商品名:Plenaxia(阿巴瑞克abarelix)用于不适宜接受LHRH激动剂治疗又拒绝手术切除、并具有下述1种或儿种情况的晚期症状前列腺癌(PCA)的姑息治疗:①由于肿瘤转移可能出现神经危害;②由于局部侵袭或转移性疾病出现翰尿管或膀胱出口阻塞;③由于肿瘤骨转移而出现严重骨痛需依赖麻醉性镇痛药。

一、简介

本品由美国Praecis Pharmaceuticals公司研制，2004年在美国上市。在同年还在澳大利亚，欧洲、中东、新西兰、俄罗斯和南非用于治疗前列腺癌的权利转让给先令公司。

商品名:Plenaxia

通用名:阿巴瑞克abarelix

专利号:US5843902，优先权日为1995年12月。

开发与上市厂商

本品由美国PraecisPha口naceuticals公司研制，2004年1月30日首次在美国上市。此外奥地利、比利时、丹麦、芬兰、法国、德国、希腊、爱尔兰、意大利、卢森堡、荷兰、葡萄牙、西班牙和瑞典等14个国家处于注册前状态。2004年4月28日，PraecisPharmaceuticals公司将本品在澳大利亚、欧洲，中东、新西兰、俄罗斯和南非等国用于前列腺癌的权利投让给ScheringAG公司。

二、适应证

本品获准用于不适宜接受LHRH激动剂治疗又拒绝手术切除、并具有下述1种或儿种情况的晚期症状前列腺癌(PCA)的姑息治疗:①由于肿瘤转移可能出现神经危害;②由于局部侵袭或转移性疾病出现翰尿管或膀胱出口阻塞;③由于肿瘤骨转移而出现严重骨痛需依赖麻醉性镇痛药。

药理

一般药理

本品通过直接抑制黄体生成素(LH)和促卵泡激素(FSH)分泌而减少辜丸内皋酮的生成。由于直接抑制LH的分泌，因此血浆皋酮浓度不会有先升高后降低的现象。饱和结合研究[satuaratianbindingstudies)结果显示[125I]_abarelix对大鼠垂体LHRH受体的亲和力很高(Kp=0.1nmol/L)。

药代动力学

14例健康志愿者(52-75岁，体重51.6-110.5kg)接受单剂量本品100mg肌肉注射治疗，药动学参数见表1:

吸收:肌肉注射本品100mg后，吸收缓慢，平均达峰时间为3天，血浆峰浓度为43.4ng/mL。

分布:消除终末期的表观分布容积为4040+1607L，提示本品在体内广泛分布。

代谢:肝细胞体外试验〔大鼠、猴子、人)和体内试验(大鼠、猴子)显示，本品主要代谢方式是通过肤键水解。无论体内z是体外试验均未发现显著的氧化或结合代谢方式。尚无证据表明细胞色素P450参与了本品的代谢过程。
消除:人肌肉注射1知留咏本品后约有13%以原型随尿液排出，尿液中未检出其他代谢产物。注射100mg本品后的肾清除率为14.4L/天[A10ML/min}。

临床评价
一项针对如采用LHRH激动剂治疗可能出现临床恶化的晚期症状性前列腺癌患者的临床研究，募集了81例患者。此项开放性多中心无对照单组临床研究的目的是证明这类患者通过12周的治疗能避免辜丸切除术。在该项研究中，所有患者至少治疗6周，然后选择是否继续进行后续研究。

在募集的81例患者中，9例患者由于资料不全被排除于疗效分析之外。剩余的72例患者纳入研究的原因包括;前列腺癌骨转移引起骨痛(31例)，前列腺或盆腔肿块导致膀脱颈山口梗阻(25例);双侧腹膜后淋巴腺增大并伴有输尿管梗阻((9例);脊柱、脊髓或硬膜外转移即将出现神经损害(6例);或其他(1例)。年龄40-94岁，平均73岁。给药方案为第1、15和29天肌肉注射本品lOOmg，每4周重复。有12例患者在第169天前中止治疗，原因如下：不良反应(2例)、自愿退出(3例)、死亡(4例)和其他(3例)。有60例患者至少接受了24周的治疗。有33例至少治疗了48周，15例至少治疗了96周(中位治疗时间为40周)。在本研究中，有57例(79％)在第8天达到了药物去势效果(血浆总睾酮浓度≤50ng／dL)，68例(96％)在第4周达到了药物去势。

虽然本研究的设计目标并不是评估特定临床效果，但观察结果如下：①8例脊椎或硬膜外转移但未出现神经学症状的患者中无l例发展出神经损害症状；②13例因膀胱出口梗阻而插膀胱引流管的患者中有1O例在12周后拔除了引流管；③15例骨转移患者在12周后疼痛减轻，使用麻醉性镇痛药的药效强度、用量和频率降低。不良反应急性全身性过敏反应在针对晚期症状性前列腺癌患者的临床研究中，81例患者中有3例在给药后数分钟内出现了急性全身性过敏反应。这些过敏反应有荨麻疹(第15天)、麻疹和瘙瘁(第29天)及低血压和昏厥(第141天)。患者注射本品后应至少观察3O分钟。在出现低血压和昏厥的情况下，应采取适当的救助措施，如抬高腿部、给氧、静脉输液、给予抗组胺药物、糖质激素和肾上腺素等。

在所有进行的本品用于前列腺癌的临床研究中(大部分为晚期无症状性前列腺癌)，急性全身性过敏反应(在给药后30分钟内发生)的发生率为1．1％(15例／1397例)。在发生过敏反应的15例患者中有14例在注射后8分钟内就出现症状。这类反应的累积风险随着治疗时间的延长而增加。在第56、141、365和676天的累积发生率分别为O．51％、0．80％、1．24％和2．91％。发生低血压和昏厥哟患者有7例，发生率为0．5％。这类过敏反应在第56、141、365和676天的累积发生率分别为0．22％、O．32％、O．61％和1．67％。

实验室指标变化
在小部分患者中观察到具有临床意义的血浆转氨酶升高。血浆转氨酶超过正常范围上限的2．5倍或>~200U／L的发生率分别为3．1％和0．8％。血红蛋白轻微下降为化学去势后的生理反应。在治疗组还观察到血浆甘油三酯水平出现平均10％的上升。

注意事项

一般注意事项

在体重超过225磅的患者中，本品总体疗效下降、治疗持续时间延长程度较大。这部分患者应确保严格的血浆睾酮监测。

在部分接受本品或类似药物的患者中观察到具有临床意义的转氨酶升高。在开始应用本品治疗前应测定血浆转氨酶水平并在治疗期间定期监测。GnRH抑制剂和LHRH抑制剂可能导致骨密度下降。

药物相互作用

有关本品的药物相互作用研究尚未正式进行。本品的代谢是否涉及细胞色素P450尚不可知。本品的血浆蛋白结合率较高(96％-99％)。

三、用法与用量

出于安全考虑，本品获准时带有市场限制。只有具有一定资格并表明承担相关义务、并在此基础上加入PraecisPharmaceuticals公司PlenaxisPLUSProgram的医生才有权开具本品的处方。

推荐的用药方案为第1、15和29天给予本品100mg肌肉注射，每4周为一疗程式。在第29天注射前测定血浆睾酮浓度以确定治疗效果，其后每8周测定1次。制剂注射用无菌粉末，每瓶含本品CMC复合物113mg，临用前加入0．9％氯化钠溶液2．2mL溶解，使成2mL含本品lOOmg(50mg／mL)的一次给药剂量。

每个单包装还包括一支稀释用的0．9％氯化钠注射液10mL、一支3cc带18号1／2英寸注射针头的注射器和一个安全包装的SafetyGlide22号1／2英寸注射针头。

New drug for prostate cancer

Plenaxis® (abarelix) is our lead product. It is the first in a new class of hormonal products to treat advanced and metastatic prostate cancer
adotrophin-releasing hormone receptor (GnRH) blocker and it works by direct blockade of the GnRH receptors, resulting in a rapid and sustained reduction in testosterone levels and rapid and sustained disease control. As a result, Plenaxis® is the first antagonist hormonal for managing prostate cancer that overcomes the need for anti-androgen co-prescribing. It has a rapid onset and offset of action, leading to fast and profound PSA and prostate volume reduction.

Clinical studies have shown that no hormonal surge or clinical flare occurs with Plenaxis® (unlike with agonist hormonal therapy), the efficacy is equal to the combined use of an agonist and anti-androgen and the effects on testosterone are reversible on stopping treatment.

Plenaxis® is available in Germany and roll out across Europe is planned following the approval of the drug in eleven additional EU Countries in August 2010.

-----------------------------------------------------

Development
Abarelix (Plenaxis) is an injectable decapeptide antagonist of leutinizing hormone­releasing hormone (LHRH) that was approved by the FDA in November 2003 for the treatment of advanced prostate cancer. Because of an increased risk of serious, and potentially life-threatening, allergic reactions associated with the use of abarelix, the drug will be marketed under a voluntary risk management program (RMP) intended to restrict distribution of the drug to patients with advanced prostate cancer who have no alternative therapy. About 5% to 10% of men with prostate cancer have the type of advanced, symptomatic disease that would make them candidates for abarelix therapy. The RMP for abarelix is called the PLUS (Plenaxis User Safety) Program.

Carcinoma of the prostate is predominantly a tumor of older men, which frequently responds to treatment when widespread and may be cured when localized. The rate of tumor growth varies from very slow to moderately rapid, and some patients may have prolonged survival even after the cancer has metastasized to distant sites such as bone. Because the median age at diagnosis is 72 years, many patients, especially those with localized tumors, may die of other illnesses or old age without ever having suffered significant disability from their cancer. The approach to treatment is influenced by age and coexisting medical problems. Several different hormonal approaches are available for prostate cancer chemotherapy including bilateral orchiectomy, estrogen therapy, LHRH analogs, antiandrogens, ketoconazole, and aminoglutethimide.

Mechanism of Action
Agonists of natural leutinizing hormone­releasing hormone were first synthesized in the 1970s. It was soon realized that the repeated administration of LHRH agonists produced a decrease in gonadal function, associated with a significant drop in sex steroid levels after an initial increase. These agonists were then made available for the treatment of prostate cancer in the 1980s. Use of LHRH agonists initiated a revolution in the treatment of prostate cancer. Two LHRH agonists are commonly used in treatment of prostate cancer; leuprolide acetate (Lupron) and goserelin acetate (Zoladex).

As indicated, treatment with a LHRH agonist analog results in an initial rise in gonadotropin secretion due to its binding to pituitary gland LHRH receptors and their subsequent activation. Secondarily, in relation to the continuous occupation of the receptors, luteinizing hormone (LH) levels decrease and follicle-stimulating hormone (FSH) levels decrease also but to a lesser degree, due to the desensitization process. The transient rise in LH (seven to 10 days) stimulates production of testosterone resulting in transient stimulation and increased growth of prostate and prostate cancer cells, with such associated symptoms as increased bone pain, if the patient already has metastases to the bone. This has become known as the “flare response.” Following the initial stimulative phase, continuous high levels of LHRH agonist result in termination of natural leutinizing hormone­releasing hormone synthesis and release. As a consequence, there is no further production of either LH or testosterone. In the absence of testosterone production, the level of testosterone in the body rapidly drops to a “castrate level” of 90% to 95% of its normal level. Hence, the decrease in testosterone levels to castrate level slows growth of prostate cells and prostate cancer cells to very low levels.

Abarelix (Plenaxis) and other LHRH antagonists differ in their mechanism of antiandrogenic from agonists. Abarelix binds to LHRH receptors with high affinity (KD = 0.1 nM) but, characteristic of competitive receptor antagonism, is unable to activate receptor signaling activity. Due to the direct inhibition of the secretion of LH by abarelix, there is no initial increase in serum testosterone concentrations thereby avoiding the flare response characteristic of leutinizing hormone­releasing hormone agonist activity. The site of binding of LHRH antagonists seems to differ from those of agonists.

LHRH antagonists, like agonist structures, are produced by substitution of four to six amino acids of natural LHRH by non-natural D-amino acid residues. The structure of abarelix (Plenaxis) is illustrated in the figure:

Structure of abarelix (Trade Name Drug: Plenaxis)

Abarelix (Plenaxis): Pharmacokinetics
The labile peptide nature of abarelix rules out its oral bioavailability. Hence the drug is administered by an intramuscular route. Abarelix (100 mg) is absorbed slowly after IM administration with a mean peak concentration of 43.4 ng/mL observed approximately three days after the injection. The apparent volume of distribution during the terminal phase determined after IM administration of abarelix was 4040 ± 1607 liters, implying that the drug likely distributes extensively within the body. Abarelix (Plenaxis) is highly bound to plasma proteins (96% to 99%). In-vitro studies using animal and human hepatocytes and in-vivo studies in animals indicate that the major metabolites of abarelix are formed via hydrolysis of peptide bonds. No significant oxidative or conjugated metabolites of abarelix have been noted either in vitro or in vivo. There is no evidence of cytochrome P-450 involvement in the metabolism of abarelix. In humans, approximately 13% of unchanged abarelix is recovered in urine after a 15 µg/kg IM injection and no detectable abarelix metabolites were found in urine. Renal clearance of abarelix is 14.4 L/day after a 100-mg dose of the drug.

Clinical Profile
Abarelix (Plenaxis) is indicated for the palliative treatment of men with advanced symptomatic prostate cancer, in whom LHRH agonist therapy is not appropriate and who refuse surgical castration, and who have one or more of the following: (1) risk of neurological compromise due to metastases, (2) ureteral or bladder outlet obstruction due to local encroachment or metastatic disease, or (3) severe bone pain from skeletal metastases persisting on narcotic analgesia. As part of the manufacturer’s PLUS program, abarelix injections will only be distributed to physicians who attest to certain qualifications and are formally enrolled in the program.

The effectiveness of abarelix in suppressing serum testosterone has been studied in two randomized, open-label, active-comparator trials. Patients were not those with advanced symptomatic prostate cancer. They were randomized in a 2:1 ratio to abarelix 100 mg IM versus LHRH agonist (Study 1) or to abarelix versus LHRH agonist plus nonsteroidal antiandrogen (Study 2). Abarelix (Plenaxis) was administered IM on Days 1, 15, 29 (Week 4), then every four weeks thereafter for at least six months (24 weeks). Leutinizing hormone­releasing hormoneagonist and nonsteroidal antiandrogen were administered in standard fashion. After completing six months of treatment, patients could continue randomized treatment for an additional six months. In both studies combined, 100% (348/348) of abarelix patients and 16% (28/172) of comparator patients avoided a testosterone surge. The percentage of patients who attained serum testosterone concentration ~50 ng/dL on Study Days 2, 8, 15 and 29 were 24, 70, 73 and 94, respectively. Successful response was defined as attainment of medical castration on Day 29 and maintenance through Day 85 (where no two consecutive serum testosterone concentrations between Days 29 and 85 were greater than 50 ng/dL). In Study 1, 92% of abarelix patients responded and 96% of LHRH agonist patients responded. In Study 2, 93% of abarelix patients and 95% of LHRH agonist plus nonsteroidal antiandrogen patients responded.

A study of abarelix (Plenaxis) was conducted in 72 men with advanced symptomatic prostate cancer who were at risk for clinical exacerbation if treated with an LHRH agonist (“flare response”). The objective of this open-label, multicenter, uncontrolled, single-arm study was to demonstrate that such patients could avoid orchiectomy through at least 12 weeks of treatment. In this trial, treatment was to be given for at least six months with the option to continue treatment in an extension trial. The specific reasons given for enrollment of the 72 patients were: bone pain from prostate cancer skeletal metastases (n = 31); an enlarged prostate gland or pelvic mass causing bladder neck outlet obstruction (n = 25); bilateral retroperitoneal adenopathy with ureteral obstruction (n = 9); impending neurological compromise from spinal, spinal cord, or epidural metastases (n = 6); or other (n = 1). The median age was 73 years, range 40 to 94 years. There were 62 Caucasians, six African-Americans and four Hispanics.

Abarelix (Plenaxis) 100 mg was administered via IM injection on Days 1, 15, and 29, then every four weeks thereafter. Twelve patients discontinued prior to Day 169 for the following reasons: adverse event (n = 2), voluntary withdrawal (n = 3), death (n = 4), and other (n = 3). Sixty patients were treated for at least 24 weeks; in the extension phase, 33 patients for at least 48 weeks and 15 patients for at least 96 weeks. None (0%) of the 72 patients required orchiectomy while being treated with abarelix; including during the extension phase (median combined duration of therapy was 40 weeks). However, two patients were withdrawn before week 12 for treatment-related adverse events (immediate-onset systemic allergic reactions consisting of urticaria and pruritus) and received alternate therapy. In this trial, medical castration (serum testosterone concentration of 50 ng/dL) was achieved in 57 of the 72 patients (79%) by Day 8, and by 68 of 71 patients (96%) by Week 4.

Also observed in this study was that none of eight patients with vertebral or epidural metastases and without neurological symptoms developed neurological symptoms; 10 of 13 patients with bladder outlet obstruction and a bladder drainage catheter had the catheter removed by 12 weeks; 11 of 15 patients with pain due to skeletal metastases were able to reduce the potency, dose and/or frequency of narcotic analgesia at 12 weeks.

Adverse Reactions
The most common side effects seen in clinical trials were hot flashes, sleep disturbances, pain, including back pain, breast enlargement or pain, and constipation.

The labeling for abarelix contains a black box warning concerning immediate-onset systemic allergic reactions, some resulting in hypotension and syncope following administration of the drug. The cumulative risk of such a reaction increases with the duration of treatment. Patients should be observed for at least 30 minutes following each injection of abarelix in the event of an allergic reaction and, if such a reaction should occur, managed appropriately. In the clinical trial of patients with advanced, symptomatic prostate cancer 3.7% of patients experienced an immediate-onset systemic allergic reaction within minutes of receiving abarelix. The allergic reactions were urticaria (Day 15), urticaria and pruritus (Day 29), and hypotension and syncope (Day 141).

Abarelix (Plenaxis): Drug Interactions
No formal drug/drug interaction studies with abarelix (Plenaxis) have been reported. Cytochrome P-450 isozymes are not known to be involved in the metabolism of this decapeptide.

Dosage and Administration
Abarelix for injection is supplied as a sterile dry powder. Dilution with 0.9% Sodium Chloride Injection, USP generates the depot suspension intended for intramuscular injection. The single-dose vial contains 113 mg of anhydrous free base abarelix peptide supplied in an abarelix-carboxymethylcellulose (CMC) complex. This complex also contains 19.1 to 31 mg of CMC. After the vial is reconstituted with 2.2 mL of 0.9% sodium chloride injection, 2 mL is administered to deliver a dose of 100 mg of abarelix (net) as the abarelix CMC complex at a pH of 5±1.

The recommended dose of abarelix (Plenaxis) is 100 mg administered intramuscularly to the buttock on Days 1, 15, 29 (Week 4) and every four weeks thereafter. Treatment failure can be detected by measuring serum testosterone concentrations just prior to abarelix administration, beginning on Day 29 and every eight weeks thereafter.

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