维罗非尼 | 918504-65-1

• 物质功能分类: 原料药 - 抗肿瘤药 - 激素类抗肿瘤药
• 分子结构分类: 有机化合物 - 有机氧化合物
• 中文名称: 维罗非尼
• 英文名称: vemurafenib
• 英文别名: PLX4032；N-(3-(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide；propane-1-sulfonic acid {3-[5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide；zelboraf；RG7204；N-(3-[[5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]carbonyl]-2,4-difluorophenyl)-1-propanesulfonamide；N-(3-{[5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]carbonyl}-2,4-difluorophenyl)propane-1-sulfonamide；vemurafinib；R05185426；N-[3-[5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluorophenyl]propane-1-sulfonamide
• CAS: 918504-65-1
• 化学式: C₂₃H₁₈ClF₂N₃O₃S
• 分子量: 489.93
• InChiKey: GPXBXXGIAQBQNI-UHFFFAOYSA-N

物化性质

• 密度：
  1.46
• 溶解度：
  溶于 DMSO（高达 100 mg/ml）
• 颜色/状态：
  White to off-white crystalline solid
• 熔点：
  272°C
• 蒸汽压力：
  8.21X10-15 mm Hg at 25 °C (est)
• 稳定性/保质期：

  Stable if stored as directed; avoid strong oxidizing agents

• 分解：
  Dangerous products of decomposition: thermal ecomposition may produce toxic gases such as carbon monoxide, carbon dioxide, and nitrogen oxides.
• Caco2细胞的药物渗透性：
  2.9e-06
• 解离常数：
  pKa = 7.2 (amine) (est)

计算性质

• 辛醇/水分配系数(LogP)：
  5
• 重原子数：
  33
• 可旋转键数：
  7
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.13
• 拓扑面积：
  100
• 氢给体数：
  2
• 氢受体数：
  7

ADMET

代谢

Vemurafenib 通过 CYP3A4 进行代谢，代谢物在血浆成分中占 5%，而母化合物则占剩余的 95%。

Vemurafenib is metabolized by CYP3A4 and the metabolites make up 5% of the components in plasma. The parent compound makes up for the remaining 95%.[A31274]

来源:DrugBank

代谢

体外研究的结果表明，CYP3A4是在维莫非尼代谢中的主要酶。使用CYP抑制剂酮康唑，单羟基代谢物的形成被抑制了大约82%。在人类肝脏微粒体中，当存在奎尼丁（CYP2D6抑制剂）、磺胺苯唑（CYP2C9抑制剂）、反式环丙胺（CYP2A6抑制剂）和（-）-N-3-苯基-苯巴比妥（CYP2C19抑制剂）时，没有观察到显著的代谢抑制作用。此外，CYP3A4还负责单羟基化代谢物的形成。

The results from in vitro studies indicate that CYP3A4 was the major enzyme responsible in the metabolism of vemurafenib. The formation of mono-hydroxyl metabolites were inhibited for approximately 82% using the CYP inhibitor ketoconazole. No significant inhibition in the metabolism was observed in human liver microsomes in the presence of quinidine (CYP2D6 inhibitor), sulfaphenazole (CYP2C9 inhibitor), tranylcypromine (CYP2A6 inhibitor) and (-)-N-3-benzyl-phenobarbital (CYP2C19 inhibitor). In addition, CYP3A4 was responsible for the formation of the mono-hydroxylation metabolites.

来源:Hazardous Substances Data Bank (HSDB)

代谢

体外代谢在小鼠、大鼠、狗、食蟹猴和人类中进行了分析。对维莫非尼的代谢进行了研究，既包括使用各种物种的微粒体和肝细胞的体外研究，也包括在大鼠、狗和人体内的研究。在体外分析中，将维莫非尼在肝细胞中的浓度设为10微摩尔时，人类、狗和食蟹猴并没有广泛代谢维莫非尼（未改变的维莫非尼大于或等于89%）。

In vitro metabolism was analyzed for rat, mouse, dog, cynomolgus and human. The metabolism of vemurafenib was investigated both in vitro using microsomes and hepatocytes of various species and in vivo in rat, dog and human. In vitro analysis of vemurafenib metabolism in liver hepatocytes at the concentration of 10 uM, humans, dogs, and cynomolgus monkeys did not metabolize vemurafenib extensively (unchanged vemurafenib > or = 89%).

来源:Hazardous Substances Data Bank (HSDB)

代谢

在研究/患者/中，对血浆、粪便和尿液中维莫拉非尼及其代谢物进行了前96小时的鉴定，总收集期为432小时（18天）。7名患者的平均数据显示，在调查期间（0至96小时），潜在代谢物在尿液中的总量小于0.5%，在粪便中占给药总量的0.6%。在48小时后剂量的合并粪便样本中，母体化合物占总放射活性的至少94%（剂量的37%）。在48-96小时后剂量的粪便样本中，代谢物的数量增加，M6、M3和M8分别约占色谱总峰面积的19%、14%和12%（平均值）或剂量的3%、5%和4%。在0-96小时的收集期间，潜在代谢物M3（单羟基）和M6（葡萄糖苷化）在尿液中的总量均小于0.5%。维莫拉非尼在尿液中的总量约占1%。

In study /of patients/, identification of vemurafenib and metabolites in plasma, feces and urine was made for the first 96 hr, with a total collection period of 432 hrs (18 days). Mean data from the 7 patients indicated that over the period investigated (0 to 96 hours), potential metabolites each accounted for < 0.5% of the total administered dose in urine and .6% of the total administered dose in feces. In pooled fecal samples up to 48 hours post post-dose, parent compound accounted for at least 94% of total radioactivity (37% of the dose). In fecal samples taken 48-96 hr post-dose, the amount of metabolites increased, with M6, M3, and M8 representing approximately 19%, 14% and 12%, of the total chromatographic peak area, respectively (mean values) or 3%, 5% and 4% of the dose, respectively. Over the 0-96 hr collection period, potential metabolites M3 (mono-hydroxy) and M6 (glucosylation) each accounted for <0.5% of the total administered dose in urine. Vemurafenib accounted for approximately 1% of the total dose in urine.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 肝毒性

在大规模的临床试验中，服用维莫非尼的患者常见的肝脏检测异常，其中高达三分之一的患者出现血清转氨酶升高。ALT和AST值超过正常上限5倍的情况发生在3%的患者中，尽管有报告称极少数患者出现了临床上明显的肝损伤，但损伤的临床特征尚未被描述。肝脏检测异常的出现通常在开始服用维莫非尼后3到6周内，异常通常会自发地迅速解决，或者在暂时停药后解决。维莫非尼还与药物相关的皮疹伴嗜酸性粒细胞增多和系统表现（DRESS）以及史蒂文斯-约翰逊综合征有关，这两种情况都可能导致肝功能异常，在某些情况下还会伴有黄疸和临床上明显的肝损伤。

In large clinical trials of vemurafenib, abnormalities in routine liver tests were common and serum aminotransferase elevations occurred in up to one third of patients. ALT and AST values greater than 5 times the upper limit of normal (ULN) occurred in 3% of patients, and rare instances of clinically apparent liver injury were reported, but the clinical features of the injury have not been described. The onset of liver test abnormalities was typically within 3 to 6 weeks of starting vemurafenib, and the abnormalities resolved rapidly either spontaneously or with temporary drug discontinuation. Vermurafenib has also been linked to instances of drug related rash with eosinophilia and systemic manifestations (DRESS) as well as Stevens Johnson syndrome, both of which can be accompanied by liver dysfunction and in some cases jaundice with clinically apparent liver injury.

来源:LiverTox

毒理性

• 相互作用

制造商不推荐将vemurafenib与已知会延长QT间期的药物同时使用，包括Ia类（例如，奎尼丁，普鲁卡因胺）和III类（例如，胺碘酮，索他洛尔）抗心律失常药，一些抗精神病药（例如，氯丙嗪，硫利达嗪，氯丙嗪，阿塞那平，奥氮平，帕利哌酮，匹莫齐特，喹硫平，齐拉西酮），一些抗生素（例如，加替沙星，莫西沙星）和四苯氮唑。

Concomitant use of vemurafenib with drugs known to prolong the QT interval, including class Ia (e.g., quinidine, procainamide) and class III (e.g., amiodarone, sotalol) antiarrhythmic agents, some antipsychotic agents (e.g., chlorpromazine, thioridazine, haloperidol, asenapine, olanzapine, paliperidone, pimozide, quetiapine, ziprasidone), some antibiotics (e.g., gatifloxacin, moxifloxacin), and tetrabenazine is not recommended by the manufacturer.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

联合使用维莫非尼和CYP2C9底物可能导致CYP2C9底物血浆浓度升高，可能出现毒性。当CYP2C9底物华法林与维莫非尼同时给药时，S-华法林的系统暴露增加了18%。维莫非尼和华法林应谨慎联合使用，并考虑增加国际标准化比率（INR）的监测。

Concomitant use of vemurafenib with CYP2C9 substrates may result in increased plasma concentrations of the CYP2C9 substrate and possible toxicity. When the CYP2C9 substrate warfarin was administered concomitantly with vemurafenib, the systemic exposure of S-warfarin increased by 18%. Vemurafenib and warfarin should be used concomitantly with caution and additional monitoring of the international normalized ratio (INR) should be considered.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

与CYP3A4底物同时使用vemurafenib可能会导致CYP3A4底物的血浆浓度降低，可能会降低疗效。当CYP3A4底物咪达唑仑与vemurafenib同时给药时，咪达唑仑的系统暴露量降低了39%。应避免将vemurafenib与治疗指数狭窄的CYP3A4底物同时使用。

Concomitant use of vemurafenib with CYP3A4 substrates may result in decreased plasma concentrations of the CYP3A4 substrate and possible decreased efficacy. When the CYP3A4 substrate midazolam was administered concomitantly with vemurafenib, the systemic exposure of midazolam decreased by 39%. Concomitant use of vemurafenib with CYP3A4 substrates that have a narrow therapeutic index should be avoided.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

维莫非尼与CYP2D6底物的联合使用可能会导致CYP2D6底物血浆浓度升高，可能出现毒性。当CYP2D6底物右美沙芬与维莫非尼同时使用时，右美沙芬的系统暴露量增加了47%。应避免将维莫非尼与治疗指数狭窄的CYP2D6底物联合使用。如果无法避免联合使用，应考虑减少CYP2D6底物的剂量，并且在使用时应谨慎。

Concomitant use of vemurafenib with CYP2D6 substrates may result in increased plasma concentrations of the CYP2D6 substrate and possible toxicity. When the CYP2D6 substrate dextromethorphan was administered concomitantly with vemurafenib, the systemic exposure of dextromethorphan increased by 47%. Concomitant use of vemurafenib with CYP2D6 substrates that have a narrow therapeutic index should be avoided. If concomitant use cannot be avoided, dosage reduction of the CYP2D6 substrate should be considered, and the drugs should be used concomitantly with caution.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

• 吸收

口服给药后，Vemurafenib吸收良好。[A31273] 当患者每天两次口服960毫克，连续15天时，3小时达到峰值浓度。在相同条件下，Vemurafenib的Cmax为62微克/毫升，AUC为601微克·小时/毫升。[FDA标签] 目前尚不清楚食物如何影响Vemurafenib的吸收。在重复剂量960毫克后，其积累比为7.36。[L1014]

Vemurafenib is well absorbed after oral administration.[A31273] Peak concentrations are reached in 3 hours when an oral dose of 960 mg twice daily for 15 days has been given to patients. In the same conditions, Vemurafenib presents a Cmax of 62 mcg/ml and AUC of 601 mcg h/ml.[FDA label] It is unknown how food affects the absorption of vemurafenib. It presents an accumulation ratio of 7.36 after repeating doses of 960 mg [L1014]

来源:DrugBank

吸收、分配和排泄

• 消除途径

分析显示，94%的服用维莫非尼通过粪便排出，1%通过尿液排出。[A31274]

Analysis showed that 94% of administered Vemurafenib is excreted via feces and 1% is excreted by urine.[A31274]

来源:DrugBank

吸收、分配和排泄

• 分布容积

维莫非尼的分布体积估计为106升。[A31274]

The estimation of the volume of distribution for Vemurafenib is 106 L.[A31274]

来源:DrugBank

吸收、分配和排泄

• 清除

总体身体清除率为31升/天。[A31274]

The total body clearance is 31 L/day.[A31274]

来源:DrugBank

吸收、分配和排泄

在口服了960毫克片剂形式的(14)C-维莫拉非尼后，对血浆样本进行了48小时的分析，以测定维莫拉非尼及其代谢物。平均数据显示，维莫拉非尼及其代谢物分别占血浆中成分的95%和5%。

Following oral administration of (14)C-vemurafenib 960 mg in the tablet formulation, plasma samples were analyzed over 48 hours for vemurafenib and its metabolites. Mean data showed that vemurafenib and its metabolites represented 95% and 5% of the components in plasma, respectively.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 海关编码：
  2935009090
• 危险性防范说明：
  P261,P305+P351+P338
• 危险性描述：
  H315,H319,H335
• 储存条件：
  -20°C

制备方法与用途

理化性质

维罗非尼是白色粉末或块状粉末。易溶于N,N-二甲基乙酰胺，难溶于丙酮，几乎不溶于水。

药理作用及作用机制

维罗非尼是一种低分子量口服可吸收的BRAF丝氨酸-苏氨酸激酶抑制剂，特别针对包括某些BRAFV600E突变形式。在体外相似浓度下，它还抑制其他激酶如CRAF、ARAF、野生型RAF、SRMS、ACK1、MAP4K5和FGR。BRAF基因突变导致BRAF蛋白持续激活，在没有相关生长因子刺激的情况下促进细胞的持续增殖。

药代动力学

维罗非尼的Tmax中位数约为3小时，Cmax和AUC0-12的平均值分别为(62±17)μg/ml和(601±170)μg·h/ml。其表观分布容积约为106 L，并且与人白蛋白和α-1酸性糖蛋白血浆蛋白的结合率超过99%。口服14C标记维罗非尼960 mg后，粪便中检测到放射性物质占给药剂量的94%，尿样中的比例为1%。表观清除率为31 L/d，消除半衰期约为57小时，在15～22天内达到稳态，并且在血浆中的平均暴露量稳定，累积比为1.13。

生物活性

VemuRAfenib (PLX4032, RG7204, RO5185426) 是一种新型有效的B-RAfV600E抑制剂，IC50值为31 nM。相较于野生型B-RAf，其对B-RAfV600E的选择性高10倍，在细胞实验中选择性可高达100倍以上。该药物还可诱导自噬。

靶点

Target	Value
SRMS	18 nM
ACK1	19 nM
B-RAf (V600E)	31 nM
C-RAf	48 nM
MAP4K5	51 nM

体外研究

PLX4032 抑制B-RAF突变的黑色素瘤细胞系，其作用效果依赖于B-RAF突变状态。此药物有效抑制含B-RAF V600E突变的黑色素瘤。

体内研究

PLX4032 在6 mg/kg至20 mg/kg剂量下对携带B-RAF V600E突变的黑色素瘤细胞系表现出显著抑制效果。在12.5 mg/kg至100 mg/kg剂量下，该药物作用于LOX、Colo829和A375移植瘤小鼠时能有效抑制肿瘤生长并延长小鼠寿命。