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ADCetris(Brentuximab Vedotin(Genetical Recombination))

2015-11-06 03:27:17  作者:新特药房  来源:互联网  浏览次数:7  文字大小:【】【】【
简介: ADCetris(Brentuximab Vedotin[Genetical Recombination])-武田研发的抗体偶联药物Adcetris(brentuximab vedotin)获日本批准,用于治疗复发性或难治性CD30阳性霍奇金淋巴瘤(HL)和复发性或难治性C ...

ADCetris(Brentuximab Vedotin[Genetical Recombination])-武田研发的抗体偶联药物Adcetris(brentuximab vedotin)获日本批准,用于治疗复发性或难治性CD30阳性霍奇金淋巴瘤(HL)和复发性或难治性CD30阳性系统性间变性大细胞淋巴瘤(sALCL)成人患者。
治疗类别名称
抗肿瘤剂/微管抑制剂缀合的抗-CD30单克隆抗体
批准上市:2014年4月
商標名
ADCetris
一般名
ブレンツキシマブ ベドチン(遺伝子組換え)
Brentuximab Vedotin(Genetical Recombination))〔JAN〕
本質
Brentuximab Bedochin(分子量:约153000)是抗体药物缀合物,重组单克隆抗体(分子量:约148000)中Bedochin的平均3-5 Cys残基由MMAE和接头(1- (6 - {[(2S)-1 - ({(2S)-5-氨基甲酰基-1 - [(4 - {[(2S) - {[(2S)-1 - {[(3R,4S, 5S)-1 - {(2S)-2 - [(1R,2R)-3 - {[(1S,2R)-1-羟基-1-苯基丙-2-基]氨基} -1-甲氧基-2-- 甲基-3-氧代 - 丙基]吡咯烷-1-基} -3-甲氧基-5-甲基-1-氧代 - 庚烷-4-基](甲基)氨基} -3-甲基-1-氧代-2-基]氨基} -3-甲基-1-氧代-2-基]甲基氨基甲酰基氧基}甲基苯基)氨基] -1-氧代-2-基}氨基)-3-甲基-1-氧代-2-基]氨基} -6-氧代己基)-2,5-二氧代吡咯烷-3-基氧基; C68H106N11O15;分子量:1317.63)连接。抗体部分,嵌合单克隆抗体(cAC10),小鼠抗人CD30抗体的可变区和包含人IgG1的恒定区的,在中国仓鼠卵巢细胞中产生的。蛋白部分是L链(κ链)组成的糖蛋白,所述的H链(γ1链)2分子和218个氨基酸残基的447个氨基酸残基组成的两个分子。
構造式


审批条件
由于临床试验的情况下在日本是非常有限的,上市后,直到一定数量案件的数据被集成,通过实施的所有情况下,使用效果的调查,该药物以及了解病人使用的背景资料,搜集有关这种药物的安全性和有效性的数据,采取必要措施,正确使用此药。
药效药理
1. 作用机序
Brentuximab Bedochin]是通过接头与MMAE和具有由蛋白酶(ADC),裂解的细胞毒活性的抗CD30IgG1型嵌合抗体结合的抗体 - 药物偶联物。这种药物的肿瘤生长的抑制作用是第一ADC结合CD30表达细胞,被带入小区作为由MMAE表示ADC-CD30复合物可通过蛋白水解反应中解放出来之后。通过游离的MMAE结合至微管蛋白,微管形成被抑制,它诱导逮捕和细胞周期的细胞凋亡。
2. 抗肿瘤作用
(1)在体外试验
抑制了从卡帕斯希299细胞系衍生的CD30阳性霍奇金淋巴瘤衍生的将L540cy细胞系和CD30阳性间变性大细胞淋巴瘤的生长。
(2)在体内试验
CD30阳性霍奇金淋巴瘤衍生的L428细胞株和将L540cy细胞系,或卡帕斯299细胞系抑制肿瘤生长的皮下植入的异种移植物的小鼠,并在注射卡帕斯希299细胞系的小鼠静脉内存活时间我被延长。
适应证和用途
ADCETRIS是一种CD30-导向抗体药物结合物适用于:
(1)霍杰金淋巴瘤患者用自身干细胞移植(ASCT)失败后或不是ASCT备选者患者至少2次既往多药化疗方案失败后的治疗。
(2)有系统性间变性大细胞淋巴瘤患者至少1次既往多药化疗方案失败后的治疗。
这些适应证是根据缓解率。可得到的资料没有证实用ADCETRIS报道患者结局或生存改善。
剂量和给药方法
(1)推荐剂量是1.8mg/kg只作为历时30分钟静脉输注给药每3周1次。
(2)继续治疗直至最大16个疗程,疾病进展或不可接受的毒性。
包装规格:
静脉滴注:50毫克:1瓶


生产厂商
武田药品有限公司
Adcetris® (brentuximab vedotin) is an antibody-drug conjugate composed of a CD30-directed monoclonal antibody that is covalently linked to the antimicrotubule agent monomethyl auristatin E (MMAE).
ADCETRIS Indications
ADCETRIS® (brentuximab vedotin) is indicated for treatment of patients with:
Classical Hodgkin lymphoma (HL) after failure of autologous hematopoietic stem cell transplantation (auto-HSCT) or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not auto-HSCT candidates.
Classical HL at high risk of relapse or progression as post-auto-HSCT consolidation.
Systemic anaplastic large cell lymphoma (sALCL) after failure of at least one prior multi-agent chemotherapy regimen.
Accelerated approval was granted for the sALCL indication based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.
Important Safety Information
BOXED WARNING
Progressive multifocal leukoencephalopathy (PML): JC virus infection resulting in PML and death can occur in patients receiving ADCETRIS.
Contraindication
ADCETRIS is contraindicated with concomitant bleomycin due to pulmonary toxicity (e.g., interstitial infiltration and/or inflammation).
Warnings and Precautions
Peripheral neuropathy: ADCETRIS treatment causes a peripheral neuropathy that is predominantly sensory. Cases of peripheral motor neuropathy have also been reported. ADCETRIS-induced peripheral neuropathy is cumulative. Monitor patients for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain or weakness and institute dose modifications accordingly.
Anaphylaxis and infusion reactions: Infusion-related reactions, including anaphylaxis, have occurred with ADCETRIS. Monitor patients during infusion. If an infusion-related reaction occurs, interrupt the infusion and institute appropriate medical management. If anaphylaxis occurs, immediately and permanently discontinue the infusion and administer appropriate medical therapy.
Hematologic toxicities: Prolonged (≥1 week) severe neutropenia and Grade 3 or 4 thrombocytopenia or anemia can occur with ADCETRIS. Febrile neutropenia has been reported with ADCETRIS. Monitor complete blood counts prior to each dose of ADCETRIS and consider more frequent monitoring for patients with Grade 3 or 4 neutropenia. Monitor patients for fever. If Grade 3 or 4 neutropenia develops, consider dose delays, reductions, discontinuation, or G-CSF prophylaxis with subsequent doses.
Serious infections and opportunistic infections: Infections such as pneumonia, bacteremia and sepsis or septic shock (including fatal outcomes) have been reported in patients treated with ADCETRIS. Closely monitor patients during treatment for the emergence of possible bacterial, fungal or viral infections.
Tumor lysis syndrome: Closely monitor patients with rapidly proliferating tumor and high tumor burden.
Increased toxicity in the presence of severe renal impairment: The frequency of ≥Grade 3 adverse reactions and deaths was greater in patients with severe renal impairment compared to patients with normal renal function. Avoid the use of ADCETRIS in patients with severe renal impairment.
Increased toxicity in the presence of moderate or severe hepatic impairment: The frequency of ≥Grade 3 adverse reactions and deaths was greater in patients with moderate or severe hepatic impairment compared to pateints with normal hepatic function. Avoid the use of ADCETRIS in patients with moderate or severe hepatic impairment.
Hepatotoxicity: Serious cases of hepatotoxicity, including fatal outcomes, have occurred with ADCETRIS. Cases were consistent with hepatocellular injury, including elevations of transaminases and/or bilirubin, and occurred after the first dose of ADCETRIS or rechallenge. Preexisting liver disease, elevated baseline liver enzymes, and concomitant medications may also increase the risk. Monitor liver enzymes and bilirubin. Patients experiencing new, worsening, or recurrent hepatotoxicity may require a delay, change in dose, or discontinuation of ADCETRIS.
Progressive multifocal leukoencephalopathy (PML): JC virus infection resulting in PML and death has been reported in ADCETRIS-treated patients. First onset of symptoms occurred at various times from initiation of ADCETRIS therapy, with some cases occurring within 3 months of initial exposure. In addition to ADCETRIS therapy, other possible contributory factors include prior therapies and underlying disease that may cause immunosuppression. Consider the diagnosis of PML in any patient presenting with new-onset signs and symptoms of central nervous system abnormalities. Hold ADCETRIS if PML is suspected and discontinue ADCETRIS if PML is confirmed.
Pulmonary Toxicity: Events of noninfectious pulmonary toxicity including pneumonitis, interstitial lung disease, and acute respiratory distress syndrome (ARDS), some with fatal outcomes, have been reported. Monitor patients for signs and symptoms of pulmonary toxicity, including cough and dyspnea. In the event of new or worsening pulmonary symptoms, hold ADCETRIS dosing during evaluation and until symptomatic improvement.
Serious dermatologic reactions: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), including fatal outcomes, have been reported with ADCETRIS. If SJS or TEN occurs, discontinue ADCETRIS and administer appropriate medical therapy.
Embryo-fetal toxicity: Fetal harm can occur. Advise pregnant women of the potential hazard to the fetus
Adverse Reactions
ADCETRIS was studied as monotherapy in 160 patients with classical HL and sALCL in two uncontrolled single-arm trials. Across both trials, the most common adverse reactions (≥20%), regardless of causality, were neutropenia, peripheral sensory neuropathy, fatigue, nausea, anemia, upper respiratory tract infection, diarrhea, pyrexia, rash, thrombocytopenia, cough and vomiting
ADCETRIS was studied in 329 patients with classical HL at high risk of relapse or progression post-auto-HSCT in a placebo-controlled randomized trial. The most common adverse reactions (≥20%) in the ADCETRIS-treatment arm (167 patients), regardless of causality, were neutropenia, peripheral sensory neuropathy, thrombocytopenia, anemia, upper respiratory tract infection, fatigue, peripheral motor neuropathy, nausea, cough, and diarrhea.
Drug Interactions
Concomitant use of strong CYP3A4 inhibitors or inducers, or P-gp inhibitors, has the potential to affect the exposure to monomethyl auristatin E (MMAE).
Use in Specific Populations
MMAE exposure and adverse reactions are increased in patients with moderate or severe hepatic impairment or severe renal impairment. Avoid use.
http://www.info.pmda.go.jp/go/pack/4291425D1021_1_02/
武田抗体偶联药物Adcetris(brentuximab vedotin)获日本批准
2014年1月18日,武田(Takeda)研发的抗体偶联药物Adcetris(brentuximab vedotin)获日本卫生劳动福利部(MHLW)批准,用于2种适应症:(1)复发性或难治性CD30阳性霍奇金淋巴瘤(HL)成人患者;(2)复发性或难治性CD30阳性系统性间变性大细胞淋巴瘤(sALCL)成人患者。此前,日本MHLW已授予Adcetris治疗HL和sALCL的孤儿药地位,并授予Adcetris优先审查资格。
Adcetris的获批,是基于在日本复发性或难治性CD30阳性霍奇金淋巴瘤(HL)患者、复发性或难治性CD30阳性系统性间变性大细胞淋巴瘤(sALCL)患者中开展的一项I/II期临床试验、及2项全球性关键II期临床试验的数据。临床试验中,ADCETRIS已被证明能够在这2种适应症中,提供较高的总体反应率及持续完整响应。
关于Adcetris:
Adcetris是一种抗体偶联药物(ADC),由靶向CD30蛋白的一种单克隆抗体、以及一种微管破坏剂(单甲基auristatin E,MMAE),通过一种蛋白酶敏感的交联剂偶联而成,该偶联技术为西雅图遗传学公司(Seattle Genetics)的专有技术。CD30蛋白是经典HL及sALCL的明确标志物,而Auristatin E可通过抑制微管蛋白的聚合作用阻碍细胞分裂。Adcetris在血液中可稳定存在,在被CD30阳性肿瘤细胞内化后,可释放出MMAE。
此前,Adcetris已于2011年8月获FDA批准,于2012年10月获欧盟有条件批准,同时于2013年2月获加拿大批准。

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