N-[(3S,6S,9S,11R,20R,21S,24S,25S)-21-(2-aminoethylamino)-3-[(1R)-3-amino-1-hydroxypropyl]-6-[(1S,2S)-1,2-dihydroxy-2-(4-hydroxyphenyl)ethyl]-11,20,25-trihydroxy-15-[(1R)-1-hydroxyethyl]-2,5,8,14,17,23-hexaoxo-1,4,7,13,16,22-hexazatricyclo[22.3.0.09,13]heptacosan-18-yl]-10,12-dimethyltetradecanamide | 162808-62-0

• 物质功能分类: 原料药 - 专科用药 - 眼科用药
• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: N-[(3S,6S,9S,11R,20R,21S,24S,25S)-21-(2-aminoethylamino)-3-[(1R)-3-amino-1-hydroxypropyl]-6-[(1S,2S)-1,2-dihydroxy-2-(4-hydroxyphenyl)ethyl]-11,20,25-trihydroxy-15-[(1R)-1-hydroxyethyl]-2,5,8,14,17,23-hexaoxo-1,4,7,13,16,22-hexazatricyclo[22.3.0.09,13]heptacosan-18-yl]-10,12-dimethyltetradecanamide
• CAS: 162808-62-0
• 化学式: C₅₂H₈₈N₁₀O₁₅
• 分子量: 1093.3
• InChiKey: JYIKNQVWKBUSNH-WKWIBHCQSA-N

物化性质

• 沸点：
  1408.1±65.0 °C(Predicted)
• 密度：
  1.36±0.1 g/cm3(Predicted)
• 溶解度：
  In water, 28 mg/L at 25 °C (est)

计算性质

• 辛醇/水分配系数(LogP)：
  0.3
• 重原子数：
  77
• 可旋转键数：
  23
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.75
• 拓扑面积：
  412
• 氢给体数：
  16
• 氢受体数：
  18

ADMET

代谢

通过水解和N-乙酰化缓慢代谢；同时发生自发的化学降解，并进一步水解为构成氨基酸及其降解产物，包括二羟基同酪氨酸和N-乙酰二羟基同酪氨酸。

Slowly metabolized by hydrolysis and N-acetylation; also undergoes spontaneous chemical degradation and further hydrolysis to constitutive amino acids and their degredates, including dihydroxyhomotyrosine and N-acetyl-dihydroxyhomotyrosine.

来源:Hazardous Substances Data Bank (HSDB)

代谢

卡泊芬净在肝脏通过水解和N-乙酰化缓慢代谢；单次静脉注射放射性标记剂量后，分别有35%和41%的母药及其代谢物通过粪便和尿液排出。

Caspofungin is slowly metabolized in the liver via hydrolysis and N-acetylation; 35 and 41% of the parent drug and metabolites were excreted in feces and urine, respectively, following a single IV radiolabeled dose.

来源:Hazardous Substances Data Bank (HSDB)

代谢

研究了小鼠、大鼠、兔和猴单次静脉注射卡泊芬净后的代谢、排泄和药代动力学。...在所有研究物种中，放射性物质的排泄速度都较慢，在整个延长的收集期内，每日尿液和粪便样本中都能检测到低水平的放射性物质。尽管尿液中存在多种代谢物（M0、M1、M2、M3、M4、M5和M6）的迹象，但大部分总放射性物质与极性代谢物M1 [4(S)-羟基-4-(4-羟基苯基)-L-苏氨酸]和M2（N-乙酰-4(S)-羟基-4-(4-羟基苯基)-L-苏氨酸）有关。因此，卡泊芬净主要通过代谢转化消除；然而，代谢速率较慢。...

The metabolism, excretion, and pharmacokinetics of caspofungin were investigated after administration of a single intravenous dose to mice, rats, rabbits, and monkeys. ... Excretion of radioactivity in all species studied was slow, and low levels of radioactivity were detected in daily urine and fecal samples throughout a prolonged collection period. Although urinary profiles indicated the presence of several metabolites (M0, M1, M2, M3, M4, M5, and M6), the majority of the total radioactivity was associated with the polar metabolites M1 [4(S)-hydroxy-4-(4-hydroxyphenyl)-L-threonine] and M2 (N-acetyl-4(S)-hydroxy-4-(4-hydroxyphenyl)-L-threonine). Caspofungin was thus primarily eliminated by metabolic transformation; however, the rate of metabolism was slow. ...

来源:Hazardous Substances Data Bank (HSDB)

代谢

醋酸卡泊芬净通过水解和N-乙酰化缓慢代谢。醋酸卡泊芬净还会自发化学降解为开环肽化合物L-747969。在较晚的时间点（≥5天剂量后），单次给药后血浆中存在低水平的（≤7皮摩尔/毫克蛋白，或≤1.3%的给药剂量）放射性标记的共价结合，这可能是由于醋酸卡泊芬净化学降解为L-747969时形成的两个反应中间体。额外的代谢涉及水解成构成氨基酸及其降解物，包括二羟基同酪氨酸和N-乙酰二羟基同酪氨酸。这两种酪氨酸衍生物仅存在于尿液中，表明这些衍生物通过肾脏迅速清除。/醋酸卡泊芬净/

Caspofungin is slowly metabolized by hydrolysis and N-acetylation. Caspofungin also undergoes spontaneous chemical degradation to an open-ring peptide compound, L-747969. At later time points (> or = 5 days postdose), there is a low level (< or = 7 picomoles/mg protein, or < or = 1.3% of administered dose) of covalent binding of radiolabel in plasma following single-dose administration of (3)H caspofungin acetate, which may be due to two reactive intermediates formed during the chemical degradation of caspofungin to L-747969. Additional metabolism involves hydrolysis into constitutive amino acids and their degradates, including dihydroxyhomotyrosine and N-acetyl-dihydroxyhomotyrosine. These two tyrosine derivatives are found only in urine, suggesting rapid clearance of these derivatives by the kidneys. /Caspofungin acetate/

来源:Hazardous Substances Data Bank (HSDB)

代谢

... 在对健康受试者进行70毫克(3)HCaspofungin醋酸盐1小时静脉输液后，药物相关物质的排泄非常缓慢，以至于在27天内，分别有41%和35%的给药放射性在尿液和粪便中回收。在给药后约24小时收集的血浆和尿液样本中，主要含有未改变的卡泊芬净醋酸盐，以及微量的肽水解产物M0，一种线性肽。然而，在随后的采样时间点，M0被证明是循环中的主要成分，而相应的尿液样本主要含有水解代谢物M1和M2，以及M0和未改变的MK-0991，其在给药后前16天的累积尿排泄分别占尿放射性的13%、71%、1%和9%。主要代谢物M2在酸性条件下极性很高且非常不稳定，当其转化为识别为N-乙酰-4(S)-羟基-4-(4-羟基苯基)-L-苏氨酸γ-内酯的较不极性产物时。在水相介质中对M2进行衍生化，导致其被识别为相应的γ-羟基酸，N-乙酰-4(S)-羟基-4-(4-羟基苯基)-L-苏氨酸。代谢物M1极性极高，从高效液相色谱柱空隙体积后立即洗脱，通过化学衍生化被识别为脱乙酰-M2。因此，MK-0991的主要尿液和血浆代谢物来自于肽水解和/或N-乙酰化。/卡泊芬净醋酸盐/

... Following a 1 hr IV infusion of 70 mg of (3)HCaspofungin acetate to healthy subjects, excretion of drug-related material was very slow, such that 41 and 35% of the dosed radioactivity was recovered in urine and feces, respectively, over 27 days. Plasma and urine samples collected around 24 hr postdose contained predominantly unchanged caspofungin acetate, together with trace amounts of a peptide hydrolysis product, M0, a linear peptide. However, at later sampling times, M0 proved to be the major circulating component, whereas corresponding urine specimens contained mainly the hydrolytic metabolites M1 and M2, together with M0 and unchanged MK-0991, whose cumulative urinary excretion over the first 16 days postdose represented 13, 71, 1, and 9%, respectively, of the urinary radioactivity. The major metabolite, M2, was highly polar and extremely unstable under acidic conditions when it was converted to a less polar product identified as N-acetyl-4(S)-hydroxy-4-(4-hydroxyphenyl)-L-threonine gamma-lactone. Derivatization of M2 in aqueous media led to its identification as the corresponding gamma-hydroxy acid, N-acetyl-4(S)-hydroxy-4-(4-hydroxyphenyl)-L-threonine. Metabolite M1, which was extremely polar, eluting from HPLC column just after the void volume, was identified by chemical derivatization as des-acetyl-M2. Thus, the major urinary and plasma metabolites of MK-0991 resulted from peptide hydrolysis and/or N-acetylation. /Caspofungin acetate/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

在这项研究中，研究了卡泊芬净和美罗培南单独使用以及联合使用在患有播散性念珠菌病的小鼠中的疗效。免疫功能正常的小鼠通过静脉注射感染了2x10(6) CFU的白念珠菌。在感染后24小时，开始进行腹腔内治疗，并持续7天。治疗组包括那些接受卡泊芬净（0.5、1.25、5 mg/kg/天）、美罗培南（20 mg/kg/天）以及这两种药物联合使用的组。肾脏CFU计数显示，接受了两种药物的小鼠残留负担较低。与未治疗的感染对照组相比，卡泊芬净在0.5、1.25、5 mg/kg的剂量下有效。在体外，卡泊芬净和美罗培南的最低抑菌浓度分别为<0.075 ug/mL和>64 ug/mL。联合使用时观察到协同作用。组织病理学显示，与单药治疗相比，联合治疗的炎症程度降低了25%，肾小管坏死更为局限。结果表明，同时使用卡泊芬净和美罗培南治疗可能有益。

... In this study the efficacies of caspofungin and meropenem - separately and together - in mice with disseminated candidiasis were studied. Immunocompetent mice were infected intravenously with 2x10(6) CFU of Candida albicans. At 24 hr postinfection, intraperitoneal therapy was initiated and was continued for 7 days. Therapy groups included those given caspofungin (0.5, 1.25, 5 mg/kg/day), meropenem (20 mg/kg/day), and a combination of the two drugs. ... Kidney CFU counts showed that mice that had received both drugs had lower residual burdens. Caspofungin was effective at doses of 0.5, 1.25, 5 mg/kg compared to infected untreated controls. In vitro, MICs of caspofungin and meropenem were <0.075 ug/mL and >64 ug/mL, respectively. Synergism was observed with the combination. Histopathology showed that the degree of inflammation was 25% less and tubular necrosis was more restricted in combined therapy than monotherapy. The results indicate that concurrent caspofungin and meropenem therapy may be beneficial.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

与Tacrolimus同时使用可能会导致Tacrolimus血药浓度降低；建议监测Tacrolimus的浓度，并可能需要调整剂量。

Concomitant use /with tacrolimus/ may result in decreased tacrolimus blood concentrations; monitoring of tacrolimus concentrations is recommended, and dosage adjustments may be required.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

潜在的药物动力学相互作用（降低卡泊芬净的血药浓度）。与清除药物的诱导剂或混合诱导剂/抑制剂（如依非韦伦、奈非那韦、奈韦拉平、苯妥英、利福平、地塞米松或卡马西平）联合使用卡泊芬净可能会导致临床上重要的卡泊芬净血药浓度降低。...

Potential pharmacokinetic interaction (reduction in caspofungin plasma concentrations.). Coadministration of caspofungin with inducers or mixed inducer/inhibitors of drug clearance such as efavirenz, nelfinavir, nevirapine, phenytoin, rifampin, dexamethasone, or carbamazepine may result in clinically important reductions in plasma caspofungin concentrations. ...

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

在两项平行板研究中评估了卡泊芬净与利托那韦或利福平之间的相互作用。在研究A中，健康受试者接受了14天的卡泊芬净单独治疗（50毫克静脉注射[IV]，每日一次）（n = 10），或者与利托那韦（1,250毫克口服，每日两次）（n = 9）或利福平（600毫克口服，每日一次）（n = 10）联合治疗。在研究B中，14名受试者接受了28天的利福平治疗（600毫克口服，每日一次），在最后14天同时给予卡泊芬净（50毫克IV，每日一次），12名受试者接受了14天的卡泊芬净单独治疗（50毫克IV，每日一次）。根据给药后24小时内的时间-浓度曲线下面积[AUC(0-24)]计算的联合给药/单独给药的几何平均比率如下（括号内的值是90%置信区间[CI]）：利托那韦为1.08（0.93-1.26），研究A中的利福平为1.12（0.97-1.30），研究B中的利福平为1.01（0.91-1.11）。利福平改变了卡泊芬净血浆轮廓的形状，导致24小时后给药低谷浓度（C(24h)）降低了14至31%，与稳态下的净诱导效应一致。在研究A中，利福平联合给药的前几天，AUC和C(24h)均升高（第1天分别升高61%和170%），但在研究B中并未升高，这与完全诱导前的瞬时净抑制一致。在研究A的第14天，利福平AUC(0-24)的联合给药/单独给药几何平均比率为1.07（90% CI，0.83-1.38）。利托那韦不会显著改变卡泊芬净的药代动力学。利福平既抑制又诱导卡泊芬净的处置，导致稳态下的C(24h)降低。当卡泊芬净与利福平联合给药时，应考虑将卡泊芬净的剂量增加到70毫克，每日一次。

The potential for interactions between caspofungin and nelfinavir or rifampin was evaluated in two parallel-panel studies. In study A, healthy subjects received a 14-day course of caspofungin alone (50 mg administered intravenously [IV] once daily) (n = 10) or with nelfinavir (1,250 mg administered orally twice daily) (n = 9) or rifampin (600 mg administered orally once daily) (n = 10). In study B, 14 subjects received a 28-day course of rifampin (600 mg administered orally once daily), with caspofungin (50 mg administered IV once daily) coadministered on the last 14 days, and 12 subjects received a 14-day course of caspofungin alone (50 mg administered IV once daily). The coadministration/administration alone geometric mean ratio for the caspofungin area under the time-concentration profile calculated for the 24-hr period following dosing [AUC(0-24)] was as follows (values in parentheses are 90% confidence intervals [CIs]): 1.08 (0.93-1.26) for nelfinavir, 1.12 (0.97-1.30) for rifampin (study A), and 1.01 (0.91-1.11) for rifampin (study B). The shape of the caspofungin plasma profile was altered by rifampin, resulting in a 14 to 31% reduction in the trough concentration at 24 hr after dosing (C(24h)), consistent with a net induction effect at steady state. Both the AUC and the C(24hr) were elevated in the initial days of rifampin coadministration in study A (61 and 170% elevations, respectively, on day 1) but not in study B, consistent with transient net inhibition prior to full induction. The coadministration/administration alone geometric mean ratio for the rifampin AUC(0-24) on day 14 was 1.07 (90% CI, 0.83-1.38). Nelfinavir does not meaningfully alter caspofungin pharmacokinetics. Rifampin both inhibits and induces caspofungin disposition, resulting in a reduced C(24hr) at steady state. An increase in the caspofungin dose to 70 mg, administered daily, should be considered when the drug is coadministered with rifampin.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

/SRP:/ 基本治疗：建立专利气道（如有需要，使用口咽或鼻咽气道）。如有必要，进行吸痰。观察呼吸不足的迹象，如有需要，协助通气。通过非循环呼吸面罩以10至15升/分钟的速度给予氧气。监测肺水肿，如有必要，进行治疗...。监测休克，如有必要，进行治疗...。预防癫痫发作，如有必要，进行治疗...。对于眼睛污染，立即用水冲洗眼睛。在运输过程中，用0.9%的生理盐水（NS）持续冲洗每只眼睛...。不要使用催吐剂。对于摄入，如果患者能够吞咽、有强烈的呕吐反射且不流口水，则用温水冲洗口腔，并给予5毫升/千克，最多200毫升的水进行稀释...。在去污后，用干燥的无菌敷料覆盖皮肤烧伤...。/毒药A和B/

/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

消除：粪便：35%作为药物或代谢物。肾脏：41%作为药物（大约1.4%未改变）或代谢物。透析：血液透析不排除。

Elimination: Fecal: 35% as drug or metabolites. Renal: 41% as drug (approximately 1.4% unchanged) or metabolites. In dialysis: Not removed by hemodialysis.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

在给予单次70毫克照射剂量后，大约92%的放射性在36至48小时内分布到组织中。进入红细胞的分布是最小的。

Following administration of a single 70 mg irradiated dose, approximately 92% of the administered radioactivity was distributed into tissues within 36 to 48 hours. Distribution into red blood cells in minimal.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

卡泊芬净可穿过大鼠和兔子的胎盘，在给予卡泊芬净的怀孕动物胎儿的血浆中可以检测到卡泊芬净。

Caspofungin crosses the placenta in rats and rabbits and was detected in the plasma of fetuses of pregnant animals who were dosed with caspofungin.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

卡泊芬净在大鼠中会分布到乳汁中；尚不清楚卡泊芬净在人类中是否会分布到乳汁中。

Caspofungin is distributed into milk in rats; not known whether caspofungin is distributed into milk in humans.

来源:Hazardous Substances Data Bank (HSDB)

制备方法与用途

理化性质

卡泊芬净 (Caspofungin) 是第一个获准用于治疗侵袭性真菌感染的棘白菌素类药物。体外和体内试验均证实，卡泊芬净对于重要机会性感染病原菌——念珠菌和曲霉菌具有良好的抗菌活性。通过抑制1,3-β-葡聚糖的合成，该药物导致细胞壁破裂，并在临床中显示了对各种念珠菌病和曲霉菌病的良好治疗效果。

产品特点

卡泊芬净是一种由Glarea Lozoyensis发酵产物合成而来的半合成脂肽（棘白菌素，echinocandin）化合物。醋酸卡泊芬能抑制许多丝状真菌和酵母菌细胞壁的基本成分——β(1,3)-D-葡聚糖的合成。哺乳类动物细胞中不存在这种成分。体外药理学研究显示，卡泊芬净对多种致病性曲霉菌属和念珠菌属真菌具有抗菌活性。

作用机制

(1,3)- D -葡聚糖合成酶是真菌细胞壁合成的关键成分。卡泊芬净通过非竞争性抑制该酶发挥抗真菌作用。静脉给药后，药物在组织中的分布迅速导致血浆药物浓度下降，随后逐渐从组织中释放。随着剂量的增加，药物代谢也会增加，并且多次给药达到稳态的时间也具有剂量相关性。因此，在临床应用中需注意调整剂量，以避免不良反应。

市场情况

卡泊芬净是默沙东通过发酵半合成技术开发的脂肽类化合物。2001年1月26日获得美国FDA批准上市，成为全球首个获批的棘白菌素类抗真菌剂。2002年9月24日在我国获批上市，并以“科赛斯”为商品名。作为临床指南推荐的抗真菌感染用药，卡泊芬净具有良好的市场表现和稳定销售记录。然而，随着专利保护到期后销售额逐步下滑，2018年的全球销售额约为3.26亿美元。

不良反应

由于哺乳动物细胞中不存在真菌细胞壁中的(1,3)- D -葡聚糖，卡泊芬净的不良反应相对较少。常见的不良反应包括发热、畏寒、静脉炎、血栓性静脉炎、乳糜泻、恶心、呕吐、皮疹、头痛、腹痛及腹泻。此外，有报道指出使用该药物后会出现转氨酶升高的情况，这可能与肝脏代谢缓慢有关。

市场数据

卡泊芬净2010年至2018年的全球销售额如下表所示：

2010年： 5.46亿美元
2011年： 6.37亿美元
2012年： 7.29亿美元
2013年： 8.21亿美元
2014年： 9.12亿美元
2015年： 10.03亿美元
2016年： 10.94亿美元
2017年： 11.85亿美元
2018年： 3.26亿美元

卡泊芬净2010-2018年全球销售额（百万美元）