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艾曲波帕片eltrombopag-治疗特发性血小板减少性紫癜

2010-08-26 13:54:49  作者:新特药房  来源:中国新特药网天津分站  浏览次数:1014  文字大小:【】【】【
简介: 艾曲波帕是首个FDA获准治疗成人慢性ITP患者的口服非肽类血小板生成素受体激动剂,用于治疗经糖皮质激素类药物、免疫球蛋白治疗无效或脾切除术后慢性特发性血小板减少性紫癜(ITP)患者的血小板减少。 ...

 艾曲波帕是首个FDA获准治疗成人慢性ITP患者的口服非肽类血小板生成素受体激动剂,用于治疗经糖皮质激素类药物、免疫球蛋白治疗无效或脾切除术后慢性特发性血小板减少性紫癜(ITP)患者的血小板减少。

美国FDA批准葛兰素史克公司的艾曲波帕片(Promacta)上市,用于治疗经糖皮质激素类药物、免疫球蛋白治疗无效或脾切除术后慢性特发性血小板减少性紫癜(ITP)患者的血小板减少。

艾曲波帕是首个获准治疗成人慢性ITP患者的口服非肽类血小板生成素受体激动剂,临床前和临床研究显示刺激艾曲波帕可升高血小板的骨髓巨核细胞的增生和分化。

对慢性特发性血小板减少性紫癜患者随机临床研究的大量数据支持了艾曲波帕的新药申请获准。此适应证是基于2项关键的短期治疗和1项正在进行长期治疗ITP患者的临床研究数据。防止血小板被破坏一直是治疗ITP患者的主要方法。艾曲波帕临床研究的新进展显示,增加血小板的产生来治疗此种疾病也起着重要作用。
本品还正在进行治疗丙型肝炎病毒、慢性肝病引起的血小板减少症和肿瘤相关的血小板减少症的研究。

慢性特发性血小板减少性紫癜(ITP)是一种自身免疫性疾病,由致血小板减少的一种自身免疫反应引起,其特征是血小板数降低,其患者面临出血高风险,往往导致患者小血管出血,症状为淤青、鼻出血和牙龈出血,严重者可出现致命性胃肠道和脑内出血。据统计,在美国,确诊为慢性ITP的患者达20万之多。

目前治疗ITP的主要手段是使用免疫抑制类药物,如皮质类固醇、静注免疫球蛋白、抗D免疫球蛋白和Genentech公司产品利妥昔单抗(Rituxan),而对严重衰竭性病人的最后一着则是行脾切除术。其中大多数治疗药物未曾经历随机安慰剂对照临床试验的考察,虽对不同患者群均有效,但同时也会产生严重毒副作用,其作用机制是阻止血小板破坏,而非促进血小板产生。

由葛兰素史克(GSK)公司开发的小分子血小板生成素受体激动剂eltrombopag  ( Promacta /Revolade)则为一种治疗慢性ITP的口服新药,其作用机制与Amgen公司开发的同类产品romiplostim(即Nplate,已在欧美、澳大利亚和加拿大报批) 相似, 即促进血小板产生, 但eltrombopag是通过结合于血小板生成素受体跨膜区及刺激巨核细胞(一种骨髓细胞,可产生血小板)增殖和分化而发挥作用,为每日1次口服产品;后者却是一种血小板生成刺激型Fc肽融合蛋白,靶向血小板生成素受体的天然结合域,通过激活补体而起作用,为1周1次皮下注射用产品。血小板生成素受体为骨髓细胞的生长和成熟所必需,对血小板数的增加起着极为重要的作用。一般认为,血小板数低于5万/μL时具出血高风险, 正常的血小板数应为15万/μL~40万/μL。

在一项为期6 周的安慰剂对照Ⅲ期临床试验中,144名先前曾至少接受过一种疗法治疗(约75%和40%接受过糖皮质类固醇和脾切除术治疗, 51%接受过3种或以上疗法治疗)、血小板数低于3万/μL的ITP患者分别接受eltrombopag 50 ~75 mg/d和安慰剂治疗,且依据WHO划分的出血等级,即按出血严重程度从0 级(无出血)到4 级(衰竭性失血),对受试者每周进行评价。结果显示,本品组和安慰剂组中分别有59%和16%的受试者达到主要终点指标的预期,即6周后血小板数等于或超过5万/μL;本品组的出血事件发生率明显低于安慰剂组,两组的临床显著出血( 2 ~4 级)发生率分别为16%和36% ( P = 01029) ;两组常见不良反应为头痛、恶心、鼻咽炎和腹泻,其中头痛发生率相似。

另一项涉及血小板数低于3 万/μL 的118 名ITP患者、为期6周的安慰剂对照Ⅱ期临床试验也显示,本品30、50和75mg剂量组中分别有28%、70%和81%的受试者达到同上的主要终点指标预期,而安慰剂组的此疗效率仅为11% ( P < 0. 001) ;本品3个剂量组和安慰剂组中分别有14%、37%、50%和4%的受试者血样中血小板数超过20万/μL。

上述两项试验数据已被包含于GSK公司在美国递交的本品新药申请(NDA)中,此NDA仅涉及本品短期用于ITP。该公司期待于2009年申报支持本品长期使用的试验数据,其中将包括目前还在进行中的长期开标记EXTEND临床试验结果以及涉及189名患者、为期6个月的RA ISE临床实验和涉及50名患者、旨在考察重复短期使用本品疗效的开标记REPEAT试验的数据。
              
GSK公司曾于2007年在美国佐治亚州亚特兰大举行的美国血液学会会议上报告了EXTEND试验的初步阳性结果,该项试验为一Ⅲ期延长期临床试验,旨在评价eltrombopag长期使用的安全性和有效性。94名受试的ITP患者中有61人治疗前的血小板数低于3万/μL;受试者的中值治疗期为151 d,最长治疗期为333 d;开始剂量为50 mg/d, 3周后可增至75mg/d,直至疗效降低。结果发现,血小板数低于3万/μL的受试者经本品治疗后,有73%的人血小板数达5 万/μL 或以上,其血小板数中值达14. 35万/μL;本品耐受性良好,常见不良反应仍为头痛, 13%的受试者出现一种严重不良反应。

目前, GSK公司还在开发eltrombopag用于治疗化疗所致血小板减少症和丙型肝炎感染,且已进入临床研究阶段。不过,于2006年进行的本品用于化疗所致血小板减少症的一项Ⅱ期临床试验其结果未达到主要终点指标的预期。而本品用于74名丙型肝炎患者的一项Ⅱ期临床试验结果则达到了其主要终点指标的预期,即4周后本品30、50和75mg剂量组中分别有75%、79%和95%的受试者血小板数增加至10万/μL或以上,安慰剂组中则无一人达此疗效( P < 0. 001)。旨在评价本品促进血小板数升高以致丙型肝炎患者产生持久性病毒学反应能力的两项Ⅲ期临床试验———ENABLE1 和ENABLE2 正在进行中。接受丙型肝炎治疗的患者往往会因多种因素导致出现血小板减少,其中包括产生血小板生成素的肝细胞受损、干扰素或丙型肝炎病毒所致骨髓抑制、血小板自身免疫性破坏增加及肝硬化致病情恶化,而血小板数的降低又会影响有效剂量的抗病毒疗法治疗,甚至不得不完全中止治疗。
最近, eltrombopag已获美国FDA肿瘤药物咨询委员会(ODAC)的一致“可获准”推荐,用于短期治疗那些先前曾接受过治疗的ITP患者,尽管FDA还有些许保留意见。在芝加哥举行的2008年美国临床肿瘤学会(ASCO)年度会议上,本品获得了ODAC成员16∶0的赞成票,因为最新的临床数据已表明本品短期用于ITP具有良好的风险-疗效比。但他们也表示,希望在本品获准上市前,出台一项适宜的强效风险处置方案。若本品获准上市,它将成为用于慢性ITP患者以升高血小板数的首个短期口服治疗药。
                
Eltrombopag短期使用的重要意义在于,可使那些需要外科或牙科手术的ITP患者血小板数升高,因为低血小板数者具过度失血高风险,不宜手术。
GSK公司称, ITP患者经本品的短期治疗后,可阻止或预防急性出血,可参加具出血风险的活动,可减小旅途中出血的风险,并可短期使用非甾体抗炎药治疗关节炎。
                
美国FDA的主要关注点是,一旦本品获准短期使用,势必导致本品非适应证的长期使用,因为ITP为一种慢性疾病,而在本品的若干项短期临床试验中已暴露出安全性问题,包括停药后的出血风险和肝毒性,且来自无对照的长期EXTEND试验的中期临床数据也显示本品可能导致骨髓纤维化。GSK公司则声称,本品停药后虽会重现血小板减少,但并未伴有临床意义的出血增加,而出现的肝胆实验室检查指标异常也一般较轻且可逆。

Promacta
 
WARNING: RISK FOR HEPATOTOXICITY

Promacta may cause hepatotoxicity:

●Measure serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and bilirubin prior to initiation of Promacta, every 2 weeks during the dose adjustment phase and monthly following establishment of a stable dose. If bilirubin is elevated, perform fractionation.

●Evaluate abnormal serum liver tests with repeat testing within 3 to 5 days. If the abnormalities are confirmed, monitor serum liver tests weekly until the abnormality(ies) resolve, stabilize, or return to baseline levels.

●Discontinue Promacta if ALT levels increase to ≥3X the upper limit of normal (ULN) and are:

●progressive, or
●persistent for ≥4 weeks, or
●accompanied by increased direct bilirubin, or
●accompanied by clinical symptoms of liver injury or evidence for hepatic decompensation.

Because of the risk for hepatotoxicity and other risks [see Warnings and Precautions (5.1-5.6)], Promacta is available only through a restricted distribution program called Promacta CARES. Under Promacta CARES, only prescribers, pharmacies, and patients registered with the program are able to prescribe, dispense, and receive Promacta. To enroll in Promacta CARES, call 1-877-9-Promacta [see Warnings and Precautions (5.8)].

Indications and Usage for Promacta
Promacta is indicated for the treatment of thrombocytopenia in patients with chronic immune (idiopathic) thrombocytopenic purpura (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. Promacta should be used only in patients with ITP whose degree of thrombocytopenia and clinical condition increases the risk for bleeding. Promacta should not be used in an attempt to normalize platelet counts.

Promacta Dosage and Administration

Only prescribers enrolled in Promacta CARES may prescribe Promacta [see Warnings and Precautions (5.8)].

Monitor liver tests (ALT, AST, and bilirubin) and complete blood counts (CBCs), including platelet counts and peripheral blood smears, prior to initiation of Promacta and throughout therapy with Promacta. If bilirubin is elevated, perform fractionation. Monitor CBCs, including platelet counts, for at least 4 weeks following discontinuation of Promacta [see Warnings and Precautions (5.3)]. In clinical studies, platelet counts generally increased within 1 to 2 weeks after starting Promacta and decreased within 1 to 2 weeks after discontinuing Promacta [see Clinical Studies (14)].

Use the lowest dose of Promacta to achieve and maintain a platelet count ≥50 x 109/L as necessary to reduce the risk for bleeding. Dose adjustments are based upon the platelet count response. Do not use Promacta in an attempt to normalize platelet counts [see Warnings and Precautions (5.4)].

Take Promacta on an empty stomach (1 hour before or 2 hours after a meal) [see Clinical Pharmacology (12.3)]. Allow at least a 4-hour interval between Promacta and other medications (e.g., antacids), calcium-rich foods (e.g., dairy products and calcium fortified juices), or supplements containing polyvalent cations such as iron, calcium, aluminum, magnesium, selenium, and zinc [see Drug Interactions (7.4) and Clinical Pharmacology (12.3)].

Initial Dose Regimen

Initiate Promacta at a dose of 50 mg once daily except in patients who are of East Asian ancestry or who have moderate to severe hepatic impairment.

For patients of East Asian ancestry (such as Chinese, Japanese, Taiwanese, or Korean), initiate Promacta at a reduced dose of 25 mg once daily [see Clinical Pharmacology (12.3)].

For patients with moderate or severe hepatic impairment, initiate Promacta at a reduced dose of 25 mg once daily [see Use in Specific Populations (8.6)].

Monitoring and Dose Adjustment

After initiating Promacta, adjust the dose to achieve and maintain a platelet count ≥50 x 109/L as necessary to reduce the risk for bleeding. Do not exceed a dose of 75 mg daily. Monitor clinical hematology and liver tests regularly throughout therapy with Promacta and modify the dosage regimen of Promacta based on platelet counts as outlined in Table 1. During therapy with Promacta, assess CBCs, including platelet count and peripheral blood smears, weekly until a stable platelet count has been achieved. Obtain CBCs including platelet counts and peripheral blood smears, monthly thereafter.

Table 1. Dose Adjustments of Promacta
Platelet Count Result Dose Adjustment or Response
<50 x 109/L following at least 2 weeks of Promacta Increase daily dose by 25 mg to a maximum of 75 mg/day.
≥200 x 109/L to ≤400 x 109/L at any time Decrease the daily dose by 25 mg. Wait 2 weeks to assess the effects of this and any subsequent dose adjustments.
>400 x 109/L

Stop Promacta; increase the frequency of platelet monitoring to twice weekly.

Once the platelet count is <150 x 109/L, reinitiate therapy at a daily dose reduced by 25 mg.
>400 x 109/L after 2 weeks of therapy at lowest dose of Promacta Permanently discontinue Promacta.

 

Modify the dosage regimen of concomitant ITP medications, as medically appropriate, to avoid excessive increases in platelet counts during therapy with Promacta. Do not administer more than one dose of Promacta within any 24-hour period.

Discontinuation

Discontinue Promacta if the platelet count does not increase to a level sufficient to avoid clinically important bleeding after 4 weeks of therapy with Promacta at the maximum daily dose of 75 mg. Excessive platelet count responses, as outlined in Table 1, or important liver test abnormalities also necessitate discontinuation of Promacta [see Warnings and Precautions (5.1)].

Dosage Forms and Strengths

25 mg tablets — round, biconvex, orange, film-coated tablets debossed with GS NX3 and 25 on one side. Each tablet, for oral administration, contains eltrombopag olamine, equivalent to 25 mg of eltrombopag free acid.

50 mg tablets — round, biconvex, blue, film-coated tablets debossed with GS UFU and 50 on one side. Each tablet, for oral administration, contains eltrombopag olamine, equivalent to 50 mg of eltrombopag free acid.

75 mg tablets — round, biconvex, pink, film-coated tablets debossed with GS FSS and 75 on one side. Each tablet, for oral administration, contains eltrombopag olamine, equivalent to 75 mg of eltrombopag free acid.

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