当前位置：药品说明书与价格首页 >> 呼吸系统病 >> 其他类用药 >> Glassia（α1-proteinase inhibitor (human))-α1-人蛋白酶抑制剂

Glassia（α1-proteinase inhibitor (human))-α1-人蛋白酶抑制剂

2012-12-08 22:32:25 作者：新特药房来源：互联网浏览次数：147 文字大小：【大】【中】【小】

简介： 7月6日Kamada宣布其Alpha-1蛋白酶抑制剂Glassia已经获得美国食品药品监督管理局(FDA)批准上市，这是全球首个液体且可以立即使用的Alpha 1蛋白酶抑制剂。FDA审查了Kamada于2009年5月提交的生物许可证申请 ...

关键字：α1-人蛋白酶抑制剂肺气肿

7月6日Kamada宣布其Alpha-1蛋白酶抑制剂Glassia已经获得美国食品药品监督管理局(FDA)批准上市，这是全球首个液体且可以立即使用的Alpha 1蛋白酶抑制剂。
FDA审查了Kamada于2009年5月提交的生物许可证申请(BLA)，审查内容包括临床开发情况、生产设施、质量保证和控制等情况。
Glassia是唯一的、高品质、立即可用的液体Alpha 1蛋白酶抑制剂，可用于因先天性Alpha-1蛋白酶抑制剂缺乏而引起的成人肺气肿病的慢性治疗和维持疗法，该产品是采用专利保护的色谱提纯方法生产的。

美国FDA2010年7月1日批准Glassia(α1-人蛋白酶抑制剂[α1-proteinase inhibitor (human)])注射剂- 既往名AAT-IV

Glassia现在是世界范围第一个和唯一的液体α-1-蛋白酶抑制剂。

批准日期：2010年7月1日；公司：Kamada Ltd.

一般描述
GLASSIA是一种灭病毒无菌，备用，纯制人α1-蛋白酶抑制剂(α1-PI)的液体制剂，也被称为α1-抗胰蛋白酶(AAT)。溶液含2%活性α1-PI在磷酸缓冲盐水溶液中。
GLASSIA是从持美国许可证的血浆采集中心用冷乙醇分离过程修改版本得到的人血浆制备的和然后用色谱方法纯化α1-PI。
用美国FDA-许可的对乙肝表面抗原(HBsAg)和对丙型肝炎病毒(HCV)和人免疫缺陷病毒1和2型(HIV-1/2)抗体的血清学分析，以及用美国FDA-许可的对HCV和HIV-1核酸检验(NAT)检验为生产GLASSIA所用各血浆单位。在所有检验中各血浆单位必须是无反应(阴性)。通过进程内(in-process)核酸检验过程还检验血浆微小病毒B19而制造合并中B19 DNA的限量被设定为不超过104 IU每mL。
为减低病毒传播风险，为GLASSIA制造工艺过程包括两步专门设计去除或灭活病毒。第一步是通过一个15 nm过滤器纳米过滤(NF)可去除包膜和非包膜病毒媒介而第二步是溶剂/去垢剂(S/D)处理，用三正丁基磷酸醋和山梨醇80(吐温80)混合物灭活包膜病毒媒介例如HIV，HBV和HCV。
曾用一系列物化特征范围的病毒评估S/D处理和纳米过滤步骤对减低病毒内容物的有效性。表6中总结了病毒攻击的结果。

作用机制
α1-PI缺乏是一种慢性，常染色体的，共显性遗传性疾病特征是在血和肺中α1-PI水平的减低(1, 2)。有α1-PI缺乏患者中吸烟是对发生肺气肿的一种重要风险因子(3)。因为肺气肿影响许多，但不是全部有α1-PI缺乏(AAT缺乏)更严重的遗传变种个体，用α1-蛋白酶抑制剂(人)增强治疗是只适用于有严重α1-PI缺乏，有临床上明显肺气肿的患者。
存在大量α1-PI缺乏表型变种，并非全部都伴有临床疾病。被鉴定α1-PI缺乏个体的约95%有PiZZ变种，典型地特征为正常α1-PI血清水平< 35%。有Pi(无)/(无)变种个体在他们血清中没有α1-PI蛋白(2, 3)，α1-PI的内源性血清水平缺乏，或低个体，即，低于11 μM，表现出对发生肺气肿显著增加风险，高于一般人群背景风险(4, 5)。此外，PiSZ个体，他们的血清α1-PI水平范围从9至23 μM被认为中度地增加发生肺气肿风险，不管他们的血清α1-PI水平是否高于或低于11 μM(6)。
通过静脉输注扩增功能性蛋白酶抑制剂的水平是治疗α1-PI缺乏患者一种方法。但是，尚未在随机化，对照临床试验中证实增强治疗在影响肺气肿进程的疗效。意向的理论上目标是通过纠正嗜中性粒细胞弹性酶和蛋白酶抑制剂间的不平衡对下呼吸道提供保护。尚未在充分加权，随机化对照临床试验证实用GLASSIA或任何α1-PI产品增强治疗是否真正从进展的肺气肿变化保护下呼吸道。尽管维持血α1-PI(抗原测定)血清水平高于11 μM在历史上曾被假定提供治疗上有意义的抗-嗜中性粒细胞弹性酶保护，这尚未被证明。有严重α1-PI缺乏个体曾显示肺上皮衬里液体中嗜中性粒细胞和嗜中性粒细胞弹性酶浓度比较正常PiMM个体增加。而且某些有α1-PI高于11 μM PiSZ个体有肺气肿归咎于α1-PI缺乏。这些观察强调关于增强治疗期间α1-PI的适当治疗性目标血清水平的不确定性。

适应证和用途
GLASSIA是一种α1-蛋白酶抑制剂适用于慢性增强和维持治疗由于α1-蛋白酶抑制剂(α1-PI)的先天性缺乏，也被称为α1抗胰蛋白酶缺乏的有肺气肿成年(1)。
尚未在随机化，对照临床试验证实增强治疗在α1-PI缺乏的肺病程加重和肺气肿进展用任何α1蛋白酶抑制剂的影响(1)。
没有证实GLASSIA对个体慢性增强和维持治疗长期影响临床资料可供利用(1)。
尚未确定严重Α1-PI缺乏患者中不适用GLASSIA治疗肺疾病(1)。

剂量和给药方法
1)只为静脉使用(2)。
2)不要与其它药物或稀释溶液混合(2)。
3)剂量 = 60 mg/kg体重每周1次(2.1)。
4)尚未用有效性终点每周1次剂量范围研究(2.1)。
5)在“配制”节适用用过滤针头(2.2)。
6)输注速率不应超过0.04 mL/kg体重每分钟(2.3)。
7)如发生不良反应，减低速率或中断输注直至症状消失。然后可用患者耐受速率恢复输注(2.3)。

剂型和规格
单次使用小瓶含1 gram of 功能性Α1-PI在50 mL备用溶液中(3).

禁忌证
1)IgA缺乏患者有对IgA抗体(4)。
2)对α1-PI产品严重立即的超敏性反应史，包括过敏反应(4)。

警告和注意事项
对IgA超敏性
GLASSIA可能含少量IgA。有选择性或严重IgA缺乏和有已知对IgA抗体患者，有更大风险发生严重超敏性和过敏反应。输注自始至终连续监查生命征象和仔细观察患者，如发生过敏或严重过敏样反应，立即停止输注。为治疗任何急性过敏或过敏样反应可得到肾上腺素和其它充分支持治疗。

在特殊人群中的使用
1) 妊娠：无人或动物资料. 只有明确需要才使用(8.1)。

不良反应
临床研究用GLASSIA期间在两种分离机会观察到2例严重不良反应是胆管炎和慢性阻塞性非疾病(COPD)加重。
被研究者认为受试者接受GLASSIA最常见药物相关不良反应至少可能与GLASSIA给药相关，发生率 >3% 是头痛和眩晕。

Glassia approved for treating alpha 1 antitrypsin deficiency

Glassia approved for treating alpha 1 antitrypsin deficiency Kamada announced that the FDA has approved Glassia (alpha1-proteinase inhibitor liquid) for chronic augmentation and maintenance therapy in adults with emphysema due to congenital deficiency of alpha1-proteinase inhibitor (AATD). Glassia is a high purity, ready-to-use liquid alpha1-proteinase inhibitor.
Glassia
Generic Name: alpha-1-proteinase inhibitor (human)
Dosage Form: injection, solution
Indications and Usage for Glassia
Alpha-1-Proteinase Inhibitor (Human), Glassia is indicated for chronic augmentation and maintenance therapy in individuals with emphysema due to congenital deficiency of alpha1-proteinase inhibitor (Alpha1-PI), also known as alpha1-antitrypsin (AAT) deficiency.

•The effect of augmentation therapy with Glassia or any Alpha1-PI product on pulmonary exacerbations and on the progression of emphysema in Alpha1-PI deficiency has not been demonstrated in randomized, controlled clinical trials.
•Clinical data demonstrating the long-term effects of chronic augmentation and maintenance therapy of individuals with Glassia are not available.
•Glassia is not indicated as therapy for lung disease in patients in whom severe Alpha1-PI deficiency has not been established.

Glassia Dosage and Administration
•For Intravenous Use Only.
•Use aseptic technique for all preparation and administration steps.
•Administer Glassia alone; do not mix with other agents or diluting solutions.
•Administer product brought to room temperature within three hours of entering the vials.
Treatment of Congenital Alpha1-Proteinase Inhibitor Deficiency
The recommended dosage of Glassia is 60 mg/kg body weight administered once weekly by intravenous infusion. Dose ranging studies using efficacy endpoints have not been performed.

Preparation
1.Inspect the vial of Glassia. The solution should be clear and colorless to yellow-green and may contain a few protein particles. Do not use if the product is cloudy.
2.Infusion can be made directly from the vial or alternatively, vials may be pooled in an empty, sterile intravenous container.
3.When infusing directly from the vial, use a vented spike adapter and a 5 micron in-line filter (neither is supplied).
4.When infusing from a sterile intravenous container, attach an appropriate intravenous administration set to the intravenous container. Use a vent filter (not supplied) to withdraw the material from the vial and then use the supplied 5 micron filter needle to transfer the product into the infusion container. In addition, during infusion, it is recommended to use a 5 micron in-line filter (not supplied).
5.Administer intravenously to the patient as described in section 2.3.
Administration
1.Inspect parenteral products visually for particulate matter and discoloration prior to administration whenever solution and container permit.
2.Administer Glassia within three hours of entering the vials to avoid the potential ill effect of any inadvertent microbial contamination.
3.Administer Glassia at room temperature through an appropriate intravenous administration set at a rate not greater than 0.04 mL/kg body weight per minute. The recommended dosage of 60 mg/kg takes approximately 60-80 minutes to infuse.
4.Monitor the infusion rate closely during administration and observe the patient for signs of infusion related reactions. If infusion related adverse reactions occur, reduce the rate or interrupt the infusion until the symptoms subside. You may then resume the infusion at a rate tolerated by the patient.
5.Following administration, discard all open vials, unused solution and administration equipment.
Dosage Forms and Strengths
Glassia is available as a single-use vial containing 1 gram of functional Alpha1-PI in 50 mL of ready to use solution.

Contraindications

Glassia is contraindicated in immunoglobulin A (IgA) deficient patients with antibodies against IgA.

Glassia is contraindicated in individuals with a history of severe immediate hypersensitivity reactions, including anaphylaxis, to Alpha1-PI products.

Warnings and Precautions

Hypersensitivity to IgA

Glassia may contain trace amounts of IgA. Patients with selective or severe IgA deficiency and with known antibodies to IgA, have a greater risk of developing severe hypersensitivity and anaphylactic reactions. Monitor vital signs continuously and observe the patient carefully throughout the infusion. IF ANAPHYLACTIC OR SEVERE ANAPHYLACTOID REACTIONS OCCUR, DISCONTINUE THE INFUSION IMMEDIATELY. Have epinephrine and other appropriate supportive therapy available for the treatment of any acute anaphylactic or anaphylactoid reaction.

Transmissible Infectious Agents

Because this product is made from human plasma, it may carry a risk of transmitting infectious agents, such as viruses, and theoretically, the Creutzfeldt-Jakob disease (CJD) agent. The risk of transmitting an infectious agent has been minimized by screening plasma donors for prior exposure to certain viruses, by testing for the presence of certain current virus infections and by inactivating and removing certain viruses during the manufacturing process (see Description [11] for viral reduction measures). Despite these measures, such products may still potentially transmit human pathogenic agents. There is also the possibility that unknown infectious agents may be present in such products.

The physician should weigh the risks and benefits of the use of this product and discuss the risks and benefits with the patient.

All infections thought by a physician possibly to have been transmitted by this product should be reported by the physician or other healthcare provider to Kamada Ltd. at 1-866-Glassia or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

No seroconversions for hepatitis B or C (HBV or HCV) or human immunodeficiency virus (HIV) or any other known infectious agent were reported with the use of Glassia during the clinical studies.

Adverse Reactions

Two serious adverse reactions observed on two separate occasions during clinical studies with Glassia were cholangitis and exacerbation of chronic obstructive pulmonary disease (COPD).

The most common drug-related adverse reactions considered by the investigator to be at least possibly related to Glassia administration observed at a rate of >3% in subjects receiving Glassia were headache and dizziness.

Clinical Studies Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

A total of 65 subjects have received treatment with intravenous Glassia in two clinical studies, both performed in the US. Three subjects participated in both studies. However, because of the large temporal difference between studies (> 5 years) and major difference in study designs, each study was analyzed separately without excluding these three subjects who participated in both trials from either study analysis. Thus, safety and efficacy of Glassia are reported on all 18 subjects in a Phase I study and all 50 subjects who received Glassia in a Phase II/III study, for a total of 68 subjects, representing 65 unique subjects.

In an open label, Phase I non-parallel, dose-escalation study, 18 subjects received a single infusion of Glassia at dosages of 30, 60 or 120 mg/kg.

In a randomized, Phase II/III double-blind, active-control study, 50 subjects were scheduled to receive weekly infusions of Glassia or the comparator Alpha1-PI product, Prolastin, at a dosage of 60 mg/kg for a total of 12 doses after which all subjects remaining in the study were treated for another 12 weeks with Glassia only. Overall, 17 subjects received 12 doses and 21 subjects received 24 doses of Glassia during the study. Eleven subjects received either 22 or 23 doses and one subject did not receive any treatment with Glassia during the last 12 weeks of the study.

The population treated with Glassia in these two studies was 40-74 years old, 54% male, 100% Caucasian and had congenital Alpha1-PI deficiency with clinical evidence of emphysema.

Table 1 compares the adverse events reported during the initial 12 weeks (double-blind portion) of the Phase II/III study occurring in all subjects treated with Glassia with events in the concurrent Prolastin control group.

Table 1: Number of Subjects/Infusions/Adverse Events Occurring during the First 12 Weeks of Treatment
	Glassia	Prolastin
No. of subjects treated	33	17
No. of infusions	393	190
No. of subjects with adverse events regardless of causality (%)	27 (82%)	16 (94%)
No. of subjects with related adverse events according to investigator causality assessment(%)	6 (18%)	6 (35%)
No. of subjects with related serious adverse events	0	0
No. of subjects experiencing an adverse event within 24 hours of infusion, regardless of causality (%)	19 (58%)	14 (82%)
No. of adverse events regardless of causality (mean rate of adverse events per infusion)	70 (0.18)	46 (0.24)
No. of adverse events, regardless of causality, occurring within 24 hours of infusion (% of all adverse events)	35 (50%)	30 (65%)
No. of infusions associated with adverse events occurring within 24 hours of infusion, regardless of causality (% of infusions)	32 (8%)	28 (15%)

Table 2: Adverse Events Occurring in > 5% of Subjects during the First 12 Weeks of Treatment (Irrespective of Investigator Causality Assessment)
	Glassia No. of subjects: 33	Prolastin No. of subjects: 17
Adverse Event (AE)	No. of subjects with AE (percentage of all subjects)	No. of subjects with AE (percentage of all subjects)
Cough	5 (15%)	4 (24%)
Upper respiratory tract infection	4 (12%)	0 (0%)
Headache	3 (9%)	4 (24%)
COPD Exacerbation	4 (12%)	5 (29%)

Table 3: Adverse Event Frequency as a % of all Infusions (> 0.5%) (Irrespective of Investigator Causality Assessment)
aThroughout entire 24-week double-blind plus open-label trial period
b Throughout initial 12-week double-blind period
	Glassiaa No. of infusions: 960	Prolastinb No. of infusions: 190
Adverse Event (AE)	No. of AEs (percentage of all infusions)	No. of AEs (percentage of all infusions)
Upper respiratory tract infection	14 (1.5%)	0 (0.0%)
Headache	8 (0.8%)	4 (2.1%)
Nasopharyngitis	8 (0.8%)	0 (0.0%)
Cough	7 (0.7%)	4 (2.1%)
Pharyngolaryngeal pain	7 (0.7%)	1 (0.5%)
COPD	6 (0.6%)	2 (1.1%)

Table 4: Adverse Events Occurring in > 5% of Subjects during or Within 72 Hours of the End of an Infusion, in the First 12 Weeks of Treatment (Irrespective of Investigator Causality Assessment)
	Glassia No. of subjects: 33	Prolastin No. of subjects: 17
Adverse Event (AE)	No. of subjects with AE (percentage of all subjects)	No. of subjects with AE (percentage of all subjects)
Cough	3 (9%)	4 (24%)
Upper respiratory tract infection	3 (9%)	0 (0%)
Headache	3 (9%)	3 (18%)
Sinusitis	2 (6%)	1 (6%)
Chest discomfort	2 (6%)	0 (0%)
Dizziness	2 (6%)	0 (0%)
Hepatic enzyme increased	2 (6%)	0 (0%)

During the 12-week double blind portion of the Phase II/III trial, 4 subjects (12%) had a total of 7 exacerbations of chronic obstructive pulmonary disease (COPD) during Glassia treatment and 5 subjects (29%) had a total of 6 exacerbations of COPD during Prolastin treatment. Seventeen additional exacerbations in 14 subjects (28%) occurred during the 12-week open-label treatment period with Glassia. The overall rate of pulmonary exacerbations during treatment with either product was 1.3 exacerbations per subject per year.

Most adverse events were mild to moderate in severity, although two episodes of headache and one episode of cholangitis were severe. Two subjects experienced treatment emergent serious adverse events (cholangitis and infective exacerbation of COPD), both of which were considered by the investigator to be unrelated to treatment with Glassia.

Out of 68 subjects treated with Glassia during clinical studies, 14 (21%) experienced one or more adverse events that were assessed by the investigator as possibly or probably related to treatment (Table 5).

A total of 3 subjects (approximately 5%) receiving Glassia reported urticaria, irrespective of the investigator's opinion of cause.

Table 5: Adverse Reactions Assessed by Investigator as Possibly or Probably Related to Treatment with Glassia (No. of subjects: 68*: combined data from single-dose PK study and 24-week clinical study)
Adverse Event (AE)	No of subjects experiencing a related event according to investigator causality assessment (percentage of all subjects)
*Three (3) subjects participated in both the single-dose PK study and the 24-week trial, such that 65 unique subjects were administered Glassia.
Any event	14 (21%)
Headache	4 (6%)
Dizziness	2 (3%)
Dysgeusia, Influenza-like illness, Lethargy, Pyrexia, Decreased platelet count, Joint swelling, Erythema marginatum, Pruritis, Rash, Urticaria, Hypertension,	1 (1.5%)

Testing for viral markers for HBV, HCV, HIV-1 and HIV-2 showed no seroconversions during either study.

Post-Marketing Experience

No spontaneous adverse event reports have been received.

USE IN SPECIFIC POPULATIONS

Pregnancy

Pregnancy Category C
Animal reproduction studies have not been conducted with Glassia. It is also not known whether Glassia can cause fetal harm when administered to pregnant women or can affect reproductive capacity. Glassia should be given to a pregnant woman only if clearly needed.

Nursing Mothers

It is not known whether Alpha1-PI is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Glassia is administered to a nursing woman.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Clinical studies of Glassia included 11 subjects of 65 years of age or older. This number of subjects was not sufficient to determine whether they respond differently from younger subjects. As for all patients, dosing for geriatric patients should be appropriate to their overall situation. Safety and effectiveness in patients over 65 years of age have not been established.

Glassia Description

Glassia is a sterile, ready to use, liquid preparation of purified human alpha1-proteinase inhibitor (Alpha1-PI), also known as alpha1-antitrypsin (AAT). The solution contains 2% active Alpha1-PI in a phosphate-buffered saline solution.

Glassia is prepared from human plasma obtained from US-licensed plasma collection centers by a modified version of the cold ethanol fractionation process and the Alpha1-PI is then purified using chromatographic methods.

Individual plasma units used for production of Glassia are tested using FDA- licensed serological assays for hepatitis B surface antigen (HBsAg) and for antibodies to hepatitis C virus (HCV) and human immunodeficiency virus types 1 and 2 (HIV-1/2), as well as by FDA-licensed Nucleic Acid Testing (NAT) for HCV and HIV-1. Each plasma unit must be non-reactive (negative) in all tests. Plasma is also tested by in-process NAT procedures for parvovirus B19 and the limit for B19 DNA in the manufacturing pool is set not to exceed 104 IU per mL.

To reduce the risk of viral transmission, the manufacturing process for Glassia includes two steps specifically designed to remove or inactivate viruses. The first of these is nanofiltration (NF) through a 15 nm filter which can remove both enveloped and non–enveloped viral agents and the second is solvent/detergent (S/D) treatment with a mixture of tri-(n-butyl) phosphate (TNBP) and Polysorbate 80 (Tween 80) which inactivates enveloped viral agents such as HIV, HBV and HCV.

The effectiveness of the S/D treatment and nanofiltration procedures for reducing virus content has been assessed using a series of viruses with a range of physico-chemical characteristics. The results of the viral challenge studies are summarized in Table 6.

Table 6: Log10 Virus Reduction during Manufacture of Glassia
N/A - Not Applicable. The S/D treatment is not relevant for non-enveloped viruses.
ND - Not Done
HIV-1 Human immunodeficiency virus Type 1			WNV West Nile virus
PRV Pseudorabies virus			HAV Hepatitis A virus
BVDV Bovine viral diarrhea virus			PPV Porcine parvovirus
	Enveloped Viruses				Non-enveloped Viruses
Process Step	HIV-1	PRV	BVDV	WNV	HAV	PPV
Nanofiltration	> 5.59	> 5.57	> 5.74	ND	> 4.99	4.04
S/D treatment	> 6.41	> 6.14	> 5.61	> 6.32	N/A	N/A
Global Reduction Factor	> 12.00	> 11.71	> 11.35	> 6.32	> 4.99	4.04

Glassia - Clinical Pharmacology

Mechanism of Action

Alpha1-PI deficiency is a chronic, autosomal, co-dominant hereditary disorder characterized by reduced levels of Alpha1-PI in the blood and lungs (1, 2). Smoking is an important risk factor for the development of emphysema in patients with Alpha1-PI deficiency (3). Because emphysema affects many, but not all individuals with the more severe genetic variants of Alpha1-PI deficiency (AAT deficiency), augmentation therapy with Alpha1-Proteinase Inhibitor (Human) is indicated only in patients with severe Alpha1-PI deficiency who have clinically evident emphysema.

A large number of phenotypic variants of Alpha1-PI deficiency exist, not all of which are associated with the clinical disease. Approximately 95% of identified Alpha1-PI deficient individuals have the PiZZ variant, typically characterized by Alpha1-PI serum levels < 35% of normal. Individuals with the Pi(null)(null) variant have no Alpha1-PI protein in their serum (2, 3). Individuals with the lack of, or low, endogenous serum levels of Alpha1-PI, i.e., below 11 μM, manifest a significantly increased risk for development of emphysema above the general population background risk (4, 5). In addition, PiSZ individuals, whose serum Alpha1-PI levels range from approximately 9 to 23 μM are considered to have moderately increased risk for developing emphysema, regardless of whether their serum Alpha1-PI levels are above or below 11 μM (6).

Augmenting the levels of functional protease inhibitor by intravenous infusion is an approach to therapy for patients with Alpha1-PI deficiency. However, the efficacy of augmentation therapy in affecting the progression of emphysema has not been demonstrated in randomized, controlled clinical trials. The intended theoretical goal is to provide protection to the lower respiratory tract by correcting the imbalance between neutrophil elastase and protease inhibitors. Whether augmentation therapy with Glassia or any Alpha1-PI product actually protects the lower respiratory tract from progressive emphysematous changes has not been demonstrated in adequately powered, randomized controlled clinical trials. Although the maintenance of blood serum levels of Alpha1-PI (antigenically measured) above 11 μM has been historically postulated to provide therapeutically relevant anti-neutrophil elastase protection, this has not been proven. Individuals with severe Alpha1-PI deficiency have been shown to have increased neutrophil and neutrophil elastase concentrations in lung epithelial lining fluid compared to normal PiMM individuals, and some PiSZ individuals with Alpha1-PI above 11 μM have emphysema attributed to Alpha1-PI deficiency. These observations underscore the uncertainty regarding the appropriate therapeutic target serum level of Alpha1-PI during augmentation therapy.

Pharmacodynamics

Administration of Glassia to patients with Alpha1-PI deficiency augments the level of the deficient protein. Normal individuals have levels of Alpha1-PI greater than 22 μM. The clinical benefit of the increased blood levels of Alpha1-PI at the recommended dose has not been established.

Pharmacokinetics

A prospective, open-label, uncontrolled multicenter pharmacokinetic study was conducted in 7 females and 11 males with Alpha1-PI deficiency, ranging in age from 40 to 69 years. Subjects with congenital Alpha1-PI deficiency received a single dose of Glassia either 30 mg/kg, 60 mg/kg or 120 mg/kg. Blood samples for pharmacokinetic study were taken prior to and within 5 minutes of completion of the infusion, and then at 1 hour, 6 hours, 12 hours, 24 hours, 3 days and 7 days.

The mean results for pharmacokinetic parameters in the 60 mg/kg dosage group are shown in Table 7. The pharmacokinetics of Glassia were linear over the dose range of 30-120 mg/kg.

Table 7: Pharmacokinetic Parameters for Functional Alpha1-PI (Dosage 60 mg/kg; n=6)
Pharmacokinetic Parameter	60 mg/kg Dose Group
*Any assessment of the clinical relevance of half-life in this study should be viewed with caution, due to the short duration of blood sampling.
Terminal Half-Life (h)*	111 ± 33
Area under the curve(0-168 h) (mg⋅h/mL)	89 ± 10
Clearance (mL/h/kg)	0.68 ± 0.1
Volume of Distribution (L)	3.2 ± 0.3

Nonclinical Toxicology

No toxicological effects due to the solvent detergent reagents, TNBP and Tween 80, used in the virus inactivation procedure are expected since the residual levels are less than 5 and 20 ppm, respectively.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies in animals to evaluate carcinogenesis, mutagenesis or impairment of fertility have not been conducted.

Animal Toxicology and/or Pharmacology

Glassia was evaluated in two single dose general toxicology studies in Sprague-Dawley rats and New Zealand White rabbits and one repeated dose study in New Zealand White rabbits.

In single dose studies, one intravenous dose of 0, 60 and 600 mg/kg (rabbits) or 640 mg/kg (rats) was administered and the animals were observed for 14 days. There were no changes in body weight, clinical chemistry, hematology and gross pathology that could be attributed to Glassia administration.

In the repeated dose study, New Zealand White rabbits received 300 mg/kg Glassia once daily for 5 consecutive days. Animals were monitored for changes in clinical signs, body weight, clinical chemistry, hematology, necropsy and histopathology on day 1 or 14 after the last administration. A minor increase in group mean neutrophils was measured on day 1 after the last Glassia administration. Recovery was observed after 14 days.

Clinical Studies

A Phase II/III randomized, double-blind study with a partial cross-over was conducted to compare Glassia to a commercially available preparation of Alpha1-PI (Prolastin) in 50 Alpha1-PI -deficient subjects. The study objectives were to demonstrate that the pharmacokinetics of antigenic and/or functional Alpha1-PI in Glassia were not inferior to those of the control product, to determine whether Glassia maintained antigenic and/or functional plasma levels of at least 11 μM (57 mg/dL) and to compare Alpha1-PI trough levels (antigenic and functional) over 6 infusions.

For inclusion in the study, subjects were required to have lung disease related to Alpha1-PI deficiency and ‘at-risk' alleles associated with Alpha1-PI plasma levels < 11 μM. Subjects already receiving Alpha1-PI therapy were required to undergo a 5-week wash-out period of exogenous Alpha1-PI prior to dosing.

Fifty subjects received either Glassia (33 subjects) or the comparator product (17 subjects) at a dose of 60 mg/kg intravenously per week for 12 consecutive weeks. From Week 13 to Week 24 all subjects received open-label weekly infusions of Glassia at a dose of 60 mg/kg.

Trough levels of functional and antigenic Alpha1-PI were measured prior to treatment, at baseline and throughout the study until Week 24. The median trough Alpha1-PI values for Weeks 7-12 for subjects receiving Glassia were 14.5 μM (range: 11.6 to 18.5 μM) for antigenic and 11.8 μM (range: 8.2 to 16.9 μM) for functional Alpha1-PI. Eleven of 33 subjects (33.3%) receiving Glassia had mean steady-state functional Alpha1-PI levels below 11 μM. Glassia was shown to be non-inferior to the comparator product.

Serum Alpha1-PI trough levels rose substantially in all subjects by Week 2 and were comparatively stable during Weeks 7 to 12. All subjects receiving Glassia had mean serum trough antigenic Alpha1-PI levels greater than 11 μM during Weeks 7-12.

A subset of subjects in both treatment groups (n = 7 for subjects receiving Glassia) underwent broncho-alveolar lavage (BAL) and were shown to have increased levels of antigenic Alpha1-PI and Alpha1-PI - neutrophil elastase complexes in the epithelial lining fluid at Week 10-12 over levels found at baseline, demonstrating the ability of the product to reach the lung. An additional study is planned to evaluate changes in functional Alpha1-PI levels in epithelial lining fluid following administration of Glassia and a control Alpha1-PI product.

The clinical efficacy of Glassia in influencing the course of pulmonary emphysema or the frequency, duration, or severity of pulmonary exacerbations has not been demonstrated in randomized, controlled clinical trials.

REFERENCES

WHO. "α1-Antitrypsin deficiency." Memorandum from a WHO meeting. 1997;75: 397-415.
Stoller JK, et al. Augmentation therapy with α1-antitrypsin: patterns of use and adverse events. Chest 2003;123:1425-34.
Cox DW. α1-Antitrypsin Deficiency. In: Scriver C, Sly W, eds. The Metabolic and Molecular Bases of Inherited Disease. New York: McGraw Hill; 2002:5559-78.
Crystal RG, et al. The alpha1-antitrypsin gene and its mutations. Clinical consequences and strategies for therapy. Chest 1989;95:196-208.
Crystal RG. α1-Antitrypsin deficiency: pathogenesis and treatment. Hosp Pract (Off Ed) 1991;26:81-4, 8-9, 93-4.
Turino GM, et al. Clinical features of individuals with PI*SZ phenotype of α1-antitrypsin deficiency. Am J Respir Crit Care Med 1996;154:1718-25.

How Supplied/Storage and Handling

Each carton of Glassia contains a single use vial containing 1gram of functional Alpha1-PI in 50 mL of solution and a sterile filter needle (NDC 0944-2884-01).

Store Glassia at 2-8 °C (36-46 °F). Do not freeze.

责任编辑：admin

本文引用地址： http://www.referencepreparation.com/article/2012/1208/article_31949.html

发表评论　加入收藏　告诉好友　打印本页　关闭窗口　返回顶部

Glassia(α1-人蛋白酶抑制剂)注射剂使用说明书

Glassia(α1-人蛋白酶抑注射剂)

Glassia（α1-人蛋白酶抑制剂）--治疗肺气肿新药上市

Glassia（α1-proteinase inhibitor (human))-α1-人蛋白酶抑制剂

责任编辑：admin

最新文章

更多

推荐文章

更多

热点文章

更多