英文药名: Plenaxis（abarelix for injectable suspension）

中文药名:  普来纳西（阿巴瑞克注射混悬液）

生产厂家：Praecis制药
药品介绍
ABARELIX是一个促性腺素释放激素(GnRH)拮抗剂。最先由美国Praecis制药公司研制开发，现已在欧洲进行了用于前列腺癌治疗的III期临床实验。在美国也正在进行用于子宫内膜异位症治疗的临床实验。该药曾用代号为R-3827和PPI-l490。
体外实验表明，ABARELIX对促黄体激素释放素(LHRH)受体具有高亲和性(KD＝1nmol/L)，是LHRH的完全拮抗剂。该药与LHRH受体结合后，能阻断D-His6-GNRH的激动作用。体外大鼠腹膜巨噬细胞实验还证明，此化合物具有微弱的组胺释放活性，EC50为100mg/ml。此外，ABARELIX易溶于水。所有实验结果均证明，ABARELIX在阻断性激素生成方面具有潜在疗效。
包装规格（德国销售）
100mg*1
100mg*3

Plenaxis (Abarelix)- Description and Clinical Pharmacology 
DESCRIPTION

Abarelix for injectable suspension (Plenaxis®) is a synthetic decapeptide with potent antagonistic activity against naturally occurring gonadotropin releasing-hormone (GnRH).
Plenaxis® inhibits gonadotropin and related androgen production by directly and competitively blocking GnRH receptors in the pituitary.
Abarelix is chemically described as acetyl-D-(beta)-naphthylalanyl-D-4-chlorophenylalanyl -D-3-pyridylalanyl-L-seryl-L-N-methyl-tyrosyl-D-asparagyl-L-leucyl-L-N([egr]) -isopropyl-lysyl-L-prolyl-D-alanyl-amide. It is initially manufactured as an acetate water complex and converted to a carboxymethylcellulose (CMC) water complex in manufacturing the drug product. The molecular weight for abarelix anhydrous free base is 1416.06.
The structural formula for abarelix peptide is:

Abarelix for injectable suspension is supplied as a white to off-white sterile dry powder which, when mixed with the diluent, 0.9% Sodium Chloride Injection, USP, becomes a depot suspension intended for intramuscular (IM) injection.
The single-dose vial contains 113 mg of anhydrous free base abarelix peptide (net) supplied in an abarelix 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.
CLINICAL PHARMACOLOGY
MECHANISM OF ACTION
Abarelix exerts its pharmacological action by directly suppressing luteinizing hormone (LH) and follicle stimulating hormone (FSH) secretion and thereby reducing the secretion of testosterone by the testes. Due to the direct inhibition of the secretion of LH by abarelix, there is no initial increase in serum testosterone concentrations.
Saturation binding studies revealed that [125 I]-abarelix has a very high affinity (KD= 0.1 nM) for the rat pituitary LHRH receptor.
PHARMACOKINETICS
A single dose (100mg IM) of Plenaxis® was given to 14 healthy male volunteers 52 to 75 years of age, with body weight of 61.6 to 110.5 kg, and the pharmacokinetic information is provided in Table 1:
Table 1. Mean ± SD Pharmacokinetic Parameter Values of 100 mg of Plenaxis® Following a Single IM Injection (n = 14)

Cmax (ng/mL)	Tmax (days)	AUC0-(infinity) (ng · day/mL)	CL/F (L/day)	t1/2 (days)
43.4 ± 32.3	3.0 ± 2.9	500 ± 96	208 ± 48	13.2 ± 3.2

ABSORPTION
Following IM administration of 100 mg of Plenaxis®, abarelix is absorbed slowly with a mean peak concentration of 43.4 ng/mL observed approximately 3 days after the injection.
DISTRIBUTION
The apparent volume of distribution during the terminal phase determined after IM administration of Plenaxis® was 4040 ± 1607 liters, implying that abarelix probably distributes extensively within the body.
METABOLISM
In vitro hepatocyte (rat, monkey, human) studies and in vivo studies in rats and monkeys showed that the major metabolites of abarelix were formed via hydrolysis of peptide bonds. No significant oxidative or conjugated metabolites of abarelix were found either in vitro or in vivo. There is no evidence of cytochrome P-450 involvement in the metabolism of abarelix.
EXCRETION
In humans, approximately 13% of unchanged abarelix was recovered in urine after a 15 µg/kg IM injection; there were no detectable metabolites in urine. Renal clearance of abarelix was 14.4 L/day (or 10 mL/min) after administration of 100 mg Plenaxis®.
PHARMACODYNAMICS:
Effects of Plenaxis® on Serum Testosterone: The effectiveness of Plenaxis® in suppressing serum testosterone was 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 Plenaxis® 100 mg IM versus LHRH agonist (Study 1) or to Plenaxis® versus LHRH agonist + nonsteroidal antiandrogen (Study 2). Plenaxis® was administered IM on Days 1, 15, 29 (Week 4), then every 4 weeks thereafter for at least 6 months (24 weeks). LHRH agonist and nonsteroidal antiandrogen were administered in standard fashion. After completing 6 months of treatment, patients could continue randomized treatment for an additional 6 months.
Avoidance of testosterone surge: In both studies combined, 100% (348/348) of Plenaxis® patients and 16% (28/172) of comparator patients avoided a testosterone surge.
Attainment of medical castration: The percentage of patients who attained serum testosterone concentration
Table 2. Percentage of patients who attained medical castration (serum testosterone concentration 

Plenaxis®
Day	Total N	% Castrate
2	339	24%
4	333	56%
8	348	70%
15	347	73%
29	347	94%

Attainment and maintenance of medical castration: 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 Plenaxis® patients responded and 96% of LHRH agonist patients responded. In Study 2, 93% of Plenaxis® patients and 95% of LHRH agonist + nonsteroidal antiandrogen patients responded.
However, when failure was defined as any observed serum testosterone > 50 ng/dL (including transient elevations) just prior to dosing on Day 29 and every 28 days thereafter, effectiveness of testosterone suppression decreased over time. Results of this analysis are summarized in Table 3.
Table 3. Percentage of patients who attained and maintained medical castration; [no serum testosterone >50 ng/dL just prior to dosing on Day 29 and every 28 days thereafter]

Day	Study 1	N	Study 2	N
	Plenaxis®		Plenaxis®
85	84%	176	92%	164
169	75%	166	87%	155
365	62%	93	71%	86

Effects of Plenaxis® on Cardiac Electrophysiology: In a single, active-controlled, clinical study comparing Plenaxis® to LHRH agonist + nonsteroidal antiandrogen, periodic electrocardiograms were performed. Both therapies prolonged the mean Fridericia-corrected QT interval by >10 msec from baseline. In approximately 20% of patients in both groups, there were either changes from baseline QTc of >30 msec, or end-of-treatment QTc values exceeding 450 msec. Similar results were observed in 2 other Phase 3 studies with Plenaxis® and the active-control treatments. It is unclear whether these changes were directly related to study drugs, to androgen deprivation therapy, or to other variables.
SPECIAL POPULATIONS
RACE
Data from Hispanics, Blacks and Caucasians demonstrated that race appeared to have no influence on the pharmacokinetics of Plenaxis®.
RENAL AND HEPATIC INSUFFICIENCY
The pharmacokinetics of Plenaxis® in hepatically and/or renally impaired patients have not been determined.
PEDIATRIC USE
There have been no studies of Plenaxis® in pediatric patients.
CLINICAL STUDIES
One study of Plenaxis® was conducted in 81 men with advanced symptomatic prostate cancer who were at risk for clinical exacerbation ("clinical flare") if treated with an LHRH agonist. 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 6 months with the option to continue treatment in an extension trial.
Of the 81 patients who enrolled, 9 patients from one site were excluded from the efficacy analysis due to inadequate documentation by the study investigator. 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, 6 African Americans and 4 Hispanics.
Plenaxis® 100 mg was administered via IM injection on Days 1, 15 and 29, then every 4 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 Plenaxis®, including the extension phase (median combined duration of therapy was 40 weeks). However, 2 patients were withdrawn before week 12 for treatment-related adverse events (immediate-onset systemic allergic reactions consisting of urticaria, and urticaria and pruritis, respectively) and received alternate therapy. In this trial, medical castration (defined as serum total testosterone concentration Although the study was not designed to assess specific clinical outcomes, the following were observed:
None (0) of 8 patients with vertebral or epidural metastases and without neurological symptoms developed neurological symptoms.
Ten of 13 patients with bladder outlet obstruction and a bladder drainage catheter had the catheter removed by 12 weeks.
Eleven 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.
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FDA批准晚期前列腺癌的新药Plenaxis(通用名：abarelix)
11月25日，FDA批准了允许Plenaxis(普来纳西［商品名］)(通用名：abarelix［阿巴瑞克］)上市的新药申请(NDA)。Plenaxis是在患者没有其他可供选择的疗法时，用于治疗晚期前列腺癌(advanced prostate cancer)的一种药品。该药标明用于：不能采用其他激素疗法的和拒绝手术去势(surgical castration)的晚期前列腺癌男子的症状治疗。它将根据药品申报者(sponsor)同意并执行的自愿风险管理计划(voluntary risk management program［RMP］)被上市。由于与该药使用相关的严重的和潜在性威胁生命的过敏反应(allergic reactions)的风险增加，根据该计划，药品申报者将把Plenaxis的使用限于没有其他可选择疗法的晚期前列腺癌患者。患前列腺癌的男子中，大约5%-10%有晚期、征候的(symptomatic)疾病，这将使他们成为使用Plenaxis的候选人(candidates)。
Plenaxis是叫做促性腺素释放激素拮抗剂(gonadotropin-releasing hormone［GnRH］ antagonist)的一类药物，它是涉及多数前列腺癌生长的一个关键因素。对81名男子所作的试验，证明Plenaxis有降低晚期、征候的前列腺癌男子睾丸素(testosterone)生产的效果。试验表明，这些患者可以通过至少12周的治疗避免手术去势。他们中的某些还从使用此产品中获得其他益处，包括减少疼痛和缓解泌尿问题。但是，在临床试验中，81名患者中有三人发生了严重的过敏反应，其中一人还失去了知觉。
由于严重的和潜在性威胁生命的过敏反应的风险增加，FDA和生产商已同意：Plenaxis的上市销售应当被限于有晚期、征候的前列腺癌和没有其他治疗选择的那些患者。由于对Plenaxis过敏反应的一部分――低血压和晕厥(fainting)的风险，接受治疗的患者在其医疗保健提供者(health care provider)的诊所设施中接受一个剂量的该药后，要被监视至少30分钟。此外，生产商将不通过零售药店销售该药；而是，直接向参与“Plenaxis风险管理计划”(Plenaxis RMP)的医师和医院药房销售。
在治疗的第一个月，Plenaxis作为注射剂每两周一次注入臀部肌肉；此后，每四周注射一次。由于该药在某些患者身上可能不发生作用，医师应当大约每两个月对患者进行一次血液检验以确定Plenaxis通过保持睾丸素的低水平而起作用。
临床所见最通常的副作用是：热潮红(hot flashes)、睡眠失调、疼痛(包括背痛、胸部增大或疼痛)以及便秘。
该药的生产商将执行的Plenaxis风险管理计划(RMP)，被设计用于：帮助保证患者和医师在使用Plenaxis前被充分告知该药的风险和益处。该RMP强调需要医师、患者和医院药师共同努力以达到Plenaxis的益处最大化和风险最小化。
作为计划的一部分，申报者将只向达到某些资格并参与Praecis公司“Plenaxis使用者安全计划”(Plenaxis PLUS［Plenaxis User Safety］ Program)的医师销售Plenaxis。此外，该公司正就Plenaxis的风险和益处为医师、患者和医院药师建立教育项目。患者在接受该药前，将被要求阅读并签署一份患者信息单(patient information leaflet)。该公司还将建立一个收集并向FDA报告不良事件的系统。参与的医师还应当通过电话1-866-753-6294向Praecis公司或者通过电话1-800-FDA-1088向FDA的“医学监视项目”(MedWatch Program)报告严重不良事件。最后，该公司还将进行试验，评估风险管理计划，包括评估Plenaxis的处方和实际使用。
Plenaxis由美国麻萨诸塞州Waltham的Praecis Pharmaceuticals Inc.(Praecis制药公司)上市销售。