印度乐伐替尼

【印度乐伐替尼说明书，怎么吃？】

乐伐替尼（印度）又名乐伐替尼 Lenvatinib，乐伐替尼适用于1）乐伐替尼适用于有局部复发或转移，进展性，放射性碘，难治性分化型甲状腺癌患者的治疗。 2）乐伐替尼联合依维莫司治疗既往接受抗血管生成治疗的晚期肾细胞癌。的治疗，乐伐替尼用法及注意事项,:【药品特色】 乐伐替尼是血管内皮生长因子受体 1‒3（VEGFR 1-3）、成纤细胞生长因子受体 1-4（FGFR 1-4）、血小板衍生生长因子受体（PDGFR）、RET 和 KIT 的口服多靶点抑制剂，目前已经获得 FDA 批准用...

【药品特色】   

乐伐替尼是血管内皮生长因子受体 1‒3（VEGFR 1-3）、成纤细胞生长因子受体 1-4（FGFR 1-4）、血小板衍生生长因子受体α（PDGFRα）、RET 和 KIT 的口服多靶点抑制剂，目前已经获得 FDA 批准用于治疗分化型甲状腺癌和晚期肾细胞癌。 新数据显示，乐伐替尼一线治疗 uHCC，在 OS 方面非劣效于索拉非尼，在亚太人群中一线乐伐替尼治疗肝癌 OS 获益优于索拉非尼，作为 uHCC 的一线治疗方案乐伐替尼的 PFS、TTP 和 ORR 显著优于索拉非尼 。

【用法用量】
 
推荐剂量：
 
1)对于甲状腺癌患者：24mg口服，每天一次。
 
2）对于肾细胞癌患者：18mg乐伐替尼+5mg依维莫司口服，每天一次。
 
3) 在有严重肾或肝受损患者：对于甲状腺癌患者：14mg口服，每天一次；对于肾细胞癌患者：10mg口服，每天一次。
 
4) 肝细胞癌剂量：体重小于60kg的患者剂量为8mg, 每天一次，体重大于60kg的患者剂量为12mg，每天一次。
 

【注意事项】
 
1）每天在同一时间点服药。
 
2）出现漏服，距离下次服药大于12小时则立即补服用，

3）不到12小时则不用补服，按照平时时间点及剂量进行下一次用药即可。
 
4）用药直至疾病出现进展或出现不可耐受的毒副作用。


【不良反应】
 
乐伐替尼最常见副作用有高血压、疲劳、腹泻、关节肌肉痛(关节痛/肌肉痛)、食欲降低、呕吐、尿中蛋白过多(蛋白尿)、手掌肿胀及疼痛、手和/或脚底板(手足综合征)、腹痛及发音出现变化(语音障碍)。

乐伐替尼可以引起严重副作用，包括心衰、血栓形成(动脉血栓栓塞事件)、肝损伤(肝毒性)、肾损伤(肾衰竭及损伤)、胃肠道穿孔或胃或肠之间异常连接、心电图活动发生变化(QT间隔延长)、低血钙、伴随性头痛、癫痫发作和视觉变化(可逆性白质脑病综合征)、严重出血(大出血)、如果患者妊娠期间乐伐替尼治疗会出现未出生儿风险及促甲状腺激素产生出现损伤性抑制。
 
 
【注意事项】
 
1)高血压：用药治疗前控制血压。对尽管优化高血压治疗的3级高血压不给乐伐替尼治疗；对危及生命高血压终止用药。
 
2)心力衰竭：监视心脏代偿失调的临床症状和体征。对3级心功能不全不给乐伐替尼治疗；对4级心功能不全终止用药。
 
3)一次动脉血栓栓塞事件后终止用药。
 
4)肝毒性：用药期间定期监测肝功能检验。对3级或更大肝受损不给乐伐替尼治疗；对肝衰竭终止用药。
 
5)蛋白尿：用药期间定期监测蛋白尿。对24小时尿蛋白≥2g不给乐伐替尼治疗；对肾病综合征终止用药。
 
6)肾衰竭和肾受损：对3或4级肾衰竭受损不给乐伐替尼治疗。
 
7)发生胃肠道穿孔或危及生命瘘管患者终止用药。
 
8)对发生3级或更大QT间期延长不给乐伐替尼治疗。
 
9)低钙血症：监视血钙水平，给予替代钙。
 
10)对有可逆性后部白质脑病综合征患者不给乐伐替尼治疗，直至完全解决。
 
11)出血事件：对3级出血，及大量失血，需要输血患者不给乐伐替尼治疗;对4级出血，及失血造成身体虚弱，视网膜或大脑缺血，严重休克患者终止用药。
 
12)甲状腺刺激激素抑制的受损：每月监视TSH水平和有DTC患者，需要时调整甲状腺取代药物。
 
13)胚胎胎儿毒性：可能致胎儿危害。
 
  
【特殊人群使用】
 
哺乳：终止哺乳喂养。


USES OF LENVIMA CAPSULE
Thyroid cancer

LENVIMA CAPSULE SIDE EFFECTS
Common
Tiredness
Joint pain
Muscle pain
Decreased appetite
Nausea
Vomiting
Mouth sore
Peripheral edema
Stomach pain
Rash
Cough
Weight loss
Bleeding
Skin peeling
Itching
Skin redness
Hoarseness of voice

HOW TO USE LENVIMA CAPSULE
Take this medicine in the dose and duration as advised by your doctor. Swallow it as a whole. Do not chew, crush or break it. Lenvima 4 mg Capsule may be taken with or without food, but it is better to take it at a fixed time.

HOW LENVIMA CAPSULE WORKS
Lenvatinib is a tyrosine kinase inhibitor. It works by blocking the oxygen and nutrient supply to cancer cells due to which they stop growing.

LENVIMA CAPSULE RELATED WARNINGS
warnings
Alcohol
Interaction with alcohol is unknown. Please consult your doctor.

warnings
Pregnancy
WEIGH RISKS VS BENEFITS
Lenvima 4 mg Capsule may be unsafe to use during pregnancy.
Animal studies have shown adverse effects on the fetus, however, there are limited human studies. The benefits from use in pregnant women may be acceptable despite the risk. Please consult your doctor.

warnings
Lactation
CAUTION
Lenvima 4 mg Capsule is probably unsafe to use during lactation. Limited human data suggest that the drug could represent a significant risk to the baby.

warnings
Driving
It is not known whether Lenvima 4 mg Capsule alters the ability to drive. Do not drive if you experience any symptoms that affect your ability to concentrate and react.

warnings
Kidney
CAUTION
Lenvima 4 mg Capsule should be used with caution in patients with kidney disease. Dose adjustment of Lenvima 4 mg Capsule may be needed. Please consult your doctor.

warnings
Liver
CAUTION
Lenvima 4 mg Capsule should be used with caution in patients with liver disease. Dose adjustment of Lenvima 4 mg Capsule may be needed. Please consult your doctor.

Lenvatinib

生物活性

产品描述	Lenvatinib is a Kinase Inhibitor. The mechanism of action of lenvatinib is as a Receptor Tyrosine Kinase Inhibitor.
靶点活性	FGFR1,46nM PDGFRβ,39nM VEGFR1/FLT1,22nM VEGFR2/KDR,4.0nM VEGFR3/FLT4,5.2nM
实验溶液	0.5% methylcellulose: 30 mg/mL
体外活性	体外受体酪氨酸和丝/苏氨酸激酶实验中，E7080抑制Flt-1，KDR和Flt-4，IC50分别为22，4.0和5.2 nM。最新研究显示，1 μM和10 μM E7080通过抑制FGFR和PDGFR信号通路明显抑制细胞迁移和入侵。E7080有效抑制血管生成，也明显抑制VEGF/KDR和SCF/KIT信号通路。E7080也抑制FGFR1和PDGFR酪氨酸激酶，作用于FGFR1，PDGFRα和PDGFRβ时，IC50分别为46，51和100 nM。E7080分别作用于由血管内皮生长因子和血管内皮生长因子-C刺激的HUVECs，有效抑制VEGFR2和VEGFR3磷酸化，IC50分别为0.83 nM和0.36 nM。
体内活性	与血管内皮生长因子抗体和伊马替尼处理相比，100 mg/kg E7080处理降低微脉管密度效果更好。用30和100 mg/kg E7080口服给药处理H146 移植瘤模型，可以剂量依赖性抑制H146肿瘤生长，100 mg/kg时导致肿瘤退化
激酶实验	In vitro kinase assay [1]: Tyrosine kinase assays are performed by HTRF (KDR, VEGFR1, FGFR1, c-Met, EGFR) and ELISA (PDGFRβ), using the recombinant kinase domains of receptors. In both assays, 4 μL of serial dilutions of E7080 are mixed in a 96-well round plate with 10 μL of enzyme, 16 μL of poly (GT) solution (250 ng) and 10 μL of ATP solution (1 μM ATP) (final concentration of DMSO is 0.1%). In wells for blanks, no enzyme is added. In control wells no test article is added. The kinase reaction is initiated by adding ATP solution to each well. After 30-minute incubation at 30°C, the reaction is stopped by adding 0.5 M EDTA (10 μL/well) to the reaction mixture in each well. Dilution buffer adequate to each kinase assay is added to the reaction mixture. In the HTRF assay, 50 μL of the reaction mixture is transferred to a 96-well 1/2 area black EIA/RIA plate, HTRF solution (50 μL/well) is added to the reaction mixture, and then kinase activity is determined by measurement of fluorescence with a time-resolved fluorescence detector at an excitation wavelength of 337 nm and an emission wavelengths of 620 and 665 nm. In the ELISA, 50 μL of the reaction mixture is incubated in avidin coated 96-well polystyrene plates at room temperature for 30 minutes. After washing with wash buffer, PY20-HRP solution (70 μL/well) is added and the reaction mixture is incubated at room temperature for 30 minutes. After washing with wash buffer, TMB reagent (100 μL/well) is added to each well. After several minutes (10–30 minutes), 1 M H3PO4 (100 μL/well) is added to each well. Kinase activity is determined by measurement of absorbance at 450 nm with a microplate reader.
细胞实验	HUVECs (1,000 cells in each well in serum-free medium containing 2% fetal bovine serum) and L6 rat skeletal muscle myoblasts (5,000 cells in each well in serum-free DMEM) are dispensed in a 96-well plate and incubated overnight. E7080 and either VEGF (20 ng/mL) or FGF-2 (20 ng/mL) containing 2% fetal bovine serum and PDGFβ (40 ng/mL) are added to each well. Cells are incubated for 3 days and then the ratios of surviving cells are measured by WST-1 reagent. For proliferation assay, samples are duplicated and three separate experiments are done. (Only for Reference) 细胞系： HUVECs
动物实验	动物模型：H146 tumor cells are implanted subcutaneously (s.c.) into the flank region of feBALB/c nude mice.

化学信息

分子量	426.85
分子式	C21H19ClN4O4
CAS	417716-92-8
溶解度	DMSO: 38 mg/mL (89 mM) Ethanol: <1 mg/mL （ < 1 mg/ml refers to the product slightly soluble or insoluble )
储存条件	store at -80°C
备注	For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.

配制溶液

	1 mg	5 mg	10 mg
1 mM	2.343 ml	11.714 ml	23.427 ml
5 mM	0.469 ml	2.343 ml	4.685 ml
10 mM	0.234 ml	1.171 ml	2.343 ml
50 mM	0.047 ml	0.234 ml	0.469 ml

参考文献
 
1. Matsui J, et al. Int J Cancer. 2008, 122(3), 664-671.
2. Matsui J, et al. Clin Cancer Res. 2008, 14(17),5459-5465.
3. Glen H, et al. BMC Cancer. 2011, 11, 309.