转移性乳腺癌患者服用聚乙二醇重组人粒细胞集落刺激因子后纳布-紫杉醇的群体药代动力学和暴露毒性分析。

IF 2.7 4区 医学 Q3 ONCOLOGY Cancer Chemotherapy and Pharmacology Pub Date : 2024-10-01 Epub Date: 2024-07-31 DOI:10.1007/s00280-024-04702-3
Dihong Yang, Gaoqi Xu, Haiying Ding, Like Zhong, Junfeng Zhu, Xiufang Mi, Wenxiu Xin, Tianyan Zhou, Jiaqi Wang, Luo Fang
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引用次数: 0

摘要

目的:本研究旨在建立一个群体药代动力学(PK)模型,以评估转移性乳腺癌患者服用聚乙二醇重组人粒细胞集落刺激因子(PEG-G-CSF)后总紫杉醇浓度与未结合紫杉醇浓度之间的动态关系,以及白蛋白结合型紫杉醇(nab-紫杉醇)的暴露-反应分析:方法:24 名受试者随机接受了单剂量 260 毫克/平方米的两种纳布紫杉醇制剂,并经过 21-35 天的冲洗期,共分析了 653 个紫杉醇总浓度和 334 个未结合紫杉醇浓度。在每个周期中,所有患者都服用了 PEG-G-CSF,以防止中性粒细胞减少症。利用总紫杉醇、白蛋白包裹紫杉醇和未结合紫杉醇的暴露量以及中性粒细胞计数的减少来评估暴露-反应关系。暴露数据采用非线性混合效应模型进行分析。使用线性回归模型检验了中性粒细胞计数减少百分比与暴露量之间相关性的统计学意义:结果:采用一阶消除的三室模型描述了总紫杉醇的 PK 特性,并建立了一个基于机理的模型,其中包含纳布-紫杉醇的线性释放和未结合紫杉醇与血浆成分的饱和结合。据估计,纳布-紫杉醇的紫杉醇释放率为 4.60%,输注结束时达到最大未结合部分(2.76%)。研究发现,紫杉醇总浓度> 0.19 µmol/L的持续时间越长,中性粒细胞计数就越少(r2 = 0.23,P = 0.00062)。结论:紫杉醇总浓度大于 0.19 µmol/L 与中性粒细胞数量减少有明显相关性(r2 = 0.23,P = 0.00062):结论:尽管使用了 PEG-G-CSF,纳布-紫杉醇诱导的中性粒细胞减少与紫杉醇总浓度超过 0.19 µmol/L 的持续时间显著相关。
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Population pharmacokinetic and exposure-toxicity analyses of nab-paclitaxel after pegylated recombinant human granulocyte colony-stimulating factor administration in patients with metastatic breast cancer.

Purpose: This study aimed to establish a population pharmacokinetic (PK) model to evaluate the dynamic relationship between the concentrations of total and unbound paclitaxel, and the exposure-response analysis of albumin-bound paclitaxel (nab-paclitaxel) after pegylated recombinant human granulocyte colony-stimulating factor (PEG-G-CSF) administration in patients with metastatic breast cancer.

Methods: A total of 653 concentrations corresponding to total paclitaxel and 334 concentrations corresponding to unbound paclitaxel were analyzed in 24 subjects who randomized received a single 260 mg/m2 dose of two nab-paclitaxel formulations with a 21-35-day washout period. PEG-G-CSF was administered to all the patients in each cycle to prevent neutropenia. The exposure-response relationships were evaluated using the exposure to total, albumin-coated, and unbound paclitaxel, as well as the reduction in neutrophil count. The exposure data were analyzed using nonlinear mixed-effect modeling. A linear regression model was used to test the statistical significance of the correlation between percentage of reduction in neutrophil count and exposure.

Results: The PK characteristics of total paclitaxel were described using a three-compartment model with first-order elimination, and a mechanism-based model incorporating linear release of nab-paclitaxel and the saturated binding of unbound paclitaxel to plasma components was established. The release ratio of paclitaxel from nab-paclitaxel was estimated to be 4.60% and the maximum unbound fraction (2.76%) was reached at the end of the infusion. The study found that a longer duration of total paclitaxel concentration > 0.19 µmol/L was significantly correlated with a reduction in neutrophil count (r2 = 0.23, P = 0.00062). Specifically, a duration of > 8.6 h was a predictor of a decreased neutrophil count.

Conclusion: The decrease in neutrophils induced by nab-paclitaxel was significantly correlated with the duration above a total paclitaxel concentration of 0.19 µmol/L despite the use of PEG-G-CSF.

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来源期刊
CiteScore
6.10
自引率
3.30%
发文量
116
审稿时长
2.5 months
期刊介绍: Addressing a wide range of pharmacologic and oncologic concerns on both experimental and clinical levels, Cancer Chemotherapy and Pharmacology is an eminent journal in the field. The primary focus in this rapid publication medium is on new anticancer agents, their experimental screening, preclinical toxicology and pharmacology, single and combined drug administration modalities, and clinical phase I, II and III trials. It is essential reading for pharmacologists and oncologists giving results recorded in the following areas: clinical toxicology, pharmacokinetics, pharmacodynamics, drug interactions, and indications for chemotherapy in cancer treatment strategy.
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