建立多柔比星聚乙二醇脂质体的 PBPK 模型,以同时预测组织中包裹的多柔比星和游离的多柔比星的浓度-时间曲线。

IF 5.7 3区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
Drug Delivery and Translational Research Pub Date : 2025-04-01 Epub Date: 2024-08-05 DOI:10.1007/s13346-024-01680-0
Xuewei Cao, Kejun Li, Jingyu Wang, Xiaoqian Xie, Le Sun
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引用次数: 0

摘要

本研究的目的是建立一个基于生理学的药代动力学(PBPK)模型,以预测小鼠静脉注射聚乙二醇脂质体(Doxil®)后血浆和组织中封装和游离多柔比星的浓度。本研究使用的 PBPK 模型包含脂质体和游离多柔比星处置成分。游离多柔比星处置成分用于模拟单核吞噬细胞系统(MPS)降解脂质体产生的游离多柔比星的处置。肝脏、脾脏、肾脏和肺部都含有一个额外的单核吞噬细胞系统亚室。这些分区通过血液和淋巴循环相互连接。该模型通过四种剂量的外部观察血浆和组织浓度-时间曲线进行了严格验证。折合误差 (FE) 值几乎都在三倍以内。敏感性分析表明,与 MPS 相关的参数对模型影响很大。预测的多柔比星脂质体和多柔比星溶液的体内分布特征与观察值一致。该 PBPK 模型是根据生理机制和可在体外测量的具有实际意义的参数建立的。因此,该模型可用于研究脂质体的药代动力学特性。本研究也为脂质体 PBPK 模型的建立提供了参考。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

PBPK model of pegylated liposomal doxorubicin to simultaneously predict the concentration-time profile of encapsulated and free doxorubicin in tissues.

PBPK model of pegylated liposomal doxorubicin to simultaneously predict the concentration-time profile of encapsulated and free doxorubicin in tissues.

The objective of this study was to develop a physiologically based pharmacokinetic (PBPK) model to predict the concentrations of encapsulated and free doxorubicin in plasma and tissues in mice after intravenous injection of PEGylated liposomes (Doxil®). The PBPK model used in this study contains liposomes and free doxorubicin disposition components. The free doxorubicin disposition component was used to simulate the disposition of free doxorubicin produced by mononuclear phagocyte system (MPS)-degrading liposomes. The liver, spleen, kidneys, and lungs contain an additional MPS subcompartment. These compartments are interconnected through blood and lymphatic circulation. The model was validated strictly by four doses of external observed plasma and tissue concentration-time profiles. The fold error (FE) values were almost all within threefold. The sensitivity analysis revealed that the MPS-related parameters greatly influenced the model. The predicted in vivo distribution characteristics of the doxorubicin liposomes and doxorubicin solution were consistent with the observed values. The PBPK model was established based on the physiological mechanism and parameters of practical significance that can be measured in vitro. Thus, it can be used to study the pharmacokinetic properties of liposomes. This study also provides a reference for the establishment of liposome PBPK model.

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来源期刊
Drug Delivery and Translational Research
Drug Delivery and Translational Research MEDICINE, RESEARCH & EXPERIMENTALPHARMACOL-PHARMACOLOGY & PHARMACY
CiteScore
11.70
自引率
1.90%
发文量
160
期刊介绍: The journal provides a unique forum for scientific publication of high-quality research that is exclusively focused on translational aspects of drug delivery. Rationally developed, effective delivery systems can potentially affect clinical outcome in different disease conditions. Research focused on the following areas of translational drug delivery research will be considered for publication in the journal. Designing and developing novel drug delivery systems, with a focus on their application to disease conditions; Preclinical and clinical data related to drug delivery systems; Drug distribution, pharmacokinetics, clearance, with drug delivery systems as compared to traditional dosing to demonstrate beneficial outcomes Short-term and long-term biocompatibility of drug delivery systems, host response; Biomaterials with growth factors for stem-cell differentiation in regenerative medicine and tissue engineering; Image-guided drug therapy, Nanomedicine; Devices for drug delivery and drug/device combination products. In addition to original full-length papers, communications, and reviews, the journal includes editorials, reports of future meetings, research highlights, and announcements pertaining to the activities of the Controlled Release Society.
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