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奥拉帕尼胶囊，Lynparza, 50mg hard capsules (olaparib) 近日，欧盟委员会(EC)已批准抗癌药Lynparza(olaparib)作为一种单药疗法，用于铂敏感复发性BRCA突变卵巢癌成人患者的维持治疗，该药也成为用于BRCA突变铂敏感复发性卵巢癌的首个PARP抑制剂。
Lynparza(olaparib)是一种首创口服多聚ADP核糖聚合酶(PARP)抑制剂，利用DNA修复途径的缺陷，优先杀死癌细胞。目前，阿斯利康正开展多个III期研究，调查olaparib用于BRCA突变卵巢癌、胃癌、乳腺癌的治疗。
Lynparza的获批，是基于一项II期临床研究(Study 191)的数据。该研究在携带BRCA突变卵巢癌患者中开展，数据表明，与安慰剂相比，olaparib显著延长了无进展生存期(PFS)(11.2个月 vs 4.3个月，p<0.00001)。然而，这一数据在今年6月却遭到FDA专家委员会的百般挑剔，FDA专家认为，olaparib并没有改善总生存期(OS)，研究中也发生了几个令人担忧的不良事件，同时对PFS数据的可靠性表示怀疑，因此拒绝加速审批olaparib，同时要求阿斯利康必须完成正在开展的III期研究，FDA将于2015年1月作出审查决定。(相关阅读：阿斯利康“死去”的抗癌药物Olaparib“复活”)
阿斯利康对olaparib寄予厚望，认为该药的年销售额将突破20亿美元。不过，阿斯利康对抗癌免疫疗法PD-L1抑制剂MEDI4736和另一种抗癌药AZD9291的期望更高，并预测2者的年销售峰值分别为65亿美元和30亿美元，后者目前正处于I期临床。然而，这些产品要想实现预期目标，将取决于在一系列癌症中的临床成功。
BRCA基因：
关于
BRCA1和BRCA2基因属于肿瘤抑制因子编码基因，这些基因的突变，与遗传性乳腺癌和卵巢癌相关。若一个女性继承了BRCA1或BRCA2突变，患乳腺癌和/或卵巢癌的风险将大大增加。在癌细胞扩增至卵巢以外之前，仅有15%的卵巢癌被发现。尽管当前治疗和诊断已经取得了很大进步，但癌细胞已扩散至卵巢外的患者，5年生存率低于50%。
Lynparza（olaparib）：
关于
Olaparib是一种创新的、潜在首创口服多聚ADP核糖聚合酶(PARP)抑制剂，在临床前模型中已被证明，能够利用DNA修复途径的缺陷，优先杀死癌细胞。这种作用模式，赋予olaparib治疗具有DNA修复缺陷的广泛肿瘤类型的潜力。PARP与广泛的肿瘤类型相关，尤其是乳腺癌和卵巢癌
Lynparza™approved in the European Union as first-in-class treatment for advanced BRCA-mutated ovarian cancer
Ovarian Cancer
Indicated as monotherapy for deleterious or suspected deleterious germline BRCA-mutated advanced ovarian cancer in patients who have been treated with ≥3 prior lines of chemotherapy
400 mg (eight 50-mg capsules) PO BID
Continue treatment until disease progression or unacceptable toxicity
Dosage Modifications
Management of adverse reactions
Consider dose interruption or dose reduction to manage adverse reactions
Recommended dose reduction: 200 mg (four 50-mg capsules) PO BID
If a further final dose reduction is required, then reduce to 100 mg (two 50-mg capsules) PO BID
Coadministration with CYP3A inhibitors
Strong and moderate CYP3A inhibitors: Avoid use and consider other agents
If strong CYP3A inhibitors cannot be avoided: Reduce olaparib dose to 150 mg (three 50-mg capsules) PO BID
If moderate CYP3A inhibitors cannot be avoided: Reduce olaparib dose to 200 mg (four 50-mg capsules) PO BID
Hepatic impairment
Not studied
No data in patients with baseline hepatic impairment (serum bilirubin >1.5 xULN)
Renal impairment
Preliminary data show a 1.5-fold increase in mean exposure (AUC) with mild renal impairment (CrCl 50-80 mL/min) compared with normal renal function (CrCl >80 mL/min)
CrCl 50-80 mL/min: No dose adjustment to the starting dose is required, but patients should be monitored closely for toxicity
CrCl <50 mL/min or patients on dialysis: Data are not available
Dosing Considerations
The indication is approved under accelerated approval based on objective response rate and duration of response; continued approval may be contingent upon verification and description of clinical benefit in confirmatory trials
Information on FDA-approved test for the detection of BRCA mutations is available at http://www.fda.gov/companiondiagnostics
Administration
Swallow capsule whole; do not chew, dissolve, or open capsule
Do not take capsules that appear deformed or show evidence of leakage
Missed dose: Instruct patient to take their next dose at its scheduled time
| Name |
Lynparza |
| INN or common name |
olaparib |
| Therapeutic area |
Ovarian Neoplasms |
| Active substance |
olaparib |
| Date opinion adopted |
23/10/2014 |
| Company name |
AstraZeneca AB |
| Status |
Positive |
| Application type |
Initial authorisation |
AstraZeneca today announced that the European Commission (EC) has granted Marketing Authorisation for Lynparza™ (olaparib) capsules (400mg twice daily) as the first therapy for the maintenance treatment of adult patients with platinum-sensitive relapsed BRCA-mutated (germline and/or somatic) high grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete response or partial response to platinum-based chemotherapy.
Olaparib is a poly ADP-ribose polymerase (PARP) inhibitor that exploits tumour DNA repair pathway deficiencies to preferentially kill cancer cells. It is the first PARP inhibitor to be approved for patients with platinum-sensitive relapsed BRCA-mutated ovarian cancer. Patients will be identified through a validated diagnostic test.
“We are delighted to be able to bring this much needed treatment to patients with BRCA-mutated ovarian cancer whose options are currently very limited. Today’s approval marks a significant milestone in the development of the next generation of targeted medicines,” said Briggs Morrison, Executive Vice President, Global Medicines Development and Chief Medical Officer at AstraZeneca. “We are committed to bringing new treatments to the patients who need them most and today’s news marks only the first of what we hope will be a number of indications in which Lynparza has the potential to transform the lives of cancer patients, including those with breast, pancreatic and gastric cancers.”
The EC decision is applicable to all 28 EU member states as well as Norway, Iceland and Liechtenstein. The approval of olaparib was based on data from Study 191, a Phase II clinical trial that evaluated its efficacy and safety compared to placebo in platinum-sensitive relapsed high grade serous ovarian cancer patients. The study showed that olaparib maintenance therapy significantly prolonged progression free survival (PFS) compared with placebo in patients with BRCA-mutated ovarian cancer: median PFS 11.2 months vs 4.3 months (PFS Hazard Ratio = 0.18; 95% Confidence Interval 0.10-0.31; p<0.0001). The most common adverse events associated with olaparib monotherapy to date were generally mild to moderate and included nausea, vomiting, fatigue and anaemia.
In addition to ovarian cancer, AstraZeneca will investigate the full potential of olaparib in multiple tumour types, with Phase III studies in second line gastric cancer, BRCA-mutated pancreatic cancer and adjuvant and metastatic BRCA-mutated breast cancers underway.
About ovarian cancer
In Europe, ovarian cancer is the fifth most commonly diagnosed cancer in women and the sixth leading cause of cancer death among women, mainly because it is often diagnosed late by which time the patient has an extremely poor prognosis. For the 61% of ovarian cancer patients whose cancer has metastasised by the time of diagnosis, the five-year survival rate is only 27%.
Up to 15% of women with ovarian cancer have a BRCA mutation, which is the most common cause of homologous repair deficiency. In BRCA-mutated tumour cells, homologous recombination is defective and DNA double-strand break repair is forced to occur via error-prone pathways, which can lead to genomic instability and cell death.
Lynparza (Olaparib)
Company: AstraZeneca Pharmaceuticals LP
Application No.: 206162
Approval Date: 12/19/2014
Persons with disabilities having problems accessing the PDF files below may call (301) 796-3634 for assistance.
Lynparza(olaparib)第一个获得批准用于治疗晚期卵巢癌新药
【药品名称】奥拉帕尼胶囊
【化学名称】1-(环丙甲酰基)-4-[5-[(3,4-二氢-4-氧代-1-酞嗪基)甲基]-2-氟苯甲酰]哌嗪
【CAS】763113-22-0
【分子式】 C24H23FN4O3
【分子量】 434.46
【剂型】胶囊剂
【规格】50mg
【适应症】Lynparza是一个多聚二磷酸腺苷核糖聚合酶
[poly(ADP-ribose)polymerase](PARP)抑制剂适用在有害的或被怀疑有害的生殖系突变的BRCA(当用FDA批准的测试检测)晚期卵巢癌曾被3种或更多化疗既往线治疗患者为单药治疗。
【用法用量】Lynparza的推荐剂量是400 mg(8粒50 mg胶囊)服用每天2次，每天总剂量800 mg。连续治疗直至疾病进展或不可接受毒性
【原研情况】批准日期：2014年12月19日；公司：AstraZeneca阿斯利康
本品特点
作用机制：Lynparza是一种聚(ADP-核糖)聚合酶(PARP)酶抑制剂，包括 PARP1，PARP2，和PARP3。 PARP酶是涉及正常细胞动态平衡，例如DNA转录，细胞周期调节，和DNA修复。奥拉帕尼 在体外曾被显示抑制选择肿瘤细胞株生长和在人类的小鼠异种移植人癌模型减低肿瘤生长作为单药治疗或基于铂化疗后两方面。注意到用奥拉帕尼治疗后在细胞株中和有BRCA缺陷的小鼠肿瘤模型增加细胞毒性和抗-肿瘤活性。体外研究已显示奥拉帕尼-诱导细胞毒性可能涉及PARP酶活性的抑制作用和PARP-DNA复合物形成增加，导致细胞动态平衡破坏和细胞死亡。
药代动力学：吸收：奥拉帕尼通过胶囊制剂的口服给予后，迅速被吸收有峰血浆浓度典型地在给药后1至3小时间实现。用多次给药无明显积蓄(积蓄比值1.4–1.5对每天2次给药)，3至4天内实现稳态暴露。有限数据提示在跨越剂量范围100至400mg，奥拉帕尼的全身暴露(AUC)的增加低于正比例但跨越试验PK数据是变异的。与一种高脂肪餐共同给药显示吸收速率(Tmax延迟2小时)，但不显著改变奥拉帕尼吸收的程度(均数AUC 增加约20%)。
分布：单次400mg剂量奥拉帕尼后奥拉帕尼在稳态时有一个均数(±标准差)表观分布容积167±196 L。在血浆浓度实现在400mg每天2次给药后奥拉帕尼的体外蛋白结合是约82%。
代谢：在体外，CYP3A4被显示是主要负责奥拉帕尼代谢的酶。口服给予14C-奥拉帕尼至女性患者后，未变化奥拉帕尼占血浆中循环放射性的多数(70%)。它被广泛地代谢在尿和粪中未变化药物放射性分别占15%和6%。代谢多数归咎于氧化反应与产生一些组分进行随后葡萄糖醛酸或硫酸结合。
排泄：单次400mg剂量奥拉帕尼后观察到一个均数(±标准差)末端血浆半衰期11.9±4.8小时和表观血浆清除率8.6±7.1L/h。单次剂量14C-奥拉帕尼后，在7天收集期间86%给予的放射性被回收，44%通过尿和42%通过粪。物料的多数作为代谢物被排泄。根据来自专门致力肾受损试验初步数据，当奥拉帕尼被给予有轻度肾受损患者(CLcr = 50-80mL/min; N=14)与有正常肾功能患者比较(CLcr >80 mL/min; N=8) 奥拉帕尼的均数AUC和Cmax分别增加1.5和1.2-倍。在有CLcr<50 mL/min患者或在用透析患者没有数据。
临床试验
因为临床试验是在广泛不同情况下进行的，临床试验观察到不良反应率不能与另一种药临床试验发生率直接比较而且可能不反映实践中观察到的发生率。在300例患者有gBRCA-突变的晚期卵巢癌中曾研究Lynparza 400 mg每天2次作为单药治疗，而223例这些患者曾接受3线或以上以前的化疗。在223例有gBRCA-突变的 卵巢癌患者接受3线或以上以前化疗(包括137例患者在研究1中有可测量的疾病)[见临床研究(14)] 在40%患者中不良反应导致剂量剂量中断，4%患者剂量减低，而7%患者终止药物。8例(4%)患者有不良反应导致死亡，两例归咎于急性白血病，和一例归咎于COPD，脑血管意外，小肠穿孔，肺栓塞，脓毒血症，和缝合破裂。表1 报告了223例患者的≥20%报道的不良反应的频数(在6项研究)有gBRCA-突变的晚期卵巢癌曾接受3线或以上以前的化疗被用Lynparza治疗400 mg每天2次。在这些患者中对Lynparza中位暴露是158天。在223例接受 Lynparza患者曾被鉴定以下不良反应和实验室异常≥10至<20%和不包括在表内：咳嗽，便秘，味觉障碍，周边水肿，背痛，眩晕，头痛，泌尿道感染，呼吸困难，和皮疹。在223例接受 Lynparza患者以下不良反应和实验室异常曾被鉴定≥1至<10%和未包括在表内：白细胞减少，口腔炎，周围神经病变，发热，低镁血症，高血糖，焦虑，抑郁，失眠，尿痛，尿失禁，外阴阴道疾病，干皮肤/湿疹，瘙痒，高血压，静脉血栓(包括肺栓塞)，和潮热。被报道不良反应在≥20%患者来自一项在患者用铂敏感，复发，高-级别严重卵巢癌用2或更多含铂方案治疗后随机化试验Lynparza 400 mg每天2次作为维持单药治疗与安慰剂比较。表4展示来自这个随机化试验患者中实验室异常。在96例有gBRCA-突变患者中，53例接受Lynparza，和43例接受安慰剂。对有一种gBRCA 突变患者用Lynparza治疗中位时间为11.1个月与之比较对有gBRCA突变用安慰剂患者为4.4个月。接受Lynparza患者不良反应导致剂量中断为26%和接受安慰剂患者为7%；Lynparza患者剂量减低为15%和安慰剂 患者5%；和Lynparza终止治疗9%和安慰剂患者为0%。Lynparza患者1例(2%)死亡因不良反应的结果。
毒性研究：未曾用奥拉帕尼进行致癌性研究。
奥拉帕尼在一项体外染色体试验在哺乳动物CHO细胞和在一项体内大鼠骨髓 微核试验是致染色体断裂。这个致染色体断裂性与这个致染色体断裂性与奥拉帕尼的主要药理学结果基因组不稳定性一致和表明对人中遗传毒性潜能。奥拉帕尼在细菌逆向突变(Ames)试验没有致突变性。在一项生育力研究中，雌性大鼠接受口服奥拉帕尼在剂量0.05，0.5，和15 mg/kg/day共至少14天从交配前至妊娠的第一周，在剂量直至15 mg/kg/day(母体全身暴露在推荐剂量人暴露(AUC0-24h)约11%)对交配和生育力无不良影响。在一项雄性生育力研究中，奥拉帕尼在大鼠口服剂量直至40 mg/kg/day(有全身暴露在推荐剂量人暴露(AUC0-24h)的约7%)至少70天奥拉帕尼治疗后对交配和生育力没有影响。
临床研究：在有害的或被怀疑有害的生殖系突变的BRCA(gBRCAm)晚期癌患者(研究1)单臂研究中研究Lynparza的疗效。总共纳入以前曾用3或更多化疗线治疗的137例有可测量的，gBRCAm相关联卵巢癌患者。所有患者接受Lynparza在剂量400 mg每天2次作为单药治疗直至疾病进展或不能耐受的毒性。研究者按照RECIST v1.1评估总体反应率(ORR)和反应时间(DOR)。患者的中位年龄为 58。 |
