Pharmacodynamics and safety of intravenous pegaspargase during remission induction in adults aged 55 years or younger with newly diagnosed acute lymphoblastic leukemia
Pharmacodynamics and safety of intravenous pegaspargase during remission induction in adults aged 55 years or younger with newly diagnosed acute lymphoblastic leukemia
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DOI：
10.1182/blood-2006-07-035006
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发表时间：
2007-04-01
期刊：
影响因子：
20.3
通讯作者：
Avramis, Vassilios I.
中科院分区：
文献类型：
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作者：
Douer, Dan;Yampolsky, Henry;Avramis, Vassilios I.
与儿童相比，培门冬酶在成人中的药代动力学、药效学和安全性信息非常有限。作为标准一线诱导方案的一部分，我们对25例新诊断的急性淋巴细胞白血病（ALL）成人患者单次静脉注射培门冬酶（2000 IU/m2），并在几个时间点采集血清样本。天冬酰胺酶酶活性的群体平均血清峰浓度为1 IU/mL，消除半衰期为7天，分布容积为2.43 L/m2。单次给药后，所有患者在2小时后完成天冬酰胺脱氨，第14、21和28天分别为100%、81%和44%。药效学相关性模型显示最佳天冬酰胺消耗的最小酶活性为0.2 IU/mL。动力学事后分析表明酶活性持续3周或更长时间。1例患者在给药后第22天出现中和抗天冬酰胺酶抗体。培门冬酶耐受性良好，几乎没有3/4级副作用。未观察到过敏反应或胰腺炎。在55岁或55岁以下的成人中，培门冬酶可产生长时间的天冬酰胺耗竭，可静脉给药，其安全性特征与多次肌肉注射同等剂量的大肠杆菌天冬酰胺酶相似。
In contrast to that in children, pharmacokinetic, pharmacodynamic, and safety information on pegaspargase in adults is very limited. We administered a single intravenous dose of pegaspargase (2000 IU/m(2)) as part of a standard frontline induction regimen to 25 adults with newly diagnosed acute lymphoblastic leukemia (ALL), and obtained serum samples on several time points. The population mean peak serum concentration of asparaginase enzymatic activity was I IU/mL, the elimination half-life was 7 days, and the volume of distribution was 2.43 L/m(2). After the single dose, asparagine deamination was complete in all patients after 2 hours, and in 100%, 81%, and 44% on days 14, 21, and 28, respectively. A pharmocodynamic correlation model showed minimal enzymatic activity of 0.2 IU/mL for optimal asparagine depletion. The kinetic posthoc analyses demonstrated enzymatic activity for 3 weeks or more. One patient developed neutralizing antiasparaginase antibodies on day 22 after administration. Pegaspargase was well tolerated, with few grade 3/4 side effects. No allergic reactions or pancreatitis were observed. In adults aged 55 years or younger, pegaspargase produces a long duration of asparagine depletion and can be given intravenously, with a safety profile that is similar to equivalent multiple doses of intramuscular Escherichia coli asparaginase.