近日，新型抗癌点滴静注剂brentuximab vedotin（商标名 Adcetris，アドセトリス点滴静注用）获日本批准上市，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。 アドセトリス点滴静注用50mg 药用类别名称 抗肿瘤药物/微管抑制剂结合 anti-CD30单克隆抗体 批准日期：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〕 本质 Brentskisimab Vedotin (分子量: 约 153000) 是一种抗体药物复合物, 基因修饰单克隆抗体 (分子量: 约 148000), 平均3至5胱氨酸残留物, 由 mmae 和链接器 Vedotin (1-(6-{[ 2 s)-1-({(2 s)-5-Carbamoylamino-1-[(4-{[2 s)-{[(2 s)-1-{[(3 r, 4s, 5 s)-1-{(2 s)-2-[(1 r, 2 r)-3-{[(1 s, 2 r)-1-羟基-1-苯基-2-基] Amino}-1-methoxy-2-methyl-3-oxo-propyl] pyrrolidine-1-yl}-3-methoxy-5-methyl-1-oxoheptanoate-4-yl] (甲基) amino}-3- Methyl-1-oxo-butane-2-yl] Amino}-3-methyl-1-oxo-butane-2-yl] Methylcarbamoyloxy} 甲基苯基) 氨基]-1-羰基-2 基} 氨基)-3-甲基-1-氧丁烷-2 基] 氨基}-6-Oxohexyl)-2, 5-Dioxopyrrolidine-3-基组; c68h106n11o15; 分子量: 1317.63) 粘合。 抗体基团, 嵌合体单克隆抗体 (CAC10), 由可变部分的固定部分和人 igg1 的鼠抗人 cd30 抗体在中国仓鼠卵巢细胞中产生。 蛋白质基团是由 L 链 (κ链) 2 分子组成的糖蛋白, 由 H 链 (γ1链) 2 个分子和218个氨基酸残留物组成, 由447个氨基酸残留物构成。 结构公式 审批标准 由于日本的临床试验病例极其有限, 在生产和销售后, 积累了一定数量的病例数据, 并通过对所有病例进行使用结果调查, 掌握了使用该制剂的患者的背景信息。 在早期收集有关该制剂的安全性和有效性的数据, 并采取必要措施适当使用该制剂。 药用药理学 1. 作用机制 Brentskisimab Vedotin是一种抗体药物复合体(ADC), 通过链接器被切断与蛋白酶mmae和anti-CD30IGG1嵌合体抗体具有细胞毒性活动。肿瘤生长抑制作用的药剂, 首先ADC绑定到CD30表达细胞, 后被纳入细胞作为一个adc-cd30复合体, 表达的 Mmae 是解放的蛋白水解反应。 通过游离 Mmae 与管磷结合, 诱导了细胞周期的抑制、停止和凋亡。 2. 抗肿瘤作用 (1) 体外试验 该剂抑制卡帕斯299细胞系的增殖, Cd30-positive霍奇金淋巴瘤衍生的l540cy细胞系和Cd30-positive未分化的大细胞淋巴瘤。 (2) 体内试验 该剂抑制cd30-positive霍奇金淋巴瘤衍生l428细胞系和l540cy细胞系的肿瘤增殖, 或在异种移植小鼠中卡帕斯299细胞系移植, 也卡帕斯 299细胞线被延长, 以生存的小鼠注入静脉。 适应症 复发或难治性 cd30 阳性的以下疾病: 霍奇金淋巴瘤 未分化大细胞淋巴瘤 用法与用量 通常情况下, 成年人每三周 Brentskisimab 1.8毫克/千克 (体重) 的输液。 另外, 要根据病人的病情适当用药。 包装规格 静脉输液 50mg: 1瓶 存储方法、到期日期等。 存储方法 避免冻结和保存从2到8℃。 到期日期 在到期日期内使用外部框中的显示。 (即使在到期日期内, 也应在打开后尽快使用它。 制造和销售来源 武田药业有限公司 注：以上中文资料不够完整，使用者以原资料为准。 完整说明书附件：http://www.info.pmda.go.jp/go/pack/4291425D1021_1_04/ Adcetris(brentuximab vedotin)产品特点 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。 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.