当前位置：药品说明书与价格首页 >> 抗肿瘤药 >> 新药推荐 >> 坦罗莫司注射剂, 驮瑞塞尔|Torisel(Temsirolimus Injection)

坦罗莫司注射剂, 驮瑞塞尔|Torisel(Temsirolimus Injection)

2011-09-25 11:09:39 作者：新特药房来源：互联网浏览次数：392 文字大小：【大】【中】【小】

简介： 美国FDA已经批准Torisel（Temsirolimus）中文名:驮瑞塞尔上市用于治疗进行性肾细胞癌（RCC）。驮瑞塞尔是第一个治疗肾癌的靶向治疗药物。英文药名: Torisel (Temsirolimus Injection) 中文药名: 坦罗 ...

关键字：坦罗莫司注射剂驮瑞塞尔

美国FDA已经批准Torisel（Temsirolimus）中文名:驮瑞塞尔上市用于治疗进行性肾细胞癌（RCC）。驮瑞塞尔是第一个治疗肾癌的靶向治疗药物。

英文药名: Torisel (Temsirolimus Injection)

中文药名: 坦罗莫司注射剂, 驮瑞塞尔

生产品牌药厂家: Pfizer

Torisel(temsirolimus，坦罗莫司)
本品是第1个治疗肾细胞癌的靶向药物，是惟一被批准上市的特异性抑制mTOR激酶的药物(mTOR激酶是调节细胞增殖、生长和细胞存活重要的蛋白质)，治疗晚期肾细胞癌(advancedrenalcellcarcinoma)。
体外研究中发现，本品可抑制mTOR激酶后导致一定的血管生长因子(如血管内皮生长因子)水平下降，进而阻止新生血管的发展，也是目前惟一能显著延长患者生存期的药物。共有626例来自26个国家209个地区的肾细胞癌患者入组该药的IIl期临床试验¨，随机进入干扰素治疗组(3×106—18×106U，每周3次，SC)、Torisel治疗组(25mg，每周1次，iv)和Torisel+干扰素组(Torisel15mg，每周1次，iv，干扰素6×106U，每周3次，SC)。结果显示，Torisel比d干扰素显著延长患者生存率达49％(10．9V8．7．3个月，P=0．0078)；在次级评价指标上，Torisel比仅干扰素显著延长患者的无进展(病情不进一步恶化)生存期(5．5VS．3．1个月，P=0．0001)。Torisel和q干扰素联合使用未显示更好的作用。

美国FDA已经批准Torisel（Temsirolimus）中文名: 驮瑞塞尔上市用于治疗进行性肾细胞癌（RCC）。Torisel是第一个治疗肾癌的靶向治疗药物，今年美国7月正式上市。
Torisel常见不良反应有皮疹、疲乏、口腔溃疡、恶心、水肿以及食欲降低等。其它普通实验室异常反应有高血糖、高脂血、肝肾血检值偏高，以及血红细胞、白细胞和血小板数目减少。
肾细胞癌占全部肾肿瘤的85%。美国癌症协会预计今年将有新诊断肾癌51190例，其中40%在诊断时已经是晚期或发展阶段。

【商品名】Torisel

【药理作用】
与肿瘤发生密切相关的多项细胞功能如：细胞生长增殖、细胞周期调控、生物合成、细胞迁移等均受控于mTOR；cyclinD、myc等多种癌基因的表达在翻译水平上亦受mTOR调节。现已发现，许多肿瘤伴有mTOR信号通路调节异常。越来越多的证据¨q1显示，细胞恶性转化依赖于mTOR信号通路。
细胞生长受到复杂、精细的网络调控。P13K—Akt—mTOR信号通路控制着众多在肿瘤发生发展中至关重要的细胞生物学过程，包括细胞凋亡、转录、翻译、代谢、血管新生以及细胞周期的调控。遗传学上的改变和生化条件引起的激活经常发生在恶变早期和肿瘤进展期，同时，信号通路激活程度也是肿瘤患者预后的重要指标。因此抑制该信号通路成为肿瘤预防和肿瘤靶向治疗的热点。对于该信号通路的各个激酶，均有多种抑制剂处于临床前和临床研究阶段。mTOR的抑制剂在靶向这一信号通路抑制剂中是开发最完善、研究最透彻的一类。
mTOR是一种保守的丝／苏氨酸激酶，在P13K—Akt—mToR信号通路中位于Akt的下游，控制着蛋白质的合成、血管新生和细胞周期的进程。mTOR的抑制剂有着广泛的体内抗瘤谱，在临床研究中表现出令人振奋的有效性和特异性。
本品即是一种mTOR抑制剂，它与细胞内FK—BP一12蛋白结合，形成蛋白-药物复合物，抑制细胞内的靶点mTOR激酶的活性。mTOR激酶是调节细胞增值、生长和细胞存活的重要蛋白质。当mTOR受到抑制时，将使P70s6K与s6核糖体蛋白进行磷酸化的能力受阻。体外研究表明，本品能抑制mTOR激酶的活性，同时导致诱导组织缺氧的因子HIF一1、HIF-2以及血管内皮因子的水平下降，进而阻止新生血管的发展。

【适应症】晚期肾细胞癌(RCC)。

【用法用量】
成人：推荐剂量25mg，静脉输注30～60min以上，每周1次。

【不良反应】
较常见的不良反应发生率为30％，包括皮疹、虚弱无力、黏膜炎、恶心、厌食、水肿；严重不良反应¨一1有：高敏反应、高血糖、高血脂、间质性肺炎、肠穿孔、急性肾衰等；实验室异常发生率为30％，有贫血、高血糖、高血脂、高三酰甘油血症、碱性磷酸(酯)酶升高、血清肌酸酐升高、淋巴细胞减少症、低磷酸盐血、血小板减少(症)、天冬氨酸转氨酶升高、白细胞减少症。

【注意事项】
①为使药物准确释放，最好使用输注泵，稀释好的药液应在6h内使用。
②应注意西罗莫司及其相关的过敏反应，肝功能损害，手术期间的伤口愈合，中枢神经系统肿瘤，每周监测血细胞计数以及每两周进行化学平板实验，血糖，血脂，肾功，呼吸恶化，胃肠症状(急腹症及血便)。
③老年人、孕妇、哺乳期妇女及儿童不推荐使用。

【药物相互作用】
①避免与强的cYP3A4抑制剂合用，如酮康唑、伊曲康唑、克拉霉素、茚地那韦、奈法唑酮、那非那韦、沙奎那韦、泰利霉素、优立康唑、葡萄柚汁。如果必须合用，应考虑减低本品剂量至每周12．5mg(调整剂量前停用1周CYP3A4抑制剂)。
②避免与强的CYP3A4诱导剂合用，如，地塞米松、苯妥英、卡马西平、利福平、利福布丁、异福酰胺片、苯巴比妥、圣约翰麦芽汁。如果必须合用，应考虑增加本品剂量至每周50mg。
③避免与活疫苗合用，避免密切接触已接种疫苗者。
④与西尼替尼合用可产生附加的毒性反应(皮疹、痛风、蜂窝组织炎)；与抗凝剂合用可引起颅内出血。

【临床评价】
一项评价本品与a．干扰素联(IFN)联合用药的安全性、耐受性及最大耐受量(MTD)的多中心I／II期临床试验，对71例受试者进行本品剂量递增研究。本品按5—25mg递增剂量，每周1次静脉给药；a—IFN每周3次，皮下给药6或9Mu，以出现口腔炎、疲劳、恶心、呕吐等确定限定毒性剂量。最常见的毒性反应为白细胞减少、低磷酸盐血症、无力、贫血及高三酰甘油血症。最终确定的推荐剂量为本品15mg／IFN6MU。接受推荐剂量的39例患者中，8％取得部分响应，36％至少在24周内病情稳定，所有患者的无进展生存期为9．1个月。
结果表明：本品与d-IFN联合用药对于晚期RCC患者具有抗癌活性，毒性剂鼍范围可接受，因此，III期随机临床研究联合用药的推荐剂量为本品15mg／IFN6MU。
一项考察晚期RcC患者用药剂量的II期随机、双盲、对照试验中，11l例事先进行过治疗的晚期RcC患者，随机接受本品25，75或250mg治疗，每周1次。初级评价指标为客观应答率(ORR)；次级评价指标是总生存期(OS)及非进展生存期(PFS)。结果3剂量组的ORR分别为5．0％，7．9％和8．1％；临床有效率分别为52．8％，55．3％和43．2％。所有患者中位总生存期为15个月，各剂量组生存期分布未见统计学意义上的差别。
对626例先前未进行治疗的晚期肾癌(RCC)患者进行了本品多中心、开放、随机III期临床疗效与安全性评价试验，旨在研究本品的总生存期(OS)、非进展生存期(PFs)及客观应答率(ORR)。患者平均年龄59岁(23—86岁)；男性69％，女性31％；种族分布：白人91％，黑人4％，亚裔2％，其他3％。随机分成三组，即本品试验组209例(25mg，每周1次，静脉输注30一60min以上)，本品(15mg)和d—IFN(最大剂量6Mu)联合用药组210例，及单独应用俚-IFN组(最大剂量18Mu)207例。中期分析结果表明：本品组与IFN组比较，中位生存期分别为10．9月和7．3月，有统计学意义的改善(P=0．00r78)，显著延长患者生存期达49％；次级评价指标：本品能显著延长患者的无进展(病情不进一步恶化)生存期(5．5个月对3．1个月，P=0．0001)；客观应答率分别为8．6％和4．8％(P=0．132)。本品和仅一IFN联合治疗组及单独应用o一IFN组比较，延长患者生存期15％，差别未见统计学意义，但与多种不良反应事件增加有关。
【规格】注射液：25mg／mL／瓶+1．8mL稀释液／套。
【贮存】2—8℃下避光贮存。

TORISEL is indicated for the treatment of advanced renal cell carcinomaImportant Safety Information

Hypersensitivity reactions manifested by symptoms, including, but not limited to anaphylaxis, dyspnea, flushing, and chest pain have been observed with TORISEL.
Serum glucose, serum cholesterol, and triglycerides should be tested before and during treatment with TORISEL.
The use of TORISEL is likely to result in hyperglycemia and hyperlipemia. This may result in the need for an increase in the dose of, or initiation of, insulin and/or oral hypoglycemic agent therapy and/or lipid-lowering agents, respectively.
The use of TORISEL may result in immunosuppression. Patients should be carefully observed for the occurrence of infections, including opportunistic infections.
Cases of interstitial lung disease, some resulting in death, have occurred. Some patients were asymptomatic and others presented with symptoms. Some patients required discontinuation of TORISEL and/or treatment with corticosteroids and/or antibiotics.
Cases of fatal bowel perforation occurred with TORISEL. These patients presented with fever, abdominal pain, metabolic acidosis, bloody stools, diarrhea, and/or acute abdomen.
Cases of rapidly progressive and sometimes fatal acute renal failure not clearly related to disease progression occurred in patients who received TORISEL.
Due to abnormal wound healing, use TORISEL with caution in the perioperative period.
Patients with central nervous system tumors (primary CNS tumor or metastases) and/or receiving anticoagulation therapy may be at an increased risk of developing intracerebral bleeding (including fatal outcomes) while receiving TORISEL.
Live vaccinations and close contact with those who received live vaccines should be avoided.
Patients and their partners should be advised to avoid pregnancy throughout treatment and for 3 months after TORISEL therapy has stopped.
The most common (incidence ≥30%) adverse reactions observed with TORISEL are: rash (47%), asthenia (51%), mucositis (41%), nausea (37%), edema (35%), and anorexia (32%). The most common laboratory abnormalities (incidence ≥30%) are anemia (94%), hyperglycemia (89%), hyperlipemia (87%), hypertriglyceridemia (83%), elevated alkaline phosphatase (68%), elevated serum creatinine (57%), lymphopenia (53%), hypophosphatemia (49%), thrombocytopenia (40%), elevated AST (38%), and leukopenia (32%).
Most common grades 3/4 adverse events included asthenia (11%), dyspnea (9%), hemoglobin decreased (20%), lymphocytes decreased (16%), glucose increased (16%), phosphorus decreased (18%), and triglycerides increased (44%).
Strong inducers of CYP3A4/5 (eg, dexamethasone, rifampin) and strong inhibitors of CYP3A4 (eg, ketoconazole, atazanavir) may decrease and increase concentrations of the major metabolite of TORISEL, respectively. If alternatives cannot be used, dose modifications of TORISEL are recommended.
St. John’s Wort may decrease TORISEL plasma concentrations, and grapefruit juice may increase plasma concentrations of the major metabolite of TORISEL, and therefore both should be avoided.
The combination of TORISEL and sunitinib resulted in dose-limiting toxicity (Grade 3/4 erythematous maculopapular rash, and gout/cellulitis requiring hospitalization).

肾癌新药-名为Torisel(temsirolimus，坦罗莫司)

5月 30日，美国食品和药品管理局（FDA）批准了一种治疗肾癌的新药，名为Torisel (temsirolimus)。FDA药物评估和研究中心的负责人史蒂文·加尔森说：“我们在对抗肾癌的过程中取得了显著的进步，Torisel是过去18个月以来，第三种被批准的肾癌治疗药物。研究证明，这种药物能够延长一部分肾癌患者的生命。”
研究者对Torisel进行了随机临床试验，626位患者分别接受了3种不同的疗法：第一类患者使用干扰素；第二类患者同时使用干扰素和Torisel；第三类患者只使用Torisel。试验表明，只接受Torisel治疗的患者，生存时间要比前两部分患者长。这是因为，同时使用干扰素和Torisel的患者，机体吸收Torisel的剂量，反而要低于只服用Torisel一种药物时。

美国费城福克斯癌症研究中心泌尿生殖项目的负责人休迪斯医生说：“癌症的治疗目的，就是要遏制癌症的恶化和癌细胞的转移。”很多肾癌患者通过手术切除肿瘤，但其中有35％的患者又会复发，有些患者的癌细胞还会扩散到身体的其他部位。他指出，Torisel能够适度地改善大部分肾癌转移患者的生存状况。

在此之前，已经有两种治疗肾癌的药物被批准使用。2005年12月，Nexavar (多吉美，sorafenib索拉非尼)获得批准，这种药物能够减慢肾癌的恶化速度。2006年1月，Sutent (sunitinib舒尼替尼)成为第二种获得批准使用的药物，它可以持久地减慢肾癌发展的速度，并且能够使肿瘤变小，延缓肿瘤的生长。

TORISEL™ (temsirolimus) injection

TORISEL is the first mTOR inhibitor approved for the treatment of patients with advanced renal cell carcinoma (RCC). Learn more about the TORISEL mechanism of action. TORISEL provides significantly higher median overall survival and progression-free survival compared with interferon-alpha (IFN-α).1 Learn more about the efficacy of TORISEL. The TORISEL safety profile has been evaluated in clinical trials. Learn more about the adverse events profile of TORISEL in patients with advanced RCC. The recommended dose of TORISEL for advanced RCC is 25 mg infused over 30 to 60 minutes once weekly. Learn more about TORISEL dosage and administration. Important Safety Information
Hypersensitivity reactions manifested by symptoms, including, but not limited to anaphylaxis, dyspnea, flushing, and chest pain have been observed with TORISEL. Serum glucose, serum cholesterol, and triglycerides should be tested before and during treatment with TORISEL.
The use of TORISEL is likely to result in hyperglycemia and hyperlipemia. This may result in the need for an increase in the dose of, or initiation of, insulin and/or oral hypoglycemic agent therapy and/or lipid-lowering agents, respectively. The use of TORISEL may result in immunosuppression. Patients should be carefully observed for the occurrence of infections, including opportunistic infections. Cases of interstitial lung disease, some resulting in death, have occurred. Some patients were asymptomatic and others presented with symptoms. Some patients required discontinuation of TORISEL and/or treatment with corticosteroids and/or antibiotics. Cases of fatal bowel perforation occurred with TORISEL. These patients presented with fever, abdominal pain, metabolic acidosis, bloody stools, diarrhea, and/or acute abdomen. Cases of rapidly progressive and sometimes fatal acute renal failure not clearly related to disease progression occurred in patients who received TORISEL. Due to abnormal wound healing, use TORISEL with caution in the perioperative period. Patients with central nervous system tumors (primary CNS tumor or metastases) and/or receiving anticoagulation therapy may be at an increased risk of developing intracerebral bleeding (including fatal outcomes) while receiving TORISEL. Live vaccinations and close contact with those who received live vaccines should be avoided. Patients and their partners should be advised to avoid pregnancy throughout treatment and for 3 months after TORISEL therapy has stopped. The most common (incidence ≥30%) adverse reactions observed with TORISEL are: rash (47%), asthenia (51%), mucositis (41%), nausea (37%), edema (35%), and anorexia (32%). The most common laboratory abnormalities (incidence ≥30%) are anemia (94%), hyperglycemia (89%), hyperlipemia (87%), hypertriglyceridemia (83%), elevated alkaline phosphatase (68%), elevated serum creatinine (57%), lymphopenia (53%), hypophosphatemia (49%), thrombocytopenia (40%), elevated AST (38%), and leukopenia (32%). Most common grades 3/4 adverse events included asthenia (11%), dyspnea (9%), hemoglobin decreased (20%), lymphocytes decreased (16%), glucose increased (16%), phosphorus decreased (18%), and triglycerides increased (44%). Strong inducers of CYP3A4/5 (eg, dexamethasone, rifampin) and strong inhibitors of CYP3A4 (eg, ketoconazole, atazanavir) may decrease and increase concentrations of the major metabolite of TORISEL, respectively. If alternatives cannot be used, dose modifications of TORISEL are recommended. St. John’s Wort may decrease TORISEL plasma concentrations, and grapefruit juice may increase plasma concentrations of the major metabolite of TORISEL, and therefore both should be avoided. The combination of TORISEL and sunitinib resulted in dose-limiting toxicity.

Company: Wyeth
Pharmacologic class: Antineoplastic (mTOR kinase inhibitor)

Active ingredient:
Temsirolimus 25mg/mL; ethanolic soln for IV infusion after two dilutions (first w. supplied diluent); contains alcohol, polysorbate 80.

Indication:
Advanced renal cell carcinoma.

Pharmacology:
Temsirolimus binds to an intracellular protein, and the resulting protein-drug complex inhibits the activity of an intracellular target called mTOR kinase, a cellular enzyme that regulates cell proliferation, cell growth and cell survival. In vitro studies show that inhibiting mTOR interferes with the translation of genes that regulate the cell cycle. It also resulted in reduced levels of certain cell growth factors involved in the development of new blood vessels, such as vascular endothelial growth factor.

Clinical trials:
In a study conducted in 626 previously untreated patients with advanced renal cell carcinoma, treatment with temsirolimus was compared to temsirolimus + interferon-α and to interferon-α alone. There was a statistically significant improvement in overall survival in the patients given temsirolimus (10.9 months) compared to those given interferon-α (7.3 months).

Adults:
25mg once weekly. Infuse IV over 30?0min, using an infusion pump. Continue until disease progression or unacceptable toxicity occurs. Premedicate with IV antihistamine (eg, diphenydramine). Hold dose if ANC <1000/mm3, platelets <75000/mm3, or NCI CTCAE ≥grade 3 adverse reaction occurs; may restart at a dose reduced by 5mg/week (no lower than 15mg/wk) if adverse reactions resolve to ≤grade 2. See Interactions.

Children:
Not recommended.

Precautions:
Sirolimus or related allergy. Hepatic insufficiency. Perioperative period (may interfere with wound healing). CNS tumors. Monitor CBCs weekly and chemistry panels every 2 weeks, blood glucose, lipids, renal function, and for worsening respiratory or GI symptoms (eg, acute abdomen, blood in stool). Elderly. Pregnancy (Cat.D) (avoid pregnancy during and for 3 months after therapy, male patients should use appropriate contraception), nursing mothers: not recommended.

Interactions:
Avoid strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole, grapefruit juice); if used, consider reducing temsirolimus dose to 12.5mg/week (allow 1 week after discontinuing CYP3A4 inhibitor before readjusting temsirolimus dose). Avoid strong CYP3A4 inducers (eg, dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifampicin, phenobarbital, St. John's Wort); if used, consider increasing temsirolimus dose to 50mg/week. Avoid live vaccines, close contact with vaccinees. Additive toxicity with sunitinib (rash, gout/cellulitis), anticoagulants (intracerebral bleeding).

Adverse reactions:
Rash, asthenia, mucositis, nausea, edema, anorexia, infection, pain, anemia, hyperglycemia, hyperlipemia, hypertriglyceridemia, elevated alkaline phosphatase, elevated serum creatinine, lymphopenia, hypophosphatemia, thrombocytopenia, elevated AST, leukopenia; hypersensitivity/infusion reactions (anaphylaxis, dyspnea, flushing, chest pain), immunosuppression, interstitial lung disease, bowel perforation, acute renal failure, abnormal wound healing; others (see literature).

How supplied:
Kit (vial + diluent)
TORISEL (TEMSIROLIMUS)25MG/ML+1.8ML DILU KIT

トーリセル点滴静注液25mg

一般的名称

テムシロリムス点滴静注液

商標名

TORISEL Injection 25mg

有効成分に関する理化学的知見

一般名

テムシロリムス（Temsirolimus）

化学名

(1R,2R,4S)-4-{(2R)-2-[(3S,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,26R,27R,34aS)-9,27-Dihydroxy-10,21-dimethoxy-6,8,12,14,20,26-hexamethyl-1,5,11,28,29-pentaoxo-1,4,5,6,9,10,11,12,13,14,21,22,23,24,25,26,27,28,29,31,32,33,34,34a-tetracosahydro-3H-23,27-epoxypyrido[2,1-c][1,4]oxazacyclohentriacontin-3-yl]propyl}-2-methoxycyclohexyl 3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate

構造式