Population Modeling of Filgrastim PK-PD in Healthy Adults Following Intravenous and Subcutaneous Administrations
Population Modeling of Filgrastim PK-PD in Healthy Adults Following Intravenous and Subcutaneous Administrations
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DOI：
10.1177/0091270010376966
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发表时间：
2010-09-01
影响因子：
2.9
通讯作者：
Balser, Sigrid
中科院分区：
文献类型：
--
作者：
Krzyzanski, Wojciech;Wiczling, Pawel;Balser, Sigrid
Filgrastim是一种重组人粒细胞集落刺激因子（G-CSF），刺激中性粒细胞的产生。该分析的目的是建立一个药代动力学（PK）和药效学（PD）模型，以解释由于G-CSF受体介导的内吞作用增加而导致多次给药G-CSF清除率增加的原因。来自4个健康志愿者的随机研究数据被用于分析。受试者通过皮下（SC）和静脉（IV）途径接受非格拉西姆（Neupogen）。非格昔汀以2.5、5和10 μ g/kg剂量每天给予SC，持续1周，并以单次静脉输注（5 μ g/kg超过0.5小时）和SC （1 μ g/kg）剂量给予。PK数据包括血清浓度-时间测量和血液绝对中性粒细胞计数（ANC）用于PD评估。人口非线性混合效应建模使用NONMEM VI （Version 6.1.0, Icon Development Solutions, Ellicott City, Maryland）。该模型描述了C-max值随重复剂量的衰减趋势，ANC（max）值的增加与G-CSF受体池的增加一致。总间隙的模拟时间过程呈现出增加的模式。多剂量非格昔汀清除率的增加归因于骨髓和血液中中性粒细胞计数的增加，并伴有G-CSF总受体密度的增加。
Filgrastim is a recombinant human granulocyte colony stimulating factor (G-CSF) that stimulates production of neutrophils. The objective of this analysis was to develop a pharmacokinetic (PK) and pharmacodynamic (PD) model to account for an increase in G-CSF clearance on multiple dosing because of an increase of the G-CSF receptor-mediated endocytosis. Data from 4 randomized studies involving healthy volunteers were used for analysis. Subjects received filgrastim (Neupogen) via subcutaneous (SC) and intravenous (IV) routes. Filgrastim was administered SC daily for 1 week at 2.5, 5, and 10 mu g/kg doses and as single IV infusions (5 mu g/kg over 0.5 hours) and SC (1 mu g/kg) doses. PK data comprised serum concentration-time measurements and the blood absolute neutrophil count (ANC) was used for PD evaluations. Population nonlinear mixed-effect modeling was done using NONMEM VI (Version 6.1.0, Icon Development Solutions, Ellicott City, Maryland). The model depicted the decaying trend in C-max values with repeated doses and an increase in ANC(max) values consistently with an increase in the G-CSF receptor pool. Simulated time courses of the total clearance exhibited an increasing pattern. The increase in filgrastim clearance on multiple dosing was attributed to the increased neutrophil count in the bone marrow and blood paralleled by an increase in the total G-CSF receptor density.