Belogurova Margarita B, Kizyma Zoryana P, Garami Miklós, Csóka Mónika, Lamson Michael J, Buchner Anton, Bias Peter, Lammerich Andreas
Pediatric Oncology and Hematology, City Clinical Hospital #31, 3 Dinamo Pr., St. Petersburg, Russian Federation, 197110.
Department of Surgery, West Ukrainian Specialized Children's Medical Center, Lviv, Ukraine.
Cancer Chemother Pharmacol. 2017 Jan;79(1):155-164. doi: 10.1007/s00280-016-3216-2. Epub 2016 Dec 16.
Neutropenia is a common complication from chemotherapy, limiting optimal dosing and treatment. Lipegfilgrastim is a long-acting granulocyte colony-stimulating factor developed for the management of chemotherapy-induced neutropenia. The objectives of this phase 1, multinational, open-label, single-arm study were to characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of a single body weight-adjusted dose of lipegfilgrastim and to evaluate the efficacy, safety, and tolerability of the drug in children with Ewing family of tumors or rhabdomyosarcoma treated with myelosuppressive chemotherapy.
Enrolled patients received lipegfilgrastim (100 µg/kg) 24 h after the last chemotherapy treatment in week 1. Patients were stratified into three age groups: 2 to <6, 6 to <12, and 12 to <18 years. Blood samples for PK analyses were obtained at baseline and at 3, 8, 24, 30, 48, 72, 96, 144, and 240 h postdose for the two oldest groups and up to 144 h in the youngest group.
Twenty-one patients were enrolled and received lipegfilgrastim, seven in each age group. Lipegfilgrastim exposure levels were comparable across age groups, with concentrations maintained over a prolonged period after a single injection. Differences in PD were mainly associated with chemotherapy type. Most investigator-reported adverse events were attributed to chemotherapy and not to lipegfilgrastim. Severe adverse events were noted in 57% of patients; febrile neutropenia, leukopenia, neutropenia, and thrombocytopenia were more frequent among the oldest patients.
Results support the use of a body weight-adjusted dose to achieve equivalent initial peak exposure levels of lipegfilgrastim in children of various ages.
中性粒细胞减少是化疗常见的并发症，限制了最佳剂量和治疗。聚乙二醇非格司亭是一种长效粒细胞集落刺激因子，用于治疗化疗引起的中性粒细胞减少。这项1期、多中心、开放标签、单臂研究的目的是确定单剂量按体重调整的聚乙二醇非格司亭的药代动力学（PK）和药效学（PD），并评估该药物在接受骨髓抑制化疗的尤因家族肿瘤或横纹肌肉瘤患儿中的疗效、安全性和耐受性。
入组患者在第1周最后一次化疗后24小时接受聚乙二醇非格司亭（100μg/kg）治疗。患者被分为三个年龄组：2至<6岁、6至<12岁和12至<18岁。年龄最大的两个组在给药后基线以及3、8、24、30、48、72、96、144和240小时采集用于PK分析的血样，最小组在给药后最多144小时采集血样。
21名患者入组并接受了聚乙二醇非格司亭治疗，每个年龄组7名。各年龄组的聚乙二醇非格司亭暴露水平相当，单次注射后浓度在较长时间内维持。PD差异主要与化疗类型有关。大多数研究者报告的不良事件归因于化疗而非聚乙二醇非格司亭。57%的患者出现严重不良事件；年龄最大的患者中发热性中性粒细胞减少、白细胞减少、中性粒细胞减少和血小板减少更为常见。
结果支持使用按体重调整的剂量，以使不同年龄儿童的聚乙二醇非格司亭达到等效的初始峰值暴露水平。
