(1R,9S,12S,15R,16Z,18R,19R,21R,23S,24Z,26Z,28Z,30S,32S,35R)-1,18-dihydroxy-12-[(2R)-1-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxycyclohexyl]propan-2-yl]-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.04,9]hexatriaconta-16,24,26,28-tetraene-2,3,10,14,20-pentone | 159351-69-6

• 物质功能分类: 原料药 - 影响免疫功能药 - 免疫抑制药
• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 大环内酯内酰胺
• 英文名称: (1R,9S,12S,15R,16Z,18R,19R,21R,23S,24Z,26Z,28Z,30S,32S,35R)-1,18-dihydroxy-12-[(2R)-1-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxycyclohexyl]propan-2-yl]-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.04,9]hexatriaconta-16,24,26,28-tetraene-2,3,10,14,20-pentone
• CAS: 159351-69-6
• 化学式: C₅₃H₈₃NO₁₄
• 分子量: 958.2
• InChiKey: HKVAMNSJSFKALM-ADNAJIBWSA-N

物化性质

• 熔点：
  NA
• 沸点：
  998.7±75.0 °C(Predicted)
• 密度：
  1.18±0.1 g/cm3(Predicted)
• 闪点：
  2℃
• 溶解度：
  可溶于DMSO（高达100mg/ml）或乙醇（高达100mg/ml）。
• 稳定性/保质期：

  Stable under recommended storage conditions.

计算性质

• 辛醇/水分配系数(LogP)：
  5.9
• 重原子数：
  68
• 可旋转键数：
  9
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.75
• 拓扑面积：
  205
• 氢给体数：
  3
• 氢受体数：
  14

ADMET

代谢

依维莫司是CYP3A4和PgP的底物。口服给药后，依维莫司是人类血液中的主要循环成分。已在人类血液中检测到依维莫司的六个主要代谢物，包括三种单羟基化代谢物、两种水解开环产物以及一种依维莫司的磷脂酰胆碱共价结合物。这些代谢物也在毒性研究中使用的动物物种中被识别，并且显示出比依维莫司本身大约低100倍的活动性。

Everolimus is a substrate of CYP3A4 and PgP. Following oral administration, everolimus is the main circulating component in human blood. Six main metabolites of everolimus have been detected in human blood, including three monohydroxylated metabolites, two hydrolytic ring-opened products, and a phosphatidylcholine conjugate of everolimus. These metabolites were also identified in animal species used in toxicity studies, and showed approximately 100-times less activity than everolimus itself.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 肝毒性

血清酶水平升高发生在多达四分之一的服用依维莫司的患者中，但这些异常通常是轻微的、无症状的，并且是自限性的，很少需要调整剂量或停药。肝功能测试升高超过上限五倍的情况只发生在1%到2%的治疗患者中。相比之下，尽管依维莫司在多种恶性和非恶性综合征中广泛使用，但特异质、临床上明显的急性肝损伤并未与依维莫司治疗相关联。血清酶、胆红素升高和肝炎在依维莫司的产品标签中被列为潜在的副作用。因此，由于依维莫司导致的临床上明显的急性肝损伤并伴有黄疸的情况可能非常罕见，甚至可能根本不会发生。 重要的是，依维莫司具有免疫抑制作用，在接受癌症治疗的患者中，已与乙型肝炎病毒再激活的发作相关联，这可能是严重的，甚至可能是致命的。反向血清转换（在预先存在乙型肝炎抗体的人中发展HBsAg，无论是抗-HBs还是抗-HBc）也已有报道。 可能性评分：E*（未证实的，也不太可能是临床上明显肝损伤的原因，但能够诱导乙型肝炎病毒的再激活）。

Serum enzyme elevations occur in up to a quarter of patients taking everolimus, but the abnormalities are usually mild, asymptomatic and self-limiting, rarely requiring dose modification or discontinuation. Liver test elevations above 5 times ULN occur in only 1% to 2% of treated patients. In contrast, idiosyncratic, clinically apparent acute liver injury has not been linked to everolimus therapy despite its wide scale use in several malignant and non-malignant syndromes. Elevations in serum enzymes and bilirubin and hepatitis are listed as potential adverse events in the product label for everolimun. Thus, acute clinically apparent liver injury with jaundice due to everolimus is probably quite rare, if it occurs at all. Importantly, everolimus is immunosuppressive and therapy in patients with cancer has been associated with episodes of reactivation of hepatitis B, which can be severe and even fatal. Reverse seroconversion (development of HBsAg in a person with preexisting antibody to hepatitis B, either anti-HBs or anti-HBc) has also been reported. Likelihood score: E* (unproven and also unlikely cause of clinically apparent liver injury but capable of inducing reactivation of hepatitis B).

来源:LiverTox

毒理性

• 相互作用

使用HMG-CoA还原酶抑制剂（如洛伐他汀或辛伐他汀）在肾移植患者中进行的依维莫司与环孢素的临床试验中强烈不推荐，因为HMG-CoA还原酶抑制剂与环孢素之间存在相互作用。Zortress的生产商建议，在接受依维莫司和环孢素治疗的同时正在接受HMG-CoA还原酶抑制剂和/或纤维酸衍生物的患者中，应监测可能发生的横纹肌溶解症和其他不良反应，这些不良反应在这些降脂药物的处方信息中有描述。

Use of HMG-CoA reductase inhibitors such as lovastatin or simvastatin was strongly discouraged in clinical trials of everolimus with cyclosporine in renal transplant patients because of an interaction between HMG-CoA reductase inhibitors and cyclosporine. The manufacturer of Zortress recommends that patients receiving everolimus and cyclosporine therapy who are concurrently receiving an HMG-CoA reductase inhibitor and/or fibric acid derivative be monitored for the possible development of rhabdomyolysis and other adverse effects, which are described in the prescribing information for these antilipemic agents.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

在健康个体中进行的研究表明，单次剂量的依维莫司与阿托伐他汀（CYP3A4底物）或普伐他汀（非CYP3A4底物和P-糖蛋白底物）之间没有临床重要的药代动力学相互作用；血浆中HMG-CoA还原酶的生物活性也没有受到显著影响。因此，当依维莫司与阿托伐他汀或普伐他汀同时使用时，不需要调整剂量。在一项群体药代动力学分析中，辛伐他汀（CYP3A4底物）并未影响依维莫司的清除率。Zortress的生产商警告，这些结果不能推广到其他HMG-CoA还原酶抑制剂。

Studies in healthy individuals indicate that there are no clinically important pharmacokinetic interactions between single-dose everolimus and atorvastatin (a CYP3A4 substrate) or pravastatin (a non-CYP3A4 substrate and P-gp substrate); HMG-CoA reductase bioactivity in plasma also was not substantially affected. Therefore, dosage adjustments are not necessary when everolimus and atorvastatin or pravastatin are used concurrently. In a population pharmacokinetic analysis, simvastatin (a CYP3A4 substrate) did not affect clearance of everolimus. The manufacturer of Zortress cautions that these results cannot be extrapolated to other HMG-CoA reductase inhibitors.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

与依维莫司联合使用血管紧张素转换酶（ACE）抑制剂可能会增加血管性水肿的风险。如果需要，应考虑在依维莫司治疗的患者中使用其他抗高血压药物。

Concomitant use of angiotensin-converting enzyme (ACE) inhibitors with everolimus may increase the risk of angioedema. The use of alternative antihypertensive agents should be considered in everolimus-treated patients, if necessary.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

如果需要对SEGA患者联合使用P-gp抑制剂，应将依维莫司的剂量减少大约50%，以保持低谷浓度在5-10 ng/mL。如果在每日接受2.5 mg剂量的患者中需要减少剂量，应考虑隔日给药。随后的剂量应根据治疗药物监测个性化调整。在添加P-gp抑制剂后大约2周应评估依维莫司的低谷浓度。如果停用P-gp抑制剂，应将依维莫司的剂量恢复到开始使用P-gp抑制剂之前的剂量，并在大约2周后重新评估依维莫司的低谷浓度。

If coadministration of a P-gp inhibitor is required in patients with SEGA, everolimus dosage should be reduced by approximately 50% to maintain trough everolimus concentrations of 5-10 ng/mL. If dosage reduction is required in patients receiving 2.5 mg daily, alternate-day dosing should be considered. Subsequent dosing should be individualized based on therapeutic drug monitoring. Trough everolimus concentrations should be assessed approximately 2 weeks after the addition of the P-gp inhibitor. If the P-gp inhibitor is discontinued, the everolimus dosage should be returned to the dosage used prior to initiation of the P-gp inhibitor and the trough everolimus concentration should be reassessed approximately 2 weeks later.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

依维莫司的血液到血浆比率取决于浓度，在5 ng/mL到5000 ng/mL的范围内从17%变化到73%。在健康受试者和中度肝功能损害的患者中，血浆蛋白结合率大约为74%。在维持性肾脏移植患者中，单次给药药代动力学研究的终末相表观分布体积（Vz/F）为342至107升（范围128至589升）。

The blood-to-plasma ratio of everolimus is concentration dependent ranging from 17% to 73% over the range of 5 ng/mL to 5000 ng/mL. Plasma protein binding is approximately 74% in healthy subjects and in patients with moderate hepatic impairment. The apparent distribution volume associated with the terminal phase (Vz/F) from a single-dose pharmacokinetic study in maintenance kidney transplant patients is 342 to 107 L (range 128 to 589 L).

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

依维莫司的血液到血浆比率，在5至5000 ng/mL的浓度范围内是浓度依赖性的，为17%至73%。在癌症患者中，观察到服用阿芬太尼10毫克/天的血液浓度时，血浆中受限的依维莫司量大约为20%。在健康受试者和中度肝功能损害的患者中，血浆蛋白结合率大约为74%。

The blood-to-plasma ratio of everolimus, which is concentration-dependent over the range of 5 to 5000 ng/mL, is 17% to 73%. The amount of everolimus confined to the plasma is approximately 20% at blood concentrations observed in cancer patients given Afinitor 10 mg/day. Plasma protein binding is approximately 74% both in healthy subjects and in patients with moderate hepatic impairment.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

在给予晚期实体瘤患者服用阿芬太利片后，口服剂量从5毫克到70毫克，血药浓度峰值在给药后1到2小时内达到。单次给药后，Cmax（最高血药浓度）与5毫克至10毫克每日剂量的给药呈剂量比例关系。在20毫克及以上的单次剂量中，Cmax的增加小于剂量比例，然而AUC（药时曲线下面积）在5毫克到70毫克的剂量范围内显示剂量比例性。在每日一次给药后，稳态血药浓度在2周内达到。

After administration of Afinitor tablets in patients with advanced solid tumors, peak everolimus concentrations are reached 1 to 2 hours after administration of oral doses ranging from 5 mg to 70 mg. Following single doses, Cmax is dose-proportional with daily dosing between 5 mg and 10 mg. With single doses of 20 mg and higher, the increase in Cmax is less than dose-proportional, however AUC shows dose-proportionality over the 5 mg to 70 mg dose range. Steady-state was achieved within 2 weeks following once-daily dosing.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

没有针对癌症患者进行特定的消除研究。在给予接受环孢素的病人单次3毫克的放射性标记的依维莫司后，80%的放射性物质从粪便中回收，而5%通过尿液排出。原药在尿液或粪便中未检测到。依维莫司的平均消除半衰期大约为30小时。

No specific elimination studies have been undertaken in cancer patients. Following the administration of a 3 mg single dose of radiolabeled everolimus in patients who were receiving cyclosporine, 80% of the radioactivity was recovered from the feces, while 5% was excreted in the urine. The parent substance was not detected in urine or feces. The mean elimination half-life of everolimus is approximately 30 hours.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险品标志：
  T
• 安全说明：
  S45
• 危险类别码：
  R48/25
• WGK Germany：
  2
• 海关编码：
  29349990
• 危险品运输编号：
  UN 1648 3 / PGII
• 危险性防范说明：
  P280,P305+P351+P338
• 危险性描述：
  H302

制备方法与用途

西罗莫司衍生物——依维莫司

**依维莫司**是西罗莫司的衍生物，又称40-O-(2-羟乙基)-雷帕霉素或40-O-(2-羟乙基)-西罗莫司。它是一种激酶类药物，属于干扰细胞通讯以防止肿瘤细胞生长的一类口服哺乳动物雷帕霉素(mTOR)抑制剂。临床上主要用于预防肾移植和心脏移植手术后的排斥反应，目前也可用于治疗已使用过舒尼替尼（Sutent, 辉瑞制药）和索拉非尼（Nexavar, 拜耳制药）的晚期肾癌患者，并且其毒副作用相对较轻。

作用机制

依维莫司通过与细胞内蛋白质FKBP12结合，形成抑制性的复合体mTORC1，从而抑制mTOR激酶活性。这种抑制作用会导致转录调节因子S6核糖体蛋白激酶（S6K1）和真核生物延伸因子4E结合蛋白（4E-BP）的活性下降，进而影响细胞增殖并诱导细胞凋亡及自噬。依维莫司还表现出抗血管生成/血管效果，并且在体外与RApamycin相比，具有更强的免疫抑制作用。

临床应用

**依维莫司**于2009年3月30日获得美国FDA批准用于肾癌治疗。研究结果表明，依维莫司可显著延长癌症病人的无进展生存期，并为经舒尼替尼或索拉非尼治疗无效的晚期肾细胞癌病人提供新的治疗选择。2009年8月，欧盟委员会批准诺华生产的Afinitor(依维莫司)片剂用于晚期肾细胞癌(RCC)患者的治疗。

生物活性与靶点

• Everolimus (RAD001, SDZ-RAD)是一种mTOR抑制剂，在无细胞试验中的IC50值为1.6-2.4 nM。
• 该药物作用于FKBP12和mTOR，其在无细胞实验中的IC50分别为1.6 nM-2.4 nM。

体外研究

• Everolimus与RApamycin相比，在抑制免疫活性方面表现更优。它能与固定化的FK 506竞争性结合到生物素化的FKBP12上，IC50为1.6 nM-2.4 nM。
• 在BALB/c和CBA小鼠脾脏细胞中，Everolimus抑制双向MLR的IC50值为0.12 nM-1.8 nM。此外，在VEGF诱导的HUVEC增殖和bFGF诱导的 HUVEC增殖方面，其抗血管生成/血管效果明显，IC50分别为0.12 nM和 0.8 nM。
• 最新研究显示Everolimus可抑制BT474 细胞系和原发性乳腺癌细胞的全部细胞和干细胞生长。当作用于原发性乳腺癌时，IC50为 156 nM；在BT474细胞中，该值降低至71 nM。

体内研究

• Everolimus (0.1 到 10 mg/kg)能够抑制B16/BL6黑色素瘤的原代生长和淋巴结转移，并且这种作用具有剂量依赖性。
• 在携带BT474干细胞移植瘤动物模型中，Everolimus能显著降低肿瘤体积。

以上信息展示了依维莫司在多个方面的生物学特性和临床应用潜力。随着研究的深入，更多关于其机制与效果的研究将继续推进这一药物的发展。通过不断优化和探索，有望为更多患者带来更有效的治疗选择。

Target	Value
FKBP12 (Cell-free assay)	1.6-2.4 nM
mTOR (FKBP12) (Cell-free assay)	1.6 nM-2.4 nM

文献信息

• Method of Treating Cancer
  申请人：Exelixis, Inc.

  公开号：US20140057908A1

  公开（公告）日：2014-02-27

  This invention is directed to the treatment of cancer, particularly castration-resistant prostate cancer and osteoblastic bone metastases, with a dual inhibitor of MET and VEGF.

  本发明旨在使用MET和VEGF的双重抑制剂治疗癌症，特别是去势抵抗性前列腺癌和骨转移性骨转移癌。
• LOW TEMPERATURE SYNTHESIS OF RAPAMYCIN DERIVATIVES
  申请人：BIOSENSORS INTERNATIONAL GROUP, LTD.

  公开号：US20150322086A1

  公开（公告）日：2015-11-12

  The present invention provides improved processes for obtaining rapamycin derivatives including Biolimus A9.

  本发明提供了用于获得雷帕霉素衍生物（包括Biolimus A9）的改进工艺。
• Antigen-specific CD4+ and CD8+ central-memory T cell preparations for adoptive T cell therapy
  申请人：Schmück, Michael

  公开号：EP2532740A1

  公开（公告）日：2012-12-12

  The invention relates to a method for generation of T cell preparations that are specific for at least one target antigen, comprising the steps of expanding lymphoid cells in vitro in the presence of a target antigen or peptide fragments thereof in an expansion step, isolating cells that secrete interferon gamma and culturing, the cells in the presence of interleukin 2 and interleukin 7 and either an inhibitor of the mTOR Complex 1, or in the presence of an inhibitor of IL-2/IL-2R interaction. The invention further relates to preparations obtained by the method of the invention.

  本发明涉及一种产生对至少一种靶抗原特异的T细胞制剂的方法，包括以下步骤：在体外扩增淋巴细胞，在扩增步骤中存在靶抗原或其多肽片段；分离分泌γ干扰素的细胞；在存在白细胞介素2和白细胞介素7以及mTOR复合物1抑制剂或存在IL-2/IL-2R相互作用抑制剂的情况下培养细胞。本发明还涉及通过本发明方法获得的制剂。
• Pharmaceutical composition for the use in a combination therapy for prevention or treatment of C-Met or angiogenesis factor induced diseases
  申请人：Samsung Electronics Co., Ltd

  公开号：EP2708556A1

  公开（公告）日：2014-03-19

  Provided is a method of combination therapy for prevention or treatment of c-Met-induced or angiogenesis factor-induced diseases including co-administering an angiogenesis inhibitor and an anti-c-Met antibody or an antigen-binding fragment thereof to a patient.

  本发明提供了一种用于预防或治疗 c-Met 诱导的疾病或血管生成因子诱导的疾病的联合治疗方法，包括向患者联合施用血管生成抑制剂和抗-Met 抗体或其抗原结合片段。
• Purification of rapamycin derivatives using temperature induced phase separation
  申请人：Biosensors International Group, Ltd.

  公开号：US10202402B2

  公开（公告）日：2019-02-12

  The present invention provides methods for obtaining purified rapamycin derivatives, including purified Biolimus A9. A crystalline form of Biolimus A9 is also described.

  本发明提供了获得纯化雷帕霉素衍生物（包括纯化的 Biolimus A9）的方法。本发明还描述了一种结晶形式的 Biolimus A9。