Amgen Inc., Thousand Oaks, California 91320-1799, USA.
Clin Pharmacokinet. 2011 May;50(5):295-306. doi: 10.2165/11586040-000000000-00000.
Pegfilgrastim is a sustained-duration form of filgrastim, a recombinant methionyl form of human granulocyte colony-stimulating factor (G-CSF), to which a 20 kDa polyethylene glycol molecule is covalently bound to the N-terminal methionine residue. Similar to filgrastim, pegfilgrastim increases the proliferation and differentiation of neutrophils from committed progenitor cells, induces maturation, and enhances the survival and function of mature neutrophils, resulting in dose-dependent increases in neutrophils. After subcutaneous administration, pegfilgrastim exhibits nonlinear pharmacokinetics and exposure to pegfilgrastim increases in more than a dose-proportional manner, suggesting that the clearance of pegfilgrastim decreases with increased dosing. Filgrastim is primarily eliminated by the kidney and neutrophils/neutrophil precursors; the latter presumably involves binding of the growth factor to the G-CSF receptor on the cell surface, internalization of the growth factor-receptor complexes via endocytosis, and subsequent degradation inside the cells. Pegylation of filgrastim renders renal clearance insignificant, which was demonstrated in bilaterally nephrectomized rats and confirmed in subjects with renal impairment. As a result, the neutrophil-mediated clearance is the predominant elimination pathway for pegfilgrastim. During chemotherapy-induced neutropenia, the clearance of pegfilgrastim is significantly reduced and the concentration of pegfilgrastim is sustained until onset of neutrophil recovery. Pegfilgrastim concentrations are sustained longer in patients with profound neutropenia. Evidence supports the use of a postnadir absolute neutrophil count (ANC) of ≥ 1 × 109/L as a surrogate marker threshold for the clearance of pegfilgrastim to subtherapeutic levels. After repeated administration of pegfilgrastim, the peak concentrations of pegfilgrastim decrease, likely due to increased neutrophil and neutrophil precursor mass. A pharmacokinetic-pharmacodynamic model was developed to describe the pharmacokinetic and ANC profiles of pegfilgrastim; the analysis supported that 100 μg/kg was an adequate weight-based dose of pegfilgrastim and predicted that 6 mg would be an optimal fixed dose of pegfilgrastim to simplify treatment. Data from a pivotal study confirmed that a once-per-chemotherapy-cycle injection of pegfilgrastim at 6 mg was as safe and effective as 11 daily injections of filgrastim at 5 μg/kg in reducing neutropenia and its complications in patients with breast cancer receiving four cycles of doxorubicin/docetaxel chemotherapy. Because of the highly efficient regulation of pegfilgrastim clearance via neutrophils and neutrophil precursors, a single fixed dose of pegfilgrastim can be given once per chemotherapy cycle in conjunction with a variety of myelosuppressive chemotherapy regimens.
培非格司亭是粒细胞集落刺激因子（G-CSF）的一种重组甲硫氨酸形式，与天然 G-CSF 相比，其 N 端甲硫氨酸残基上共价结合了一个 20 kDa 的聚乙二醇（PEG）分子。与粒细胞集落刺激因子类似，培非格司亭可增加中性粒细胞从定向祖细胞的增殖和分化，诱导成熟，并增强成熟中性粒细胞的存活和功能，从而使中性粒细胞呈剂量依赖性增加。皮下给药后，培非格司亭表现出非线性药代动力学特征，且药物暴露量呈超剂量比例增加，提示随着剂量增加，培非格司亭的清除率降低。粒细胞集落刺激因子主要通过肾脏和中性粒细胞/中性粒细胞前体清除，后者可能涉及生长因子与细胞表面的 G-CSF 受体结合、通过内吞作用内化生长因子-受体复合物，以及随后在细胞内降解。培非格司亭的聚乙二醇化使肾脏清除变得微不足道，这在双侧肾切除大鼠中得到了证实，并在肾功能损害患者中得到了确认。因此，中性粒细胞介导的清除是培非格司亭的主要消除途径。在化疗引起的中性粒细胞减少症中，培非格司亭的清除率显著降低，且培非格司亭的浓度持续到中性粒细胞恢复开始。在中性粒细胞严重减少的患者中，培非格司亭的浓度持续时间更长。有证据支持将化疗后最低点绝对中性粒细胞计数（ANC）≥1×109/L作为预测培非格司亭清除至治疗窗以下的替代标志物阈值。反复给予培非格司亭后，培非格司亭的峰浓度降低，可能是由于中性粒细胞和中性粒细胞前体质量增加所致。已开发出一种药代动力学-药效学模型来描述培非格司亭的药代动力学和 ANC 特征；该分析支持 100 μg/kg 是培非格司亭的合适体重剂量，并预测 6 mg 是培非格司亭的最佳固定剂量，以简化治疗。一项关键研究的数据证实，在接受多柔比星/多西他赛 4 个周期化疗的乳腺癌患者中，与每天给予 5 μg/kg 粒细胞集落刺激因子 11 次相比，每化疗周期给予 6 mg 一次的培非格司亭可更安全有效地减少中性粒细胞减少症及其并发症。由于通过中性粒细胞和中性粒细胞前体高效调节培非格司亭的清除，因此可在每个化疗周期给予单次固定剂量的培非格司亭，同时联合多种骨髓抑制性化疗方案。
