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Voraxaze(glucarpidase)注射液

2012-05-16 22:44:05 作者：新特药房来源：互联网浏览次数：212 文字大小：【大】【中】【小】

简介： 制造商：首旅集团国际类药物：羧肽酶。活性成分（S）：glucarpidase; 1000台/瓶;静脉注射冻干粉后重建;不含防腐剂。指示（S）：处理有毒血浆甲氨蝶呤（MTX）浓度在延迟甲氨蝶呤清除因肾功能受损 ...

关键字：Voraxaze(glucarpidase)注射液

制造商：
首旅集团国际

类药物：
羧肽酶。

活性成分（S）：
glucarpidase; 1000台/瓶;静脉注射冻干粉后重建;不含防腐剂。

指示（S）：
处理有毒血浆甲氨蝶呤（MTX）浓度在延迟甲氨蝶呤清除因肾功能受损的患者（> 1微摩尔每升）。

药理作用：
glucarpidase是一种重组的细菌酶，水解羧基端的叶酸和古典叶酸拮抗剂如甲氨蝶呤的谷氨酸残基。

glucarpidase转换甲氨蝶呤其活性代谢物4 - 脱氧-4-氨基-N10 - methylpteroic酸（丹巴）和谷氨酸。

glucarpidase提供替代非肾途径甲氨喋呤在高剂量MTX治疗肾功能不全患者消除。

临床试验：
在子集组成的22个治疗评估患者的疗效评价的Voraxaze。一个单臂，开放标签的研究进行了显着推迟甲氨蝶呤间隙（如超过2个标准偏差比平均为MTX的排泄曲线的定义）继发于肾功能不全患者。所有患者接受静脉注射50Units/kg Voraxaze超过5分钟;，预Voraxaze MTX的浓度>100μmol/ L的患者将接受首剂量后48小时内的第二次Voraxaze。患者继续接受静脉水化，碱化尿液和亚叶酸钙，亚叶酸钙管理进行了调整，以确保它在两小时内不前或后Voraxaze管理。

疗效评价入选患者符合纳入标准的研究的一个子集，预Voraxaze MTX浓度1μmol/ L的，并且有前和治疗后的血浆样品甲氨喋呤浓度测定的色谱方法分析。主要结果是谁取得了快速，持续的临床重要的减少（RSCIR）血浆中MTX浓度，定义为实现血浆MTX浓度≤1μmol/ L的后15分钟，持续了8天的患者比例初次注射。

对22例患者的疗效数据集，年龄中位数为15.5岁，59％为男性，潜在的癌症最常见的是骨肉瘤（50％）和白血病或淋巴瘤（45％）。

十年取得RSCIR 22例[45％（95％CI为27％，65％）]。未能实现RSCIR的12例，5例患者（23％）达到了一个短暂的血浆MTX浓度≤加入1μmol/ L在这5例患者，从他们的低谷中位数增加血浆MTX浓度为1.4μmol/ L，（0.3-2.5μmol/ L），。

法律分类：
RX

成人和儿童：
<1个月：不推荐。 ≥1个月：为丸静脉注射给超过5分钟。 50Units/kg作为一个单一的注射。继续亚叶酸钙治疗，直到MTX浓度低于至少3天的亚叶酸钙治疗阈值。

不亚叶酸钙剂量glucarpidase之前或之后2小时内管理。首后glucarpidase 48小时：管理同亚叶酸钙剂量事先向glucarpidase。超过48小时后glucarpidase：给予亚叶酸剂量的基础上测得MTX浓度。

警告/注意事项：
未标明表现出的MTX的预期间隙（MTX的排泄平均曲线特定的剂量甲氨蝶呤下辖2个标准差之内的血浆MTX的浓度）或肾功能正常或轻度受损的患者使用。监视器MTX的浓度仅在48小时内色谱法管理。继续水化和碱化尿液。怀孕（C类）。哺乳的母亲。

互动（补）：
成人和儿童。其他外源性底物，包括减少叶酸和叶酸的抗代谢药物可能会造成干扰。

不良反应（S）：
感觉异常，潮红，胃肠不适，低血压，头痛;罕见：过敏反应。

如何提供：
单次使用的小瓶-1

最后更新：
2012年5月7日

FDA：批准Voraxaze用于减轻甲氨蝶呤毒性

2012年1月18日，美国食品药品管理局(FDA)已批准Voraxaze(glucarpidase)用于甲氨蝶呤清除延迟的患者，以降低其体内毒性血浆甲氨蝶呤浓度，这种清除延迟可由患者肾功能损害导致。该药品已被FDA指定为孤儿药。Voraxaze作为一种酶，可将甲氨蝶呤降解为无活性代谢产物并通过肾外途径(主要通过肝脏)将其排出体外，从而快速降低其血浆水平。

大剂量的甲氨蝶呤化疗用于治疗骨肉瘤、白血病及淋巴瘤等某些类型的癌症或预防其复发。接受甲氨蝶呤治疗的部分患者可出现肾功能损害，导致甲氨蝶呤在血液中积聚达到毒性水平，增加患者的毒性风险。

FDA批准Vorazxaze是基于在2项单组、开放性、多中心试验中接受治疗的290例患者的数据。这些受试者的中位年龄为17岁(1个月龄~85岁)，男性占64%，32%患有骨源性肉瘤或肉瘤，63%患有白血病或淋巴瘤。支持该药审批的是该试验的药代动力学终点数据，此终点是指血浆甲氨蝶呤浓度快速、持续的降低且具有临床意义(RSCIR)(具体定义为“在给予glucarpidase后的15 min内血浆甲氨蝶呤浓度达到≤ 1 μmol/L的水平并维持长达8 d”)。

Voraxaze的疗效是通过对一个患者亚组进行的研究而得到证实的，涉及其中一项研究中22例可评估治疗的患者。入组该研究的患者存在继发于肾功能障碍的甲氨蝶呤清除延迟(标准列线图上显示超出平均值2个标准差以上)。疗效评估仅限于在治疗前后采集了血浆样本并按照正确操作规程进行处理、利用色谱法得出可靠的甲氨蝶呤测定值的患者。其中10例患者达到RSCIR(45%:95%置信区间，27%~65%)。所有可评估的患者的甲氨蝶呤浓度均较预处理时的基线水平降低95%以上，并在glucarpidase治疗后持续长达8 d。

研究中受试者报告最多的不良反应包括感觉异常、面部潮红、恶心和(或)呕吐、低血压以及头痛。

Voraxeze经静脉注射给药。在给予glucarpidase后48 h内只能利用色谱法方可测得可靠的甲氨蝶呤浓度值，而采用免疫分析法测量则会高估甲氨蝶呤浓度。

VORAXAZE

Manufacturer:

BTG International

Pharmacological Class:

Carboxypeptidase enzyme.

Active Ingredient(s):

Glucarpidase; 1,000 Units/vial; lyophilized powder for IV injection after reconstitution; preservative-free.

Indication(s):

Treatment of toxic plasma methotrexate (MTX) concentrations (>1 micromole per liter) in patients with delayed MTX clearance due to impaired renal function.

Pharmacology:

Glucarpidase is a recombinant bacterial enzyme that hydrolyzes the carboxyl-terminal glutamate residue from folic acid and classical antifolates such as methotrexate.

Glucarpidase converts MTX to its inactive metabolites 4-deoxy-4-amino-N10-methylpteroic acid (DAMPA) and glutamate.

Glucarpidase provides an alternate non-renal pathway for MTX elimination in patients with renal dysfunction during high-dose MTX treatment.

Clinical Trials:

The efficacy of Voraxaze was evaluated in a subset consisting of 22 treatment- evaluable patients. A single-arm, open-label study was conducted in patients who had markedly delayed MTX clearance (defined as more than 2 standard deviations greater than the mean excretion curve for MTX) secondary to renal dysfunction. All patients received Voraxaze 50Units/kg as an IV injection over 5 minutes; those patients with pre-Voraxaze MTX concentrations >100μmol/L were to receive a second dose of Voraxaze 48 hours after the first dose. Patients continued receiving IV hydration, urinary alkalinization and leucovorin, and that leucovorin administration was adjusted to ensure that it was not administered within two hours before or after Voraxaze.

Efficacy was evaluated in a subset of patients enrolled who met the inclusion criteria for the study, had a pre-Voraxaze MTX concentration >1μmol/L, and had both pre- and post-treatment plasma samples available for determination of MTX concentration by a chromatographic method analysis. The main outcome measure was the proportion of patients who achieved a rapid and sustained clinically important reduction (RSCIR) in plasma MTX concentration, defined as an attainment of plasma MTX concentration ≤1μmol/L at 15 minutes that was sustained for up to 8 days following the initial injection.

Of the 22 patients in the efficacy dataset, the median age was 15.5 years; 59% were male, and the most common underlying cancers were osteogenic sarcoma (50%) and leukemia or lymphoma (45%).

Ten of the 22 patients achieved RSCIR [45% (95% CI 27, 65%)]. Of the 12 patients who failed to achieve RSCIR, 5 patients (23%) attained a transient plasma MTX concentration of ≤1μmol/L. In these 5 patients, the median increase of plasma MTX concentration from their nadir was 1.4μmol/L (0.3–2.5μmol/L).

Legal Classification:

Adults & Children:

<1 month: not recommended. ≥1 month: Give as bolus IV injection over 5 minutes. 50Units/kg as a single injection. Continue leucovorin therapy until the MTX concentration is below the leucovorin treatment threshold for at least 3 days.

Do not administer leucovorin within 2 hours before or after a dose of glucarpidase. First 48 hours after glucarpidase: administer same leucovorin dose as given prior to glucarpidase. Beyond 48 hours after glucarpidase: give leucovorin dose based on the measured MTX concentration.

Warnings/Precautions:

Not indicated for use in patients who exhibit the expected clearance of MTX (plasma MTX concentrations within 2 standard deviations of the mean MTX excretion curve specific for the dose of MTX administered) or those with normal or mildly impaired renal function. Monitor MTX concentrations only by chromatographic methods within 48 hours following administration. Continue hydration and alkalinization of urine as indicated. Pregnancy (Category C). Nursing mothers.