健康受试者和化疗所致中性粒细胞减少症患者中性粒细胞对 G-CSF 反应的药代动力学-药效学模型研究。
Pharmacokinetic-pharmacodynamic modelling of neutrophil response to G-CSF in healthy subjects and patients with chemotherapy-induced neutropenia.
机构信息
Department of Clinical Pharmacology, Modeling and Simulation, Amgen Inc., Thousand Oaks, CA, USA.
SGS Exprimo NV, Mechelen, Belgium.
出版信息
Br J Clin Pharmacol. 2018 May;84(5):911-925. doi: 10.1111/bcp.13504. Epub 2018 Feb 20.
AIM
The objective of the present study was to use pharmacokinetic-pharmacodynamic modelling to characterize the effects of chemotherapy on the granulopoietic system and to predict the absolute neutrophil counts (ANCs) for patients with chemotherapy-induced neutropenia treated with filgrastim and pegfilgrastim.
METHODS
Data were extracted from 10 phase I-III studies conducted in 110 healthy adults, and 618 adult and 52 paediatric patients on chemotherapy following administration of filgrastim or pegfilgrastim. The structural model accounted for ANC dynamics and the effects of filgrastim and pegfilgrastim, chemotherapy and corticosteroids. The impact of neutrophils on drug disposition was based on a drug receptor-binding model that assumed quasi-equilibrium and stimulation of the production and maturation of neutrophils upon treatment. The chemotherapy and corticosteroid effects were represented by kinetic-pharmacodynamic-type models, where chemotherapy stimulated elimination of neutrophil precursors at the mitotic stage, and corticosteroids stimulated neutrophil production.
RESULTS
The systemic half-lives of filgrastim (2.6 h) and pegfilgrastim (10.1 h) were as expected. The effective half-life of chemotherapy was 9.6 h, with a 2-day killing effect. The rate of receptor elimination from mitotic compartments exhibited extreme interindividual variability (% coefficient of variation >200), suggesting marked differences in sensitivity to chemotherapy effects on ANCs. The stimulatory effects of pegfilgrastim were significantly greater than those of filgrastim. Model qualification confirmed the predictive capability of this model.
CONCLUSION
This qualified model simulates the time course of ANC in the absence or presence of chemotherapy and predicts nadir, time to nadir and time of recovery from different grades of neutropenia upon treatment with filgrastim and pegfilgrastim.
目的
本研究的目的是使用药代动力学-药效学模型来描述化疗对粒状系统的影响，并预测接受培非格司亭和聚乙二醇化非格司亭治疗的化疗所致中性粒细胞减少症患者的绝对中性粒细胞计数（ANC）。
方法
从 10 项在 110 名健康成年人中进行的 I-III 期研究中以及 618 名成人和 52 名儿科患者接受培非格司亭或聚乙二醇化非格司亭化疗后的数据中提取数据。结构模型解释了 ANC 动力学以及培非格司亭和聚乙二醇化非格司亭、化疗和皮质类固醇的作用。基于药物受体结合模型，假设中性粒细胞对药物处置的影响存在准平衡和治疗时中性粒细胞的产生和成熟的刺激，该模型解释了中性粒细胞的作用。该模型假设化疗刺激有丝分裂阶段中性粒细胞前体的消除，皮质类固醇刺激中性粒细胞的产生，从而建立了化疗和皮质类固醇作用的药代动力学-药效学模型。
结果
培非格司亭（2.6 h）和聚乙二醇化非格司亭（10.1 h）的全身半衰期与预期一致。化疗的有效半衰期为 9.6 h，具有 2 天的杀伤作用。从有丝分裂隔室中消除受体的速率表现出极大的个体间变异性（%变异系数>200），这表明对化疗对 ANC 影响的敏感性存在明显差异。聚乙二醇化非格司亭的刺激作用明显大于培非格司亭。模型验证证实了该模型的预测能力。
结论
该合格模型模拟了有无化疗情况下 ANC 的时间过程，并预测了接受培非格司亭和聚乙二醇化非格司亭治疗时不同程度中性粒细胞减少症的最低点、最低点时间和恢复时间。
Zotero 插件