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安贝生坦片(商品名：Letairis)-新型肺动脉高压治疗药

2010-10-15 18:42:37 作者：新特药房来源：中国新特药网天津分站浏览次数：680 文字大小：【大】【中】【小】

简介：Ambrisentan是由美国Myogen公司开发的一种内皮素受体拮抗剂(ERA).2006年11月17日美国Gilead Science公司收购Myogen作为子公司,并获得ambrisentan 的所有权.该药物于2007年6月15日获得美国FDA批准,商品名为 ...

关键字：安贝生坦片 Letairis 肺动脉高压

Ambrisentan是由美国Myogen公司开发的一种内皮素受体拮抗剂(ERA).2006年11月17日美国Gilead Science公司收购Myogen作为子公司,并获得ambrisentan 的所有权.该药物于2007年6月15日获得美国FDA批准,商品名为Letairis,口服用于治疗肺动脉高血压,其片剂具有5mg和10mg两种规格.

吉利德科学(GileadScience)公司的内皮素A型(ET)受体抑制剂安贝生坦片(商品名：Letairis)，用于治疗肺动脉高压。安贝生坦系一新分子实体，其化学名为(+)一(2s)一2一[(4，6一二甲基嘧啶一2一基)氧基卜3一甲氧3,3一二苯丙酸，分子式：c笠H笠N：0，分子量：378．42。薄膜包衣片规格：安贝生坦5mr,／片，10mr,／片。
内皮素一1(ET一1)是一强效自分泌和旁分泌肽。内皮素A型(ET^)和内皮素B型(ET。)两种亚型受体调节血管平滑肌和内皮素的ET一1作用。ETA主要作用是收缩血管和细胞增生，而ET主要作用则是舒张血管、抗内皮增生和清除ET一1。肺动脉高压患者血浆ET一1浓度可增高至10倍．与右心房平均血压和疾患的严重程度相关。肺动脉高压患者肺组织内ET一1和ET一1mRNA浓度可增至9倍，主要在肺动脉的内皮中。这些发现揭示，ET一1在肺动脉高压的病理形成和加重中起着关键作用。
安贝生坦是ETA受体高度亲和性(Ki=0．011nm)的拮抗剂，且对ET的选择性是对E1rB选择性的4000倍以上对393例肺动脉高压患者进行了12周随机双盲安慰剂对照多中心临床研究，证明了安贝生坦片安全有效.

WARNING: POTENTIAL LIVER INJURY

LETAIRIS (ambrisentan) can cause elevation of liver aminotransferases (ALT and AST) to at least 3 times the upper limit of normal (ULN). LETAIRIS treatment was associated with aminotransferase elevations >3 x ULN in 0.8% of patients in 12-week trials and 2.8% of patients including long-term open-label trials out to one year. One case of aminotransferase elevations >3 x ULN has been accompanied by bilirubin elevations >2 x ULN. Because these changes are a marker for potentially serious liver injury, serum aminotransferase levels (and bilirubin if aminotransferase levels are elevated) must be measured prior to initiation of treatment and then monthly.

In the post-marketing period with another endothelin receptor antagonist (ERA), bosentan, rare cases of unexplained hepatic cirrhosis were reported after prolonged (>12 months) therapy. In at least one case with bosentan, a late presentation (after >20 months of treatment) included pronounced elevations in aminotransferases and bilirubin levels accompanied by non-specific symptoms, all of which resolved slowly over time after discontinuation of the suspect drug. This case reinforces the importance of strict adherence to the monthly monitoring schedule for the duration of treatment.

Elevations in aminotransferases require close attention. LETAIRIS should generally be avoided in patients with elevated aminotransferases (>3 x ULN) at baseline because monitoring liver injury may be more difficult. If liver aminotransferase elevations are accompanied by clinical symptoms of liver injury (such as nausea, vomiting, fever, abdominal pain, jaundice, or unusual lethargy or fatigue) or increases in bilirubin >2 x ULN, treatment should be stopped. There is no experience with the re-introduction of LETAIRIS in these circumstances.

What is Letairis?

Letairis is used to treat elevated blood pressure in the arteries of your lungs. It can help improve your ability to exercise and help slow the worsening of your physical condition.

What is the most important information I should know about Letairis?

Letairis can cause liver injury. Your doctor will test your blood before you start Letairis and once a month thereafter to check your liver function.

Letairis can cause serious birth defects if taken during pregnancy. Women must not be pregnant when they start taking Letairis or become pregnant while on Letairis. Women who are able to get pregnant must have a negative pregnancy test before beginning treatment and each month during treatment. They must also simultaneously use two different methods of birth control while taking Letairis and for one month after stopping Letairis. If you miss your period or think you may be pregnant, tell your doctor right away.

Letairis is only available through a restricted program called the Letairis Education and Access Program (LEAP). In order to receive Letairis, you must talk to your doctor, understand the risks and benefits of taking Letairis, and agree to all of the instructions in the LEAP program.

Who should not take Letairis?

Do not take Letairis if you are pregnant or become pregnant during treatment with Letairis. You also should not take Letairis if your blood tests show possible liver injury.

What should I tell my doctor before I take the first dose of Letairis?

Tell your doctor about all prescription, over-the-counter, and herbal medications you are taking before beginning treatment with Letairis. Also, talk to your doctor about your complete medical history, especially if you are pregnant, plan on becoming pregnant, or have liver problems.

What is the usual dosage?

The information below is based on the dosage guidelines your doctor uses. Depending on your condition and medical history, your doctor may prescribe a different regimen. Do not change the dosage or stop taking your medication without your doctor's approval.

Adults: The usual initial dosage is 5 milligrams (mg) once daily with or without food. Your doctor may increase your dose to 10 mg once daily if the lower dose is well tolerated.

How should I take Letairis?

You may take Letairis with or without food. The tablets should be swallowed whole and not split, crushed, or chewed.

What should I avoid while taking Letairis?

Avoid becoming pregnant while on Letairis. Also, avoid breastfeeding while on Letairis unless your doctor instructs otherwise.

What are possible food and drug interactions associated with Letairis?

If Letairis is taken with certain other drugs, the effects of either could be increased, decreased, or altered. It is especially important to check with your doctor before combining Letairis with the following: cyclosporine A, ketoconazole, omeprazole.

What are the possible side effects of Letairis?

Side effects cannot be anticipated. If any develop or change in intensity, tell your doctor as soon as possible. Only your doctor can determine if it is safe for you to continue taking Letairis.

Side effects may include:
fluid retention; swelling of hands, legs, ankles, and feet; stuffy nose; flushing; stomach pain; constipation; headache; shortness of breath; sinus inflammation; palpitations; inflamed and sore throat and nose

Can I receive Letairis if I am pregnant or breastfeeding?

You cannot take Letairis if you are pregnant or plan to become pregnant due to potential harm to the baby. Breastfeeding is not recommended while on Letairis.

What should I do if I miss a dose of Letairis?

If you miss a dose, take it as soon as you remember that day. Then, take your next dose at the regular time the next day. Do not take two doses at the same time to make up for a missed dose.

How should I store Letairis?

Store Letairis at room temperature in its original package.

安贝生坦(ambrisentan, Letairis)是由美国Myo-gen生物制药公司开发的一种选择性内皮素受体A(ETAR)拮抗剂,其化学名为(+)-(2S)-2-[(4, 6二甲基嘧啶-2-基)氧]-3-甲氧基3, 3-二苯基丙酸,分子式为C22H22N2O4,相对分子质量378·43(结构式见图1)。安贝生坦可强效抑制内皮素所致血管收缩, 2007年6月15日获得美国FDA批准,口服用于肺动脉高压( pulmonary arterial hypertension,PAH)的治疗。现对其作用机制、药代动力学、临床试验及安全性等进行综述。

1　作用机制
PAH是一种少见的进行性肺毛细血管前肺血管病变所引起的肺动脉压力持久升高,为罕见的慢性综合病症,包括特发性PAH(IPAH),肺广泛性病变引起的PAH,肺小动脉缺氧性痉挛、左心室疾病相关性、低氧和肺疾病、慢性血栓形成栓塞等所引起的PAH等。IPAH以肺血管广泛重构,肺动脉压和肺血管阻力增高、右心室负荷持续升高引起的右心室肥厚及右心室衰竭为主要的病理生理特征。目前,获批的PAH治疗药物,根据作用机制的不同,主要分为磷酸二酯酶-5抑制剂、前列环素和内皮素受体拮抗剂3个类别。内皮素(endothelin,ET)是一组含21个氨基酸的多肽,它有4种异构体(ET-1, ET-2,ET-3和ET-4)。ET-1是肺血管生理和病理过程中的重要介质,在PAH的发病机制中发挥重要作用,它激活位于肺血管平滑肌的ET受体,引起血管张力增高及血管变形,是强有力的内源性血管收缩剂。ET通过与ET受体结合而发挥作用,内皮素A受体(ETAR)和内皮素B受体(ETBR)为已知的两种ET受体亚型。ETAR主要分布在肺血管平滑肌细胞膜, ETBR主要分布在肺血管平滑肌细胞和内皮细胞。激活位于肺血管平滑肌的ETAR和ETBR,引起血管收缩,激活位于肺血管内皮细胞的ETBR,导致血管舒张。ET受体拮抗剂依据对受体的选择而分为选择性和非选择性,其中,前者主要作用于ETAR,而后者两者兼顾,对ETAR和ETBR具有双重作用[1]。安贝生坦是一种高选择性ETAR拮抗剂,可以阻断ET与ETAR的结合,抑制ET在PAH发病机制中的作用,从而有效降低PAH[2~4]。

2　生物活性
现已研制成功的ET受体拮抗剂有波生坦(bosentan),西他生坦(sitaxentan)和安贝生坦。波生坦是一种非选择性ET受体拮抗剂。西他生坦是一种选择性ETAR拮抗剂。安贝生坦作为最新研发出的ETAR拮抗剂,不仅具有高亲和力(Ki=0·011nmol·L-1),对ETAR的选择性远远高于ETBR(>4 000倍)的特点,而且对其他受体没有选择性。在PAH患者浓缩的血浆中,安贝生坦与ETAR的结合率大于90%,而与ETBR的结合率小于10%[5, 6]。目前,西他生坦和波生坦治疗效果并不理想,而且服用西他生坦或波生坦的患者均有较高的肝功能异常发生率,表现为血中转氨酶水平升高。这种不良反应一般可以通过减低药量或者暂时停药控制,但对患者必须进行经常性的监测,必要时需永久性停药。

西他生坦与PAH常用治疗药物华法林(warfarin)存在药物相互作用。在2项完成的Ⅲ期临床试验中,安贝生坦显示出比波生坦和西他生坦对PAH更具治疗潜力。安贝生坦的使用剂量为每日1次给药,而波生坦需每日2次给药,且与西他生坦相比,不存在与华法林发生相互作用。除此以外,Ⅲ期临床研究中,使用安贝生坦的患者并未出现肝脏转氨酶升高的现象,且在长期研究中,该现象的发生率也仅为2%左右[7]。
3　药代动力学
安贝生坦经口服给药,可迅速吸收进入体循环, 具有很高的生物利用度,食物并不影响其生物利用度。安贝生坦经口服,给予1 d剂量,药效达稳态持续3~4 d。PAH患者在口服安贝生坦5 mg后,终末半衰期为15 h,长期服药,达稳态时其谷浓度是其峰浓度的15%,有效半衰期9 h。安贝生坦主要以原型或者糖苷化的形式存在于肝脏和血浆中,代谢过程主要是肝脏代谢Ⅱ(葡萄糖苷酸化阶段),其次是肝脏代谢Ⅰ(羟基化反应阶段)[8, 9]。

4　安全性
临床试验的统计资料显示,安贝生坦具有良好的安全性和耐受性。Ⅱ期临床试验中,服用安贝生坦的患者出现的不良反应有轻度浮肿、上呼吸道感染、鼻衄、头痛、恶心、呕吐,且无剂量依赖性。在长期服用安贝生坦的患者中,服用安贝生坦1年,无紧急安全事件发生。在Ⅱ、Ⅲ期临床试验中,以波生坦为参照,安贝生坦出现急性肝中毒的不良反应发生率较低[7]。在Ⅱ期临床试验中,患者给予最大有效
剂量(10mg),每日1次,连续服药24周, 3%的患者谷丙转氨酶(ALT)超过正常上限3倍以上。患者长期服用安贝生坦试验中, 48%的患者给予最大有效剂量(10mg),每日1次,连续服药1年,患者的ALT没有升高,而且没有出现谷草转氨酶(AST)超过正常上限3倍以上,肝脏转氨酶升高的现象发生率仅为2%左右[9, 10]。

5　临床试验
Ⅱ期临床试验中,一项64名IPAH或者PAH患者(伴有结缔组织炎、消化不良或HIV)参加的双盲、随机、对照组临床试验,考察了安贝生坦的安全性和改善患者运动量的疗效。患者被随机分入1,2.5,5和10 mg剂量组,每日1次口服给药,治疗12周,然后再进行12周的放射示踪量试验。前12周治疗后,各剂量组患者的6 min步行距离分别增加了33.9, 37.1, 38.1和5.1 m,而被诊断为原发性PAH的患者,其6 min步行距离呈剂量依赖性增加,最远达54.1 m。整个24周的试验期间,本品的各剂量组均表现出良好的耐受性,有4名受试患者出现暂时性的血清转氨酶浓度升高,仅1人中断治疗。54名患者服用安贝生坦治疗1年后,其中的50名患者接受安贝生坦单一药物治疗,对上述患者服用安贝生坦后的疗效统计结果显示,所有剂量组患者的6 min步行距离平均增加了55 m[9, 10]。ARIES-1和ARIES-2临床试验中,分别有202名和192名PAH患者参加双盲、安慰剂组临床试验,考察了安贝生坦的疗效和安全性。ARIES-1临床研究中,患者被随机分入5和10mg剂量组,每日1次口服给药,治疗12周。12周治疗后, 5和10 mg剂量组PAH的6 min步行距离分别增加了31 m(P=0.008)和51m(P<0.001),ARIES-2临床试验中,患者被随机分入2.5和5 mg剂量组,每日1次口服给药,治疗12周。12周治疗后, 2.5和5 mg剂量组PAH的6min步行距离分别增加了32 m(P=0.022)和59m(P<0.001), 280名PAH患者经安贝生坦治疗48周后,患者均未出现AST的异常增高[11]。

6　剂型、规格、用法用量
该药常用剂型为片剂,具有5和10 mg两种规格。成人用药,开始时每日5 mg,耐受时可将剂量提至10 mg。空腹或饱腹情况下均可服用。开始服用安贝生坦时需进行肝功能测试。

7　结语
安贝生坦与波生坦、西他生坦相比,具有治疗效果好、安全性高、无重大药物相互作用发生、给药方式简便等优点,因此,安贝生坦的成功上市必将推动抗PAH药物市场的发展,同时给患者带来了福音。