织肉瘤特定类型),无法通过手术(切除)或者晚期(转移性)瘤。这种治疗被批准在先前接受过蒽环类药物的化疗患者。Halaven是首个治疗脂肪肉瘤批准的药物,并证明对生存时间有改善。(源自:药品资讯网)     

2010年美国食品与药品管理局批准的新分子实体药物研究概况

目的:介绍2010年美国食品与药品管理局(FDA)批准的新分子实体药物(NMEs)的研究概况。方法:检索FDA官方网站、Pubmed数据库及有关文献,分别对2010年FDA批准的NMEs的专利名、通用名、适应证等相关信息进行统计、分析。结果与结论:批准的11种NMEs包括心血管系统药物聚多卡醇注射剂(商品名:Asclera)与达比加群酯胶囊(商品名:Pradaxa),内分泌代谢药物利拉鲁肽注射剂(商品名:Victoza)与替莫瑞林注射剂(商品名:Egrifta),生殖系统药物地诺孕素和戊酸雌二醇酯复方片剂(商品名:Natazia)与醋酸乌力司他片剂(商品名:Ella),抗肿瘤药物卡巴他赛注射剂(商品名:Jevtana)与甲磺酸艾日布林注射剂(商品名:Halaven),神经系统药物芬戈莫德片剂(商品名:Gilenya),精神类药物盐酸鲁拉西酮片剂(商品名:Latuda)和抗感染药物头孢洛林酯注射剂(商品名:Teflaro),其中芬戈莫德片剂是美国第1个用于一线治疗复发型多发性硬化症的药物。2010年新批准的NMEs在治疗转移性肿瘤的抗肿瘤药物等方面较以前有所突破。     

阿帕替尼治疗三线或以上晚期肺腺癌的近期疗效观察

目的观察甲磺酸阿帕替尼治疗化疗失败的晚期肺腺癌的临床疗效及不良反应。方法 28例患者接受甲磺酸阿帕替尼治疗,500毫克/次,1次/天,口服,若出现严重不可耐受的不良反应,改为250 mg/d,并维持治疗,通过影像学检查评价近期疗效。结果 28例接受甲磺酸阿帕替尼靶向治疗的晚期腺癌患者中,完全缓解(CR)0例,部分缓解(PR)8例,稳定(SD)14例,进展(PD)6例,总有效率为28.6%(8/28),疾病控制率78.6%(22/28)。且肺癌不同转移部位对预后影响均无统计学意义(P均>0.05)。不良反应主要是高血压及蛋白尿,发生率分别为67.9%和46.4%。结论甲磺酸阿帕替尼治疗三线或以上晚期肺腺癌患者近期疗效较好,不良反应可以耐受及控制,可在临床使用并研究其长期疗效及远期不良反应。     

海洋抗肿瘤候选药物普那布林(Plinabulin)及类似物的研究进展孙天文1,2,丁忠鹏1, 王世潇2, 赵建春1,2, 管华诗1,2,

【】 微管蛋白是细胞骨架的重要组成部分,在维持形态、信号传导及有丝分裂等过程中起着重要的作用。普那布林(Plinabulin)是在从海洋焦曲霉菌中分离得到的天然产物 Phenylahistin 结构基础上,经构效关系研究,合成出的二酮哌嗪类微管蛋白抑制剂。普那布林作为抗肿瘤候选药物,目前已进入临床二期研究。近年来,为了获得高效、低毒和生物利用度更高的普那布林衍生物,本领域研究人员进行了大量的优化研究,获得了一些具有更好活性的衍生物。本文就普那布林及其类似物优化的研究进展进行综述。     

甲磺酸伊马替尼新辅助治疗低位直肠恶性间质瘤效果观察

目的 探讨甲磺酸伊马替尼新辅助治疗低位直肠恶性间质瘤的临床效果.方法 对应用甲磺酸伊马替尼新辅助治疗的中晚期低位直肠恶性间质瘤患者42例临床资料进行回顾性分析.结果 术前经新辅助治疗后临床完全缓解(CR)1例,部分缓解(PR)28例,稳定(SD)13例,有效率达76.2％(29/42),无肿瘤进展病例.化疗过程中未发现严重并发症.Ⅱb期患者新辅助治疗的有效率明显高于Ⅲa期和Ⅲb期患者(P＜0.05).27例肿瘤切除患者均恢复良好,未见肿瘤转移病例.结论 甲磺酸伊马替尼新辅助治疗低位直肠恶性间质瘤效果显著,不良反应少,方便易行,值得临床推广.     

eribulin mesylate的药理与临床研究

通过文献回顾,评价eribulin mesylate治疗转移性乳腺癌中的药理作用、药动学、临床研究和安全性。本品作为微管抑制剂,临床试验结果显示,对化疗药物产生多重耐药性的转移性乳腺癌具有很好的疗效,主要的不良反应为中性粒细胞减少症。本品可延长转移性乳腺癌患者的总存活时间,更多的研究有待进一步的评价。     

Eribulin mesylate for the treatment of late-stage breast cancer

INTRODUCTION: Chemotherapy agents, particularly anthracycline and taxane, have demonstrated their significance in metastatic breast cancer. However, improving overall survival in late-stage breast cancer remains a challenge. Eribulin mesylate, a new chemotherapy agent, has a proven significance in this setting. Eribulin mesylate is a synthetic analog of a macrolide isolated from a marine sponge. It inhibits microtubule polymerization, inducing mitosis arrest and apoptosis, and aggregates soluble tubulin in nonproductive form. In Phase II studies, this drug has shown a partial and stable response. The Phase III EMBRACE study showed that eribulin mesylate improved overall survival, compared with the physician's choice of treatment, in women who had received two to five prior chemotherapy regimens, including anthracycline and taxane for advanced breast cancer (median overall survival: 13.1 versus 10.6 months HR 0.81, p = 0.041). This compound is well tolerated. The most common adverse event is neutropenia. AREAS COVERED: This paper provides an introduction to the drug, eribulin mesylate, along with an overview of the current drug market for late-stage breast cancer; it also reviews its pharmacodynamics, pharmacokinetics and clinical efficacy. EXPERT OPINION: Currently, eribulin mesylate is only the third single-agent chemotherapy that has improved overall survival (after anthracycline and taxane) in advanced breast cancer. These results, particularly in heavily pretreated breast cancer, suggest that this drug could become a new standard in the treatment of metastatic breast cancer, and should, therefore, be further developed in its earlier stages.     

Eribulin mesylate for the treatment of late-stage breast cancer

Introduction: Chemotherapy agents, particularly anthracycline and taxane, have demonstrated their significance in metastatic breast cancer. However, improving overall survival in late-stage breast cancer remains a challenge. Eribulin mesylate, a new chemotherapy agent, has a proven significance in this setting. Eribulin mesylate is a synthetic analog of a macrolide isolated from a marine sponge. It inhibits microtubule polymerization, inducing mitosis arrest and apoptosis, and aggregates soluble tubulin in nonproductive form. In Phase II studies, this drug has shown a partial and stable response. The Phase III EMBRACE study showed that eribulin mesylate improved overall survival, compared with the physician's choice of treatment, in women who had received two to five prior chemotherapy regimens, including anthracycline and taxane for advanced breast cancer (median overall survival: 13.1 versus 10.6 months HR 0.81, p = 0.041). This compound is well tolerated. The most common adverse event is neutropenia.

Areas covered: This paper provides an introduction to the drug, eribulin mesylate, along with an overview of the current drug market for late-stage breast cancer; it also reviews its pharmacodynamics, pharmacokinetics and clinical efficacy.

Expert opinion: Currently, eribulin mesylate is only the third single-agent chemotherapy that has improved overall survival (after anthracycline and taxane) in advanced breast cancer. These results, particularly in heavily pretreated breast cancer, suggest that this drug could become a new standard in the treatment of metastatic breast cancer, and should, therefore, be further developed in its earlier stages.     

Pharmacokinetics of eribulin mesylate in patients with solid tumours receiving repeated oral rifampicin

Aim

Eribulin mesylate is a non-taxane microtubule dynamics inhibitor that was recently approved for treatment of metastatic breast cancer. The aim of this study was to determine the effect of rifampicin, a CYP3A4 inducer, on the plasma pharmacokinetics of eribulin in patients with solid tumours.

Methods

An open-label, non-randomized phase I study was carried out. Patients received intravenous 1.4 mg m⁻² eribulin mesylate on days 1 and 15 and oral rifampicin 600 mg on days 9 to 20 of a 28 day cycle. Pharmacokinetic sampling for determination of eribulin plasma concentrations was performed up to 144 h following administration. AUC(0,∞) and C_max for eribulin exposure without or with co-administration of rifampicin were subjected to an analysis of variance (anova) and corresponding 90% confidence intervals (CI) were calculated. Subsequently, patients were allowed to continue eribulin mesylate treatment with 1.4 mg m⁻² eribulin mesylate on days 1 and 8 of a 21 day cycle. Also the adverse event profile and anti-tumour activity were assessed.

Results

Fourteen patients were included and 11 patients were evaluable for pharmacokinetic analysis. Co-administration of rifampicin had no effect on single dose exposure to eribulin (geometric least square means ratio: AUC(0,∞) = 1.10, 90% CI 0.91, 1.34 and C_max = 0.97, 90% 0.81, 1.17). The most common treatment-related grade ≥3 adverse events were grade 3 neutropenia (4/14, 29%), leucopenia and fatigue (both 3/14, 21%).

Conclusions

These results indicate that eribulin mesylate may be safely co-administered with compounds that are CYP3A4 inducers.     

Clinical efficacy of eribulin mesylate for the treatment of metastatic soft tissue sarcoma

Introduction: Metastatic soft tissue sarcoma, a devastating disease, has a median overall survival of only 12–18 months. Treatment options remain scarce. However, eribulin mesylate, a first-in-class halichondrin B-based microtubule dynamics inhibitor, has recently been approved for the management of patients with advanced liposarcoma.

Areas covered: Based on a review of the literature between 2005 and 2017, we present a summary of eribulin mesylate’s mechanism of action and the studies showing its clinical efficacy in locally advanced or metastatic sarcomas.

Expert commentary: Future development includes the definition of a biomarker signature related to patient outcome with eribulin. Further investigation via controlled clinical trials is needed to identify combination regimens that can optimize the efficacy of eribulin while providing an acceptable safety profile in sarcoma patients.     

Eribulin mesylate in patients with refractory cancers: a Phase I study

Eribulin mesylate (Halaven?, E7389) is a synthetic analog of the marine natural product halichondrin B that acts via a mechanism distinct from conventional tubulin-targeted agents. This Phase I study (clinicaltrials.gov identifier: NCT00326950) was the first to investigate eribulin mesylate in Japanese patients. The study determined the recommended dose, MTD, DLTs, safety, pharmacokinetics, and antitumor activity of eribulin administered on Days 1 and 8 of a 21-day cycle in Japanese patients with advanced solid tumors. Fifteen patients received eribulin mesylate 0.7-2.0 mg/m(2) as a 2- to 10-min intravenous injection. Neutropenia was the principal DLT. DLTs were observed in two of six patients treated at 1.4 mg/m(2), and in all three patients at 2.0 mg/m(2). The recommended dose was 1.4 mg/m(2) and the MTD was 2.0 mg/m(2). Neutropenia (67%), lymphocytopenia (20%), febrile neutropenia (33%), and fatigue (13%) were the most common grade 3 or 4 toxicities. Eribulin exhibited triphasic pharmacokinetics with a long terminal half-life, high volume of distribution, and low urinary clearance. Three patients achieved partial responses (two with NSCLC, one with head and neck cancer) at 1.4 mg/m(2) dose level. Eribulin mesylate, administered on Days 1 and 8 of a 21-day cycle, exhibits manageable tolerability at 1.4 mg/m(2). DLT was neutropenia.     

Eribulin mesylate for the treatment of breast cancer

Importance of the field: Breast cancer is the most common cause of cancer-related death among women in the USA, and additional effective and well-tolerated chemotherapeutic agents are urgently needed. Eribulin mesylate (E7389), a synthetic analog of the marine macrolide halichondrin B, is a microtubule inhibitor with a unique tubulin binding site and mechanism of action.

Areas covered in this review: Based on a review of the literature between 2005 and 2010, we present a summary of eribulin and its clinical activity, specifically in metastatic breast cancer.

What the reader will gain: The mechanism of action of eribulin, preclinical data indicating antitumor activity of eribulin and data from Phase I and II clinical trials evaluating the efficacy and tolerability of eribulin are presented.

Take home message: Based on data from Phase I and II clinical trials, we conclude that eribulin seems to have efficacy in metastatic breast cancer, even among women with heavily pretreated and taxane-resistant disease. In addition, eribulin has a manageable side-effect profile, consisting mainly of neutropenia and fatigue, and most notably a low incidence of peripheral neuropathy. With these encouraging results, additional Phase II and III studies are ongoing. Eribulin seems to be a promising new agent for the treatment of metastatic breast cancer.     

Effectiveness and safety of eribulin mesylate: a new therapeutic option in the treatment of metastatic breast cancer

INTRODUCTION: There is no standard third-line chemotherapy treatment option for patients with metastatic breast cancer who have received an anthracycline and/or a taxane. A recent Phase III randomized controlled trial compared a new agent, eribulin mesylate with physician's treatment of choice in heavily pretreated patients with metastatic breast cancer, and a survival advantage was observed. Eribulin is a non-taxane microtubule dynamics inhibitor, approved by the US Food and Drug Administration (FDA) in November 2010 for use in patients who previously received at least two prior lines of chemotherapy for metastatic breast cancer. AREAS COVERED: The mechanism of action, pharmacokinetics and the efficacy and safety data from preclinical and clinical trials of this new agent are presented in this paper. EXPERT OPINION: Phase II and a recent Phase III trial indicate that eribulin is well tolerated with a predictable safety profile. The most frequent adverse events observed in patients receiving eribulin were asthenia/fatigue, neutropenia, alopecia, peripheral neuropathy and nausea. It represents a new treatment option in the setting of anthracycline and taxane-refractory metastatic breast cancer.     

The safety of eribulin for the treatment of metastatic breast cancer

Introduction: Eribulin mesylate is a highly potent anticancer agent approved for use in pretreated metastatic breast cancer (MBC). Clinical trials of eribulin in MBC have demonstrated activity against this tumor type, and a phase 3 study in patients with MBC previously treated with an anthracycline and a taxane showed a significant increase in overall survival (OS) with eribulin versus control regimens.

Areas covered: This review presents overviews of the development of eribulin, its pharmacology, and its efficacy in MBC. A detailed review of its safety profile is presented, and the safety of eribulin is compared with other agents commonly used to treat MBC.

Expert opinion: As eribulin is the only drug shown to improve OS in patients with pretreated MBC, it is an important treatment option for many patients. Eribulin is currently considered a second-line (Europe) or third-line (United States) therapy, and studies have been examining use in the first-line setting. The use of eribulin in combination with other therapies is beginning to be explored because its manageable safety profile makes it an ideal combination-treatment partner. Emerging eribulin combination-treatment data suggest a manageable toxicity profile, and eribulin is set to be a key drug for the treatment of MBC in the future.     

新型非紫杉类微管动力抑制剂——Eribulin的研究进展

复发性和转移性乳腺癌是目前难以治愈的疾病之一。Halaven（eribulin甲磺酸盐）是来源于深海中一种黑色海绵类生物的天然产物Haichondrin（HB）的合成衍生物。它是一种非紫杉类微管抑制剂,通过抑制微管的运动,从而表现出抗有丝分裂的作用,引起癌细胞的凋亡。目前已完成Ⅲ期临床试验,于2010年11月通过美国食品药品局批准上市,成为治疗接受过至少两种化疗方案的复发性和转移性乳腺癌患者的新选择。