Department of Pharmaceutical Sciences, University at Buffalo, Buffalo, New York 14260, USA.
Clin Pharmacokinet. 2009;48(12):817-26. doi: 10.2165/11318090-000000000-00000.
Filgrastim is a human granulocyte-colony stimulating factor (G-CSF). The biological activity of filgrastim is identical to that of endogenous G-CSF. It controls neutrophil production within the bone marrow by stimulating the proliferation, differentiation and survival of myeloid progenitor cells and some end-cell function activation. The purpose of this work is to propose a target-mediated drug disposition pharmacokinetic model of filgrastim.
A mechanism-based population pharmacokinetic model was developed to account for receptor-mediated endocytosis as a mechanism for nonlinear disposition of G-CSF. Time profiles of serum filgrastim concentrations following subcutaneous doses of 2.5, 5 and 10 microg/kg and intravenous infusion of 5 microg/kg over 0.5 hour were studied. The pharmacokinetic model included first-order elimination from the serum, receptor binding, turnover of free receptors and internalization of drug-receptor complexes. The proposed target-mediated drug disposition models served as a tool to study drug absorption and the impact of receptor binding on filgrastim clearance.
Filgrastim was found to exhibit parallel absorption with first- and zero-order kinetics and bioavailability of 69.1%. The majority of the drug (58.6%) was absorbed by zero-order processes, presumably through the lymphatic system. The equilibrium dissociation constant (K(d)) was estimated as 16.38 pM.
The proposed model predicts that clearance is initially mostly governed by the binding of filgrastim to G-CSF receptors. Subsequently, the clearance slows down because of the saturation of binding sites, and occurs mostly via the linear (renal) pathway. Finally, for G-CSF concentrations lower than the K(d), target-mediated clearance dominates. The presented receptor-mediated model adequately describes filgrastim serum concentrations and quantifies the role of receptor binding in G-CSF clearance.
非格司亭是一种人粒细胞集落刺激因子（G-CSF）。非格司亭的生物学活性与内源性 G-CSF 相同。它通过刺激骨髓中髓样祖细胞的增殖、分化和存活以及一些终末细胞功能的激活来控制中性粒细胞的产生。本工作旨在提出非格司亭的靶向介导药物处置药代动力学模型。
建立了一种基于机制的群体药代动力学模型，以解释 G-CSF 非线性处置的受体介导内吞作用机制。研究了皮下给予 2.5、5 和 10μg/kg 以及静脉输注 5μg/kg 非格司亭 0.5 小时后血清中非格司亭浓度的时间曲线。药代动力学模型包括血清中一级消除、受体结合、游离受体周转和药物-受体复合物内化。所提出的靶向介导药物处置模型可用于研究药物吸收和受体结合对非格司亭清除率的影响。
发现非格司亭呈平行吸收，具有一级和零级动力学特征，生物利用度为 69.1%。大部分药物（58.6%）通过零级过程吸收，可能通过淋巴系统吸收。平衡解离常数（Kd）估计为 16.38 pM。
所提出的模型预测，清除最初主要受非格司亭与 G-CSF 受体结合的控制。随后，由于结合位点饱和，清除速度减慢，主要通过线性（肾脏）途径发生。最后，对于低于 Kd 的 G-CSF 浓度，靶向介导的清除占主导地位。所提出的受体介导模型能很好地描述非格司亭的血清浓度，并定量评估受体结合在 G-CSF 清除中的作用。
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