美国的初始批准：2006 优先审评
一般描述
索坦，一种口服多-激酶抑制剂，是舒尼替尼[sunitinib]的苹果酸盐。舒尼替尼苹果酸盐化学上描述为Butanedioic acid, hydroxy-, (2S)-, 化合物有N-[2-(diethylamino)ethyl]-5-[(Z)-(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylidine)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide (1:1)。分子式为C22H27FN4O2?C4H6O5和分子量为532.6道尔顿。
舒尼替尼苹果酸盐的化学结构是：
舒尼替尼苹果酸盐是一种黄至橙色粉有pKa 8.95。舒尼替尼苹果酸盐在水性介质中的溶解度在pH范围1.2至pH 6.8是超过25 mg/mL。在pH 7分配系数(辛醇/水)的对数是5.2。
索坦(sunitinib malate)胶囊在印硬壳胶囊供应含舒尼替尼苹果酸盐等同于12.5 mg，25 mg或50 mg舒尼替尼与甘露醇，交联羧甲基纤维素钠，聚乙烯吡啶酮(K-25)和硬脂酸镁作为无活性成分。
橙色明胶胶囊壳含二氧化钛，和红色氧化铁。酱色明胶胶囊壳含二氧化钛，和红色氧化铁，黄色氧化铁和黑色氧化铁。白色印油墨含虫胶，丙烯乙二醇，氢氧化钠，聚乙烯吡啶酮和二氧化钛。
作用机制
舒尼替尼是一个小分子，抑制多种受体酪氨酸激酶(RTKs)，其中有些涉及肿瘤生长，病理性血管生成，和癌症转移进展。舒尼替尼评价对各种各样激酶(>80种激酶)的抑制活性和被鉴定为血小板衍生生长因子受体(PDGFRα和PDGFRβ)，血管内皮生长因子受体(VEGFR1，VEGFR2和VEGFR3)，干细胞因子受体(KIT)，fms样酪氨酸激酶受体3(FLT3)，集落刺激因子受体类型1(CSF-1R)，和神经胶质细胞系衍生神经营养因子受体(RET)的抑制剂。在生化和细胞分析中曾显示舒尼替尼抑制这些受体酪氨酸激酶RTKs的活性和在细胞增殖分析中曾显示功能的抑制作用。在生化和细胞分析中主要代谢物表现出与舒尼替尼比较相似效力。
舒尼替尼在体内异种移植肿瘤表达RTK靶点中抑制多种RTKs(PDGFRβ，VEGFR2，KIT)的磷酸化和在某些实验性癌症模型中显示肿瘤生长或肿瘤消退的抑制作用和/或抑制转移。在体外舒尼替尼显示抑制表达失调[dysregulated]靶RTKs(PDGFR，RET，或KIT)肿瘤细胞的生长的能力和在体内抑制PDGFRβ-和VEGFR2-依赖肿瘤的血管生成。
适应证和用途
索坦是一种激酶抑制剂适用于治疗：
（1）胃肠道间质瘤：对伊马替尼甲磺酸盐后疾病进展或不能耐受。
（2）晚期肾细胞癌。
剂量和给药方法
（1）50mg口服每天1次，有或无食物，4周治疗接着停药2周。
（2）根据个体安全性和耐受性中断给药和/或调整12.5 mg推荐剂量。
剂型和规格
（1）胶囊：12.5mg，25mg，50mg
禁忌证
无(4)
警告和注意事项
（1）曾观察到肝毒性，包括肝衰竭。开始治疗前，每个治疗疗程期间，和当临床有指示时监查肝功能试验。对3或4级药物相关肝不良事件应中断索坦和如没有解决应终止。不要再次开始索坦如患者随后经受肝功能试验中严重变化或有肝衰竭的其它征象和症状。
（2）应告知生育能力妇女对胎儿的潜在危害和避免成为妊娠.
（3）左心室射血分数已发生降低至低于正常低限。监查患者充血性心衰征象和症状。
（4）曾观察到延长QT间期和尖端扭转型室性心动过速。对高危发生QY间期延长患者中谨慎使用。当使用索坦时，应考虑治疗时监测心电图和电解质。
（5）可能发生高血压。监查血压和需要时治疗。
（6）已发生出血事件包括肿瘤-相关出血。进行系列全血细胞计数和体格检查。
（7）可能发生甲状腺功能障碍。有提示甲状腺机能减退或甲状腺机能亢进体征和/或症状患者应进行实验室监查甲状腺功能和用标准医学治疗。
（8）在动物研究中观察到肾上腺出血。在应急时例如手术，创伤或严重感染情况监查肾上腺功能。
不良反应
（1）最常见不良反应(≥20%)是疲劳，虚弱，发热，腹泻，恶心，粘膜炎/口炎，呕吐，消化不良，腹痛，便秘，高血压，周边水肿，皮疹，手-足综合征，皮肤色素减退，干皮肤，头发颜色的变化，味觉改变，头痛，背痛，关节痛，肢体痛，咳嗽，呼吸困难，厌食，和出血。
为报告怀疑不良反应，联系Pfizer, Inc.公司电话1-800-438-1985或FDA电话1-800-FDA-1088或www.fda.gov/medwatch.
药物相互作用
（1）CYP3A4抑制剂：当给予强CYP3A4抑制剂考虑减低索坦剂量。
（2）CYP3A4诱导剂：当给予强CYP3A4诱导剂考虑增加索坦剂量。
The FDA has approved Sutent (sunitinib) for the treatment of patients with unresectable, locally advanced, or metastatic pancreatic neuroendocrine tumors (pNET). Sunitinib joins everolimus (Afinitor), which the FDA approved for pNET earlier this month, as the first new treatments for the rare disease in nearly 30 years.
Last month, the FDA’s Oncologic Drugs Advisory Committee (ODAC) voted 8-2 in support of the pNET indication for sunitinib, an oral tyrosine kinase inhibitor that blocks the vascular endothelial growth factor pathway. ODAC’s recommendation was based on data from the SUN 1111 pivotal phase III trial, which randomized 171 patients with pNET to either 37.5 mg daily of sunitinib or placebo.
The FDA reported that median progression-free survival (PFS) in the sunitinib cohort was 10.2 months versus 5.4 months in the placebo group. Sunitinib also demonstrated anti-tumor activity, with an objective response rate of 9.3% versus no response in the placebo arm.
The most frequently occurring side effects in the sunitinib population were diarrhea, nausea, vomiting, fatigue, anorexia, high blood pressure, energy loss (asthenia), stomach (abdominal) pain, changes in hair color, inflammation of the mouth (stomatitis), and a decrease in infection-fighting white blood cells (neutropenia).
An independent data and safety monitoring committee halted the trial before completion due to the greater survival benefit and fewer deaths and adverse events observed in the sunitinib cohort. Twenty-one deaths occurred in the placebo group versus 9 deaths among patients treated with sunitinib.
Given the PFS and toxicity results, “It was considered very inappropriate to continue randomizing patients [and] taking the risk of having patients entering into the trial being treated with placebo with [the associated] higher risk of death and…higher risk of adverse events,” said Eric Raymond, MD, principal investigator of the SUN 1111 phase III trial, and professor of medical oncology and head of the University Department of Medical Oncology (Service Inter Hospitalier de Cancerologie) Bichat-Beaujon, Clichy, France. “It’s very rare to have to stop a trial for [the] positivity [of its results],” Raymond added.
When the ODAC panel met in April, the committee discussed whether the early SUN 1111 discontinuation might have actually led to the overestimation of sunitinib’s benefit in patients with pNET. However, the majority of panel members concluded the PFS data were sufficient, especially given the limited treatments available for the rare pancreatic cancer.
According to the manufacturer, Pfizer Inc, sunitinib is already approved for a pNET indication in Europe and 9 other countries. Sunitinib has previously been approved by the FDA to treat patients with gastrointestinal stromal tumors and metastatic renal cell carcinoma.
Indications
SUTENT®(sunitinib malate) is indicated for the treatment of advanced renal cell carcinoma (RCC), gastrointestinal stromal tumor (GIST) after disease progression on or intolerance to imatinib mesylate, and progressive,
well-differentiated pancreatic neuroendocrine tumors (pNET) in patients with unresectable locally advanced or metastatic disease.
Important Safety Information
WARNING: HEPATOTOXICITY
Hepatotoxicity has been observed in clinical trials and post-marketing experience. This hepatotoxicity may be severe, and deaths have been reported.
Monitor liver function tests before initiation of treatment, during each cycle of treatment, and as clinically indicated. SUTENT should be interrupted for Grade 3 or 4 drug-related hepatic adverse events and discontinued if there is no resolution. Do not restart SUTENT if patients subsequently experience severe changes in liver function tests or have other signs and symptoms of liver failure.
Women of childbearing potential should be advised of the potential hazard to the fetus and to avoid becoming pregnant.
Given the potential for serious adverse reactions (ARs) in nursing infants, a decision should be made whether to discontinue nursing or SUTENT.
Cardiovascular events, including heart failure, myocardial disorders, and cardiomyopathy, some of which were fatal, have been reported. Monitor patients for signs and symptoms of congestive heart failure (CHF) and, in the presence of clinical manifestations, discontinuation is recommended. Patients who presented with cardiac events, pulmonary embolism, or cerebrovascular events within the previous 12 months were excluded from clinical studies.
SUTENT has been shown to prolong QT interval in a dose-dependent manner, which may lead to an increased risk for ventricular arrhythmias including torsades de pointes, which has been seen in <0.1% of patients. Monitoring with on-treatment electrocardiograms and electrolytes should be considered.
Hypertension may occur. Monitor blood pressure and treat as needed with standard antihypertensive therapy. In cases of severe hypertension, temporary suspension of SUTENT is recommended until hypertension is controlled.
There have been rare (<1%) nonfatal reports of subjects presenting with seizures and radiological evidence of reversible posterior leukoencephalopathy syndrome (RPLS).
Hemorrhagic events, including tumor-related hemorrhage such as pulmonary hemorrhage, have occurred. Some of these events were fatal. Perform serial complete blood counts (CBCs) and physical examinations.
Osteonecrosis of the jaw (ONJ) has been reported. Consider preventive dentistry prior to treatment with SUTENT. If possible, avoid invasive dental procedures, particularly in patients receiving bisphosphonates.
Cases of tumor lysis syndrome (TLS) have been reported primarily in patients with high tumor burden. Monitor these patients closely and treat as clinically indicated.
Thyroid dysfunction may occur. Monitor thyroid function in patients with signs and/or symptoms of hypothyroidism or hyperthyroidism and treat per standard medical practice.
Cases of impaired wound healing have been reported. Temporary interruption of therapy with SUTENT is recommended in patients undergoing major surgical procedures.
Adrenal hemorrhage was observed in animal studies. Monitor adrenal function in case of stress such as surgery, trauma, or severe infection.
CBCs with platelet count and serum chemistries including phosphate should be performed at the beginning of each treatment cycle for patients receiving treatment with SUTENT.
Dose adjustments are recommended when administered with CYP3A4 inhibitors or inducers.
The most common ARs occurring in ≥20% of patients receiving SUTENT for treatment-naïve metastatic RCC (all grades, vs IFNα) were diarrhea (66% vs 21%), fatigue (62% vs 56%), nausea (58% vs 41%), anorexia (48% vs 42%), altered taste (47% vs 15%), mucositis/stomatitis (47% vs 5%), pain in extremity/limb discomfort (40% vs 30%), vomiting (39% vs 17%), bleeding, all sites (37% vs 10%), hypertension (34% vs 4%), dyspepsia (34% vs 4%), arthralgia (30% vs 19%), abdominal pain (30% vs 12%), rash (29% vs 11%), hand-foot syndrome (29% vs 1%), back pain (28% vs 14%), cough (27% vs 14%), asthenia (26% vs 22%), dyspnea (26% vs 20%), skin discoloration/yellow skin (25% vs 0%), peripheral edema (24% vs 5%), headache (23% vs 19%), constipation (23% vs 14%), dry skin (23% vs 7%), fever (22% vs 37%), and hair color changes (20% vs <1%). The most common grade 3/4 ARs (occurring in ≥5% of patients with RCC receiving SUTENT vs IFNα) were fatigue (15% vs 15%), hypertension (13% vs <1%), asthenia (11% vs 6%), diarrhea (10% vs <1%), hand-foot syndrome (8% vs 0%), dyspnea (6% vs 4%), nausea (6% vs 2%), back pain (5% vs 2%), pain in extremity/limb discomfort (5% vs 2%), vomiting (5% vs 1%), and abdominal pain (5% vs 1%).
The most common grade 3/4 lab abnormalities (occurring in ≥5% of patients with RCC receiving SUTENT vs IFNα) included lymphocytes (18% vs 26%), lipase (18% vs 8%), neutrophils (17% vs 9%), uric acid (14% vs 8%), platelets (9% vs 1%), hemoglobin (8% vs 5%), sodium decreased (8% vs 4%), leukocytes (8% vs 2%), glucose increased (6% vs 6%), phosphorus (6% vs 6%), and amylase (6% vs 3%).
The most common ARs occurring in ≥20% of patients with GIST and more commonly with SUTENT than placebo (all grades, vs placebo) were diarrhea (40% vs 27%), anorexia (33% vs 29%), skin discoloration (30% vs 23%), mucositis/stomatitis (29% vs 18%), asthenia (22% vs 11%), altered taste (21% vs 12%), and constipation (20% vs 14%). The most common grade 3/4 ARs (occurring in ≥4% of patients with GIST receiving SUTENT vs placebo) were asthenia (5% vs 3%), hand-foot syndrome (4% vs 3%), diarrhea (4% vs 0%), and hypertension (4% vs 0%).
The most common grade 3/4 lab abnormalities (occurring in ≥5% of patients with GIST receiving SUTENT vs placebo) included lipase (10% vs 7%), neutrophils (10% vs 0%), amylase (5% vs 3%), and platelets (5% vs 0%).
The most common ARs occurring in ≥20% of patients with advanced pNET and more commonly with SUTENT than placebo (all grades, vs placebo) were diarrhea (59% vs 39%), stomatitis/oral syndromes (48% vs 18%), nausea (45% vs 29%), abdominal pain (39% vs 34%), vomiting (34% vs 31%), asthenia (34% vs 27%), fatigue (33% vs 27%), hair color changes (29% vs 1%), hypertension (27% vs 5%), hand-foot syndrome (23% vs 2%), bleeding events (22% vs 10%), epistaxis (21% vs 5%), and dysgeusia (21% vs 5%). The most commonly reported grade 3/4 ARs (occurring in ≥5% of patients with advanced pNET receiving SUTENT vs placebo) were hypertension (10% vs 1%), hand-foot syndrome (6% vs 0%), stomatitis/oral syndromes (6% vs 0%), abdominal pain (5% vs 10%), fatigue (5% vs 9%), asthenia (5% vs 4%), and diarrhea (5% vs 2%).
The most common grade 3/4 lab abnormalities (occurring in ≥5% of patients with advanced pNET receiving SUTENT vs placebo) included decreased neutrophils (16% vs 0%), increased glucose (12% vs 18%), increased alkaline phosphatase (10% vs 11%), decreased phosphorus (7% vs 5%), decreased lymphocytes (7% vs 4%), increased creatinine (5% vs 5%), increased lipase (5% vs 4%), increased AST (5% vs 3%), and decreased platelets (5% vs 0%).

索坦(SUTENT,舒尼替尼)-多靶点酪氨酸激酶抑制剂临床评价
苹果酸舒尼替尼(sunitinibmalate，索坦Sutent，SU11248)是一种新的多靶点酪氨酸激酶抑制剂,具有抗肿瘤和抗血管生成的双重作用。它是血管内皮生长因子受体(VEGFR一1，VEGFR一2)、血小板衍生生长因子受体(PDGFR—oc和PDGFR一13)、干细胞因子受体(C—kitR)、FMS样酪氨酸激酶一3(FLT-3)和RET等的抑制剂。舒尼替尼(索坦)主要由细胞色素CYP3A4代谢，药物动力学研究表明，潜在的活性靶血浆浓度~<50ng／mL，患者个体问可能有一定的差异。因本品有较长的半衰期(41～86小时)，故适于一日1次用药。FDA于2006年1月批准本品用于甲磺酸伊马替尼(imatinibmesylate，GGleevec)~疗失败或不能耐受的胃肠道间质瘤(GIST)患者，也批准其用于晚期肾细胞癌(RCC)患者，本品在其他实体瘤治疗中的应用也已进入II期临床。
二线治疗胃肠道间质瘤
胃肠道问质瘤好发于胃肠道，且具有特殊的组织学特征，是C—kit(CD117细胞表面抗原)阳性的问质肿瘤。手术切除是目前GIST惟一的根治手段，但复发率高；其对化放疗相对不敏感。选择性酪氨酸激酶抑制剂伊马替尼临床应用疗效好，逐渐成为GIST靶向治疗的典范。但原发性和继发性伊马替尼耐药者以及伊马替尼的持续应用时间等均是临床的一大难点。新的酪氨酸激酶抑制剂舒尼替尼(索坦)对伊马替尼耐药的GIST效果显著，令人鼓舞，I/Ⅱ期针对GIST的研究结果及长期随访证实，其对伊马替尼治疗失败或不耐受的GIST患者，可获得较好的临床疗效和生存期，与对照组相比，中位疾病进展时间(TTP)、疾病无进展生存期(PFS)和有效率(RR)优势显著，一项Ⅲ期随机双盲安慰剂对照多中心研究以舒尼替尼(索坦)治疗转移性和(或)不能手术切除、耐伊马替尼的GIST患者，舒尼替尼(索坦)剂量为口服一日50mg，连用4周后间隔2周，以6周为一治疗周期，与安慰剂组比较，患者中位TTP和中位PFS延长4倍以上。前者中位TTP为27．3周，后者为6．4周(P<0．0001)，两者部分缓解率(PR)分别为6．8％和0_，Demetri等报道，312例伊马替尼治疗无效或不能耐受的晚期GIST患者随机分组，研究组共207{~0，给予舒尼替尼(索坦)一El50mg，用药4周后间隔2周，以6周为一周期，结果，与安慰剂组(105例)相比，治疗组TTP明显延长至27．3周(95％置信区间C，：16．0～32．1)，而安慰剂组仅为6．4周(95％Cl：4．4～10．0，P<0．0001.本品与治疗相关的常见不良反应是疲劳，腹泻，皮肤脱色和恶心，一般可耐受。
治疗晚期肾细胞癌
肾细胞癌(RCC)的发病率居泌尿生殖系肿瘤的第二位，且呈上升趋势，手术是治疗RCC的有效方法，但65％的患者术后出现复发或转移，对放化疗敏感性不高，目前IL一2和(或)IFN—a与化疗是公认的第一线方案，但只有少数患者受益，故急需新的治疗策略。多靶向药物舒尼替尼(索坦)逐渐受到临床特别关注，I期临床表明，其最大13耐受剂量(MTD)≥50mg，推荐19剂量是50mg，应用4周后间隔2周。其主要不良反应是El腔炎、水肿、血小板减少，头发变色与皮肤黄染。Motzer等报道的多中心II期研究，63例曾用细胞因子(IFNa、IL一2)治疗失败或因不良反应不能耐受的转移I~]RCC患者单一13服舒尼替尼(索坦)一1950mg连续4周，间隔2周，6周为一周期。结果显示，63例中25例(40％)PR，17例(27％)SD持续时间>／3个月，TTP为8．7个月(95％Cl：5．5～10_7)，中位总生存期为16．4个月，且耐受良好。另一项舒尼替尼(索坦)治疗106例第一线治疗无效的转移性RCC患者，剂量方案如前，可评价疗效的105例患者中，36例达PR(34％，95％C／：25～44％)；中位PFS为8．3个月(95％C／：7．8～14．5个月)，提示本品治疗有效[4-6,11,12]。
I期临床研究针对750例透明细胞转移性RCC患者，评价舒尼替尼(索坦)与一线用药IFN—a的疗效，随机375例使用舒尼替尼(索坦)，375{~使用IFN—a，初步终点评估分析提示，舒尼替尼(索坦)效果良好，与IFN—a(900~"单位，每周3次皮下注射)相比，两者RR分别为31％~1：16％；中位TTP分别为11和5个月(HR0．415；P<0．001o在不良反应方面舒尼替尼(索坦)组腹泄、高血压和手足综合征明显较多，后者则是乏力较多[11-14]。总之，舒尼替尼(索坦)治疗转移性RCCJfl~I：LIFNa有较长的PFS、较高的RR和较佳的生活质量(QOL)。
治疗其他实体瘤与联合用药
舒尼替尼(索坦)用于其它实体瘤治疗的Il期研究评价本品用于蒽环类与紫杉醇类单一治疗失败的转移性乳腺癌患者，舒尼替尼(索坦)单一治疗临床总受益率(CBR)为16％(PR14％，SD2％，疾病无进展持续时间≥6个月)，用于不能切除的神经内分泌肿瘤、前列腺癌、结肠癌、非小细胞肺癌以及膀胱上皮癌等的单一治疗临床研究也在进行之中。
不良反应
舒尼替尼(索坦)一般不良反应有疲乏、腹泻、恶心、胃炎、消化不良、味觉减退和呕吐，皮肤脱色。严重不良反应有肺栓塞(1．1％)，血小板减少(1．1％)，肿瘤出血(O．9％)，中性白细胞降低所致的发热(O．4％)以及高血压(O．4％)等，特别需要注意的是甲状腺功能减退。Desai等报道42例接受舒尼替尼(索坦)治疗fl,*JGIST患者，中位治疗时间达37周(1O～167周)，26例(62％)出现血清促甲状腺素(TSH)异常；15例(36％)出现持续的甲状腺功能减退；4例(1O％)出现单一性TSH抑制；7例(17％)有暂时、轻度TSH升高，15例(4O％)有甲状腺炎。Rini等报道舒尼替尼(索坦)治疗的73例转移性RCC患者，可评价的66例中有56例(85％)甲状腺功能试验结果显示有一项或多项异常。虽然甲状腺激素可改善该症状，但需要常规监测，有待进一步研究。
总结与展望
GlST与转移性RCC都属于难治性恶性肿瘤。一般早期手术能够治愈，不宜手术或复发者，其对化。放疗通常均不敏感，故急需探寻有效的全身治疗用药。目前已被证实，选择性酪氨酸激酶抑制剂伊马替尼治疗GIST有良好的效果；新的酪氨酸激酶抑制剂舒尼替尼(索坦)对伊马替尼治疗失败或不能耐受的GIST患者确有临床疗效，是很好的GlST二线治疗选择。舒尼替尼(索坦)也是RCC有效的多靶点治疗药物。其不良反应一般轻微，新近发现甲状腺功能减退的发生率高，临床需常规监测和进一步评价。本品与其他靶向药物和(或)化．放疗联合应用，虽有一些理论基础和研究结果，但如何恰当地组合，多渠道有效封杀肿瘤细胞，尚需进一步研究。

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注：以下产品不同规格和不同价格，购买以咨询为准！
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产地国家: 美国
原产地英文商品名:
SUTENT 50mg/Capsule 28Capsules/bottle
原产地英文药品名:
SUNITINIB MALATE
中文参考商品译名:
索坦 50毫克/胶囊 28胶囊/瓶
中文参考药品译名:
苹果酸舒尼替尼
生产厂家中文参考译名:
CPPI CV
生产厂家英文名:
CPPI CV
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产地国家：美国
原产地英文商品名:
SUTENT 25mg/Capsule 28Capsules/bottle
原产地英文药品名:
SUNITINIB MALATE
中文参考商品译名:
索坦 50毫克/胶囊 28胶囊/瓶
中文参考药品译名:
苹果酸舒尼替尼
生产厂家中文参考译名:
CPPI CV
生产厂家英文名:
CPPI CV
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产地国家：美国
原产地英文商品名:
SUTENT 12.5mg/Capsule 28Capsules/bottle
原产地英文药品名:
SUNITINIB MALATE
中文参考商品译名:
索坦 50毫克/胶囊 28胶囊/瓶
中文参考药品译名:
苹果酸舒尼替尼
生产厂家中文参考译名:
CPPI CV
生产厂家英文名:
CPPI CV
该药品相关信息网址1:
http://www.accessdata.fda.gov/scripts/cder/onctools/summary.cfm?ID=369
该药品相关信息网址2:
http://www.sutent.com/