Department of Clinical Pharmacy, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China.
Department of Pediatric Hematology, The Affiliated Hospital of Qingdao University, Qingdao, China.
Br J Clin Pharmacol. 2021 Aug;87(8):3292-3300. doi: 10.1111/bcp.14750. Epub 2021 Feb 23.
This open-label, phase I study evaluated the pharmacokinetics and safety of pegylated recombinant human granulocyte colony-stimulating factor (PEG-rhG-CSF) for the treatment of chemotherapy-induced neutropenia in children with acute leukaemia.
PEG-rhG-CSF was administered as a single 100 mcg/kg (3 mg maximum dose) subcutaneous injection at the end of each chemotherapy period when neutropenia occurred. Blood samples were obtained from patients treated with PEG-rhG-CSF. PEG-rhG-CSF serum concentrations were determined by an enzyme-linked immunosorbent assay. Population pharmacokinetic (PPK) analysis was implemented using the nonlinear mixed-effects model. Short-term safety was evaluated through adverse events collection (registered at clinicaltrials.gov identifier: 03844360).
A total of 16 acute leukaemia patients (1.8-13.6 years) were included, of whom two (12.5%) had grade 3 neutropenia, six (37.5%) had grade 4 neutropenia, and eight (50.0%) had severe neutropenia. For PPK modelling, 64 PEG-rhG-CSF serum concentrations were obtainable. A one-compartment model with first-order elimination was used for pharmacokinetic data modelling. The current weight was a significant covariate. The median (range) of clearance (CL) and area under the serum concentration-time curve (AUC) were 5.65 (1.49-14.45) mL/h/kg and 16514.75 (6632.45-54423.30) ng·h/mL, respectively. Bone pain, pyrexia, anaphylaxis and nephrotoxicity were not observed. One patient died 13 days after administration, and the objective assessment of causality was that an association with PEG-rhG-CSF was "possible".
The AUC of PEG-rhG-CSF (100 mcg/kg, 3 mg maximum dose) in paediatric patients with acute leukaemia were similar to those of PEG-rhG-CSF (100 mcg/kg) in children with sarcoma. PEG-rhG-CSF is safe, representing an important therapeutic option for chemotherapy-induced neutropenia in paediatric patients with acute leukaemia.
本开放标签、I 期研究评估了聚乙二醇化重组人粒细胞集落刺激因子（PEG-rhG-CSF）治疗急性白血病患儿化疗引起的中性粒细胞减少症的药代动力学和安全性。
当发生中性粒细胞减少症时，PEG-rhG-CSF 作为单次 100 mcg/kg（最大 3 mg 剂量）的皮下注射，在每个化疗期结束时给予。从接受 PEG-rhG-CSF 治疗的患者中采集血样。通过酶联免疫吸附试验测定 PEG-rhG-CSF 血清浓度。采用非线性混合效应模型进行群体药代动力学（PPK）分析。通过收集不良事件（在 clinicaltrials.gov 标识符：03844360 处注册）评估短期安全性。
共纳入 16 例急性白血病患者（1.8-13.6 岁），其中 2 例（12.5%）发生 3 级中性粒细胞减少症，6 例（37.5%）发生 4 级中性粒细胞减少症，8 例（50.0%）发生严重中性粒细胞减少症。对于 PPK 建模，可获得 64 个 PEG-rhG-CSF 血清浓度。采用一室模型和一级消除法进行药代动力学数据建模。当前体重是一个显著的协变量。清除率（CL）和血清浓度-时间曲线下面积（AUC）的中位数（范围）分别为 5.65（1.49-14.45）mL/h/kg 和 16514.75（6632.45-54423.30）ng·h/mL。未观察到骨痛、发热、过敏反应和肾毒性。一名患者在给药后 13 天死亡，客观评估因果关系为与 PEG-rhG-CSF 存在“可能”关联。
急性白血病患儿给予 PEG-rhG-CSF（100 mcg/kg，最大 3 mg 剂量）的 AUC 与肉瘤患儿给予 PEG-rhG-CSF（100 mcg/kg）的 AUC 相似。PEG-rhG-CSF 是安全的，为急性白血病患儿化疗引起的中性粒细胞减少症提供了一种重要的治疗选择。
