Eltrombopag | 496775-61-2

• 物质功能分类: 生物化工 - 生化试剂 - 激动剂抑制剂
• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: Eltrombopag
• 英文别名: 3-[3-[[2-(3,4-dimethylphenyl)-5-methyl-3-oxo-1H-pyrazol-4-yl]diazenyl]-2-hydroxyphenyl]benzoic acid
• CAS: 496775-61-2
• 化学式: C₂₅H₂₂N₄O₄
• 分子量: 442.5
• InChiKey: SVOQIEJWJCQGDQ-UHFFFAOYSA-N

物化性质

• 熔点：
  242-244°C
• 沸点：
  656.8±65.0 °C(Predicted)
• 密度：
  1.33
• 溶解度：
  可溶于DMSO（高达55mg/ml）或乙醇（高达14mg/ml）。
• 颜色/状态：
  Orange solid
• 蒸汽压力：
  1.17X10-17 mm Hg at 25 °C (est)
• 亨利常数：
  Henry's Law constant = 2.44X10-20 atm-cu m/mol at 25 °C (est)
• 解离常数：
  pKa1 = 3.99 (carboxyl); pKa2 = 9.11 (benzyl alcohol); pKa3 = 12.69 (amine) (est)

计算性质

• 辛醇/水分配系数(LogP)：
  5.4
• 重原子数：
  33
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.12
• 拓扑面积：
  115
• 氢给体数：
  3
• 氢受体数：
  7

ADMET

代谢

艾曲泊帕主要通过包括裂解、氧化和与葡萄糖醛酸、谷胱甘肽或半胱氨酸结合的途径进行代谢。体外研究表明，CYP1A2和CYP2C8负责艾曲泊帕的氧化代谢。UGT1A1和UGT1A3负责艾曲泊帕的葡萄糖醛酸化。

Eltrombopag is predominantly through pathways including cleavage, oxidation, and conjugation with glucuronic acid, glutathione, or cysteine. In vitro studies suggest that CYP1A2 and CYP2C8 are responsible for the oxidative metabolism of eltrombopag. UGT1A1 and UGT1A3 are responsible for the glucuronidation of eltrombopag.

来源:DrugBank

代谢

艾曲波帕在体外的大鼠、狗和猴子的代谢轮廓在性质上是相似的。没有证据表明形成了任何特定于人类的代谢物。在体内，艾曲波帕在所有物种中都是循环中的主要成分。在大鼠中，人类循环代谢物的覆盖是充分的。M14在人类尿液中排泄占20%，在小鼠尿液中最高可达9.2%，但在大鼠中未检测到，狗的相关信息不可用。

The metabolic profiles of eltrombopag in vitro were qualitatively similar in rats, dogs and monkeys. There has been no evidence for the formation of any human specific metabolites. In vivo eltrombopag was the predominant circulating component in all species. In rats there was adequate coverage for the circulating metabolites in humans. M14 which accounts for a 20% in human urine excretion was present up to 9.2% in mice urine but was not detected in rats and information is not available in dogs.

来源:Hazardous Substances Data Bank (HSDB)

代谢

14(C)-eltrombopag与人类肝脏微粒体和超微体孵化后，形成了代谢物J（eltrombopag的单氧化产物）。CYP1A2和CYP2C8是eltrombopag体外氧化代谢的主要酶。UGT1A1和UGT1A3将eltrombopag代谢形成代谢物K（葡萄糖醛酸苷结合物）。将[14C]eltrombopag与人类肝细胞孵化后，观察到的的主要代谢途径是与葡萄糖醛酸（代谢物K）或半胱氨酸（代谢物G）结合。其他次要途径包括与谷胱甘肽（代谢物F）结合以及氧化，导致形成M+14的代谢物。检测到的其他代谢物包括代谢物J（单氧化）和代谢物O（甲基氧化成羧酸）。人类肾脏微粒体在体外对eltrombopag的代谢能力极小。

Following incubation of 14(C)-eltrombopag with human liver microsomes and supersomes resulted in the formation of metabolite J (a mono-oxygenation product of eltrombopag). CYP1A2 and CYP2C8 were the primary enzymes involved in the in vitro oxidative metabolism of eltrombopag. UGT1A1 and UGT1A3 metabolized eltrombopag to form metabolite K (glucuronide conjugate). Following incubation of [14C]eltrombopag with human hepatocytes, the major metabolic pathways observed were conjugation with glucuronic acid (metabolite K) or cysteine (metabolite G). Other minor pathways were conjugation with glutathione (metabolite F) and oxidation that led to formation of an M+14 metabolite. Additional metabolites detected included metabolite J (mono-oxygenated) and metabolite O (oxidation of a methyl to a carboxylic acid). Human kidney microsomes exhibited minimal capacity to metabolize eltrombopag in vitro.

来源:Hazardous Substances Data Bank (HSDB)

代谢

eltrombopag被吸收后，会广泛代谢，主要通过包括裂解、氧化以及与葡萄糖醛酸、谷胱甘肽或半胱氨酸结合的途径。体外研究表明，CYP1A2和CYP2C8负责eltrombopag的氧化代谢。UGT1A1和UGT1A3负责eltrombopag的葡萄糖醛酸化。

Absorbed eltrombopag is extensively metabolized, predominantly through pathways including cleavage, oxidation, and conjugation with glucuronic acid, glutathione, or cysteine. In vitro studies suggest that CYP1A2 and CYP2C8 are responsible for the oxidative metabolism of eltrombopag. UGT1A1 and UGT1A3 are responsible for the glucuronidation of eltrombopag.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

Eltrombopag可能会导致肝毒性，特别是在与干扰素和利巴韦林联合用于慢性丙型肝炎患者时（可能会增加肝功能失代偿的风险）。

Eltrombopag may cause hepatotoxicity, especially if administered in combination with interferon and ribavirin in patients with chronic hepatitis C (may increase the risk of hepatic decompensation).

来源:DrugBank

毒理性

• 毒性总结

识别和使用：艾曲泊帕是一种橙色的固体。它是一种非肽类促血小板生成素受体激动剂，用于口服片剂治疗血小板减少症。人类暴露和毒性：艾曲泊帕可能会导致肝脏和胆道功能受损。在接受该药物的患者中，有10%的患者报告了血清酶ALT、AST和胆红素浓度2级（或更低）的异常。在接受艾曲泊帕的患者中，有1例报告了血清肝酶4级（国家癌症研究所常见毒性标准术语（NCI CTCAE）毒性量表）升高，以及潜在心肺疾病恶化随后死亡。对于慢性丙型肝炎患者，这种药物与干扰素和利巴韦林联合使用可能会增加肝功能失代偿的风险。动物研究：在小鼠中，艾曲泊帕在剂量高达75 mg/kg/天时没有致癌性，在大鼠中，剂量高达40 mg/kg/天时也没有致癌性。在大鼠的产前和产后发育研究中，在剂量高达20 mg/kg/天时，对母鼠的妊娠、分娩或哺乳没有不良影响，对后代的生长、发育、神经行为或生殖功能也没有影响。在另一项大鼠发育研究中，以60 mg/kg/天的剂量观察到胚胎毒性，表现为着床前和着床后损失增加（导致活产仔数减少27%）和胎儿体重减少20%至21%。在大鼠的雄性生育研究中，40 mg/kg/天时睾丸重量略有增加，但艾曲泊帕对处理过的雄性的交配和生育没有影响，对处理过的雄性后代的存活、生长或外部形态也没有影响。艾曲泊帕在细菌突变试验中或在两项大鼠体内试验（微核和不定期DNA合成）中不具有突变性或断裂性。在小鼠淋巴瘤体外试验中，艾曲泊帕的边缘阳性（突变频率增加不到3倍）。这些体内和体外的研究结果表明，艾曲泊帕对人类不具有遗传毒性风险。

IDENTIFICATION AND USE: Eltrombopag is orange solid. It is a nonpeptide thrombopoietin receptor agonist, which is used as oral tablets for treatment of thrombocytopenia. HUMAN EXPOSURE AND TOXICITY: Eltrombopag may cause hepatic and biliary impairment. Grade 2 (or less) abnormalities in serum enzymes ALT, AST, and bilirubin concentrations have been reported in 10% of patients receiving the drug. Grade 4 (National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) toxicity scale) elevations in serum liver enzymes, as well as worsening of underlying cardiopulmonary disease and subsequent death, were reported in one patient receiving eltrombopag. In patients with chronic hepatitis C, this drug in combination with interferon and ribavirin may increase the risk of hepatic decompensation. ANIMAL STUDIES: Eltrombopag was not carcinogenic in mice at doses up to 75 mg/kg/day or in rats at doses up to 40 mg/kg/day. In a pre- and post-natal development study in rats, there were no adverse effects on pregnancy, parturition or lactation of female rats and no effects on the growth, development, neurobehavioral or reproductive function of the offspring at doses up to 20 mg/kg/day. In another rat developmental study embryotoxicity was observed at 60 mg/kg/day in the form of increased pre- and post-implantation loss (leading to a 27% decrease in live litter size) and a 20% to 21% decrease in fetal weight. In a male fertility study in rats testicular weights were slightly increased at 40 mg/kg/day, but there were no effects of eltrombopag on mating and fertility of the treated males, nor any effects on survival, growth or external morphology of the fetuses sired by the treated males. Eltrombopag was not mutagenic or clastogenic in a bacterial mutation assay or in two in vivo assays in rats (micronucleus and unscheduled DNA synthesis). In the in vitro mouse lymphoma assay, eltrombopag was marginally positive (<3 fold increase in mutation frequency). These in vitro and in vivo findings suggest that eltrombopag does not pose a genotoxic risk to humans.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 肝毒性

在ITP患者的临床试验中，服用艾曲波帕的患者中有10%至11%出现ALT升高，而服用安慰剂的患者中有3%至7%出现升高，但这些升高通常是轻微和短暂的，在停用艾曲波帕后解决，有时甚至在继续使用时也会解决。有报道称，在重新开始服用艾曲波帕的患者中出现了血清酶水平升高的复发情况，一些患者在治疗期间据说发展成了严重的肝病，可能是由于门静脉血栓形成的结果。由于此类报告，艾曲波帕在治疗慢性丙型肝炎患者时有一个关于肝毒性和可能发生肝功能失代偿的黑框警告，并建议在此情况下监测肝功能测试。尽管如此，在医学文献中没有公开发表的报告表明艾曲波帕治疗与特异质临床明显的肝损伤有关，而且尚未描述药物引起的肝损伤的临床特征、发病时间、酶水平升高的模式和停止治疗后的反应。此外，随着针对丙型肝炎更有效的抗病毒药物的发展，干扰素现在很少使用，并且在使用干扰素治疗期间同时使用艾曲波帕治疗血小板减少的指征也很少遇到。

In clinical trials in patients with ITP, ALT elevations occurred in 10% to 11% of eltrombopag vs 3% to 7% of placebo treated subjects, but the elevations were usually mild and transient, resolving once eltrombopag was discontinued and sometimes even with continued use. Instances in which there was recurrence of serum enzyme elevations with restarting eltrombopag have been reported and several patients were said to have developed serious liver disease on treatment, perhaps as a result of portal vein thrombosis. Because of such reports, eltrombopag has a boxed warning about hepatotoxicity and the possibility of hepatic decompensation when treating patients with chronic hepatitis C, in which situation monitoring of liver tests is recommended. Despite this, there have been no published reports of idiosyncratic clinically apparent liver injury attributable to eltrombopag therapy in the medical literature and the clinical characteristics, timing on onset, pattern of enzyme elevations and response to withdrawal of therapy of the liver injury attributed to the drug have not been described. Furthermore, with the development of more potent antiviral agents for hepatitis C, interferon is now rarely used and the indication for concurrent use of eltrombopag for thrombocytopenia during interferon therapy is rarely encountered.

来源:LiverTox

毒理性

• 相互作用

艾曲泊帕与食物、矿物质补充剂和抗酸剂中发现的多种价态阳离子（例如铁、钙、铝、镁、硒、锌）发生螯合作用。在接受同时含有氢氧化铝、碳酸镁和海藻酸钠的抗酸治疗的患者中，艾曲泊帕的血浆浓度降低了70%；与高钙、高脂肪早餐一起使用时，艾曲泊帕的AUC（药时曲线下面积）报告减少了59%。患者在每次服用艾曲泊帕前后4小时内应避免使用含有多种价态阳离子的药物和食物，包括抗酸剂、乳制品和矿物质补充剂。

Eltrombopag chelates polyvalent cations (e.g., iron, calcium, aluminum, magnesium, selenium, zinc) found in food, mineral supplements, and antacids. Plasma concentration of eltrombopag was reduced by 70% in patients receiving concomitant antacid therapy containing aluminum hydroxide, magnesium carbonate, and sodium alginate; a 59% reduction in AUC for eltrombopag was reported in association with a high-calcium, high-fat breakfast. Patients should avoid medications and foods containing polyvalent cations, including antacids, dairy products, and mineral supplements, for 4 hours before and after each dose of eltrombopag.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

温和到强效的UGT1A1或UGT1A3抑制剂：可能导致艾曲波帕的系统暴露量增加，从而产生潜在的药物动力学相互作用。1 使用时需谨慎。

Moderate to strong inhibitors of UGT1A1 or UGT1A3: Potential pharmacokinetic interaction resulting in increased systemic exposure to eltrombopag.1 Use with caution.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

• 吸收

Eltrombopag的峰值吸收发生在口服给药后大约2-6小时，服用75毫克剂量后，与药物相关的物质的总体口服吸收率估计至少为52%。

Peak absorption of Eltrombopag occurs around 2-6 hours following oral administration, and the total oral absorption of drug-related material following a 75 mg dose was estimated to be at least 52%.

来源:DrugBank

吸收、分配和排泄

• 消除途径

艾曲泊帕主要通过粪便消除（59%），同时有31%通过肾脏排出。

Eltrombopag is eliminated primarily via the feces (59%), along with 31% being renally excreted.

来源:DrugBank

吸收、分配和排泄

• 分布容积

根据一项放射性标记研究，eltrombopag在血细胞中的浓度大约是血浆浓度的50%到79%。

Based on a radiolabel study, the concentration of eltrombopag in blood cells is approximately 50% to 79% of plasma concentrations.

来源:DrugBank

吸收、分配和排泄

艾曲泊帕的主要排泄途径是通过粪便（59%），31%的剂量在尿液中。粪便中未改变的艾曲泊帕约占剂量的20%；尿液中未检测到未改变的艾曲泊帕。

The predominant route of eltrombopag excretion is via feces (59%), and 31% of the dose is found in the urine. Unchanged eltrombopag in feces accounts for approximately 20% of the dose; unchanged eltrombopag is not detectable in urine.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

根据放射性标记研究，eltrombopag在血细胞中的浓度大约是血浆浓度的50%至79%。体外研究表明，eltrombopag与人体血浆蛋白高度结合（大于99%）。Eltrombopag是BCRP的底物，但不是P-糖蛋白（P-gp）或OATP1B1的底物。

The concentration of eltrombopag in blood cells is approximately 50% to 79% of plasma concentrations based on a radiolabel study. In vitro studies suggest that eltrombopag is highly bound to human plasma proteins (greater than 99%). Eltrombopag is a substrate of BCRP, but is not a substrate for P-glycoprotein (P-gp) or OATP1B1.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 海关编码：
  2933990090
• 危险性防范说明：
  P280,P305+P351+P338
• 危险性描述：
  H302

制备方法与用途

造血神药艾曲波帕（Eltrombopag）由英国葛兰素史克（GSK）公司研发，后与瑞士诺华公司合作开发。它是全球首个也是唯一一个获得批准的小分子非肽类TPO受体激动剂。

2008年，艾曲波帕获美国FDA批准用于治疗特发性血小板减少性紫癜（ITP）。2014年，它又获批用于治疗重型再生障碍性贫血（AA），成为近30年来首款被美国FDA批准应用于AA的药物。同年2月，葛兰素史克宣布艾曲波帕获得突破性治疗药物资格，用于对免疫疗法没有充分响应的严重型再生障碍性贫血 (SAA) 患者的血细胞减少。

2015年8月，美国FDA进一步批准艾曲波帕，可用于1岁及以上慢性免疫性血小板减少症（ITP）患者的成人和儿童血小板减少症。2018年1月4日，该药物在中国获批上市，用于治疗原发免疫性血小板减少症。

生物活性方面，艾曲波帕 (SB-497115) 是一种属于biarylhydrazone的小分子，作为thrombopoietin rECeptor (TpoR) 的非肽类激动剂，主要用于治疗慢性丙型肝炎相关的血小板减少和慢性免疫性(自发的)血小板减少（ITP）。

靶点方面：

• Target: thrombopoietin rECeptor (TpoR)

在体外研究中，艾曲波帕表现出的半数最大有效浓度（EC50）为0.27 μM。它通过结合金属铁(i.e., Zn2+)和TpoR的跨膜与近膜结构域内特异性氨基酸来激活受体。免疫印迹检测显示，Eltrombopag (30 μM) 激活N2C-Tpo 细胞中STAT5。经过两天的培育后，Eltrombopag 刺激细胞增殖，EC50 为0.03 μM，并诱导造血干细胞分化为巨核祖细胞。

Eltrombopag 剂量依赖性增加骨髓CD34+ 细胞分化为 CD41+ 巨核细胞（EC50 为 0.1 μM）。在 N2C-Tpo 和 HEL92.1.7 细胞中，Eltrombopag 抑制增殖，IC50 分别为 20.7 μg/mL 和 2.3 μg/mL。在人和小鼠白血病细胞中，Eltrombopag (20 μg/mL) 导致细胞分裂率减少、细胞周期G1期阻滞及分化增加。在 HL60 细胞中，Eltrombopag (5 μg/mL) 使细胞内游离铁离子减少，并增加 CD11b 表达。

体内研究显示，Eltrombopag（10 mg/kg 每天）在最后一次给药后的一周内显著增加了黑猩猩体内的血细胞数量，另外两只黑猩猩体内则分别增加了约 1.5 倍。此外，Eltrombopag (1 mg/mL) 还延长了白血病小鼠模型的存活时间。