Pharmacokinetic and Pharmacodynamic Properties of Calaspargase Pegol Escherichia coli L-Asparaginase in the Treatment of Patients With Acute Lymphoblastic Leukemia: Results From Children's Oncology Group Study AALL07P4
Pharmacokinetic and Pharmacodynamic Properties of Calaspargase Pegol Escherichia coli L-Asparaginase in the Treatment of Patients With Acute Lymphoblastic Leukemia: Results From Children's Oncology Group Study AALL07P4
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DOI：
10.1200/jco.2014.55.5763
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发表时间：
2014-12-01
影响因子：
45.3
通讯作者：
Hunger, Stephen P.
中科院分区：
文献类型：
--
作者：
Angiolillo, Anne L.;Schore, Reuven J.;Hunger, Stephen P.
目的天冬酰胺酶是治疗急性淋巴细胞白血病(ALL)的关键药物。聚乙二醇酯酶是一种聚乙二醇化形式的大肠杆菌L-天冬酰胺酶，带有琥珀酸亚胺(SS)接头，是儿童肿瘤学小组(COG)All试验中使用的一线天冬酰胺酶产品。Calaspargase pegol(SC-PEG)用琥珀酰亚胺氨基甲酸酯连接物取代SS-PEG中的SS连接物，产生更稳定的分子。COG AALL07P4旨在确定SC-PEG2100(SC-PEG2100；n=69)或2500IU/m(2)(SC-PEG2500；n=42)与SS-PEG2500IU/m(2)(SS-PEG2500；n=54)化疗方案的药物动力学和药效学可比性。除了更多的女性患者接受SC-PEG250治疗外，两组患者的人口学特征相似。结果两种剂量SC-PEG250的血浆天冬酰胺酶活性的平均半衰期大约是SS-PEG2500的2.5倍。根据0-25天曲线下的诱导面积定义，SC-PEG2500的全身暴露总量大于SS-PEG2500或SC-PEG2100。在接受SC-PEG2500治疗的患者中，血浆天冬酰胺酶活性=100mIU/mL和>；=400mIU/ml的患者的比例更高。在诱导第4天给予一剂聚乙二醇化天冬酰胺酶后，SS-PEG2500组和SC-PEG2500组分别在11d和18d内检测不到天冬酰胺。结论SC-PEG2500与SS-PEG2500相比，天冬酰胺酶活性在规定阈值以上的时间明显延长，天冬酰胺耗竭时间明显延长，其毒性与SS-PEG2500相似。(C)美国临床肿瘤学会2014年
PurposeAsparaginase is a critical agent used to treat acute lymphoblastic leukemia (ALL). Pegaspargase (SS-PEG), a pegylated form of Escherichia coli L-asparaginase with a succinimidyl succinate (SS) linker, is the first-line asparaginase product used in Children's Oncology Group (COG) ALL trials. Calaspargase pegol (SC-PEG) replaces the SS linker in SS-PEG with a succinimidyl carbamate linker, creating a more stable molecule. COG AALL07P4 was designed to determine the pharmacokinetic and pharmacodynamic comparability of SC-PEG to SS-PEG in patients with newly diagnosed high-risk (HR) B-cell ALL.Patients and MethodsA total of 165 evaluable patients were randomly assigned at a 2:1 ratio to receive SC-PEG at 2,100 (SC-PEG2100; n = 69) or 2,500 IU/m(2) (SC-PEG2500; n = 42) versus SS-PEG 2,500 IU/m(2) (SS-PEG2500; n = 54) as part of an otherwise identical chemotherapy regimen. The groups were similar demographically, except more female patients received SC-PEG2500.ResultsThe mean half-life of plasma asparaginase activity for both SC-PEG doses was approximately 2.5 x longer than that of SS-PEG2500. The total systemic exposure, as defined by induction area under the curve from time 0 to 25 days, was greater with SC-PEG2500 than with SS-PEG2500 or SC-PEG2100. The proportion of patients with plasma asparaginase activity >= 100 mIU/mL and >= 400 mIU/mL was higher in patients who received SC-PEG as compared with SS-PEG2500. After one dose of pegylated asparaginase on induction day 4, plasma asparagine was undetectable for 11 days for SS-PEG2500 and 18 days for both SC-PEG groups.ConclusionSC-PEG2500 achieves a significantly longer period of asparaginase activity above defined thresholds and asparagine depletion compared with SS-PEG2500 and has a comparable toxicity profile in children with HR B-cell ALL. (C) 2014 by American Society of Clinical Oncology