A physiologically based pharmacokinetic model to predict pegylated liposomal doxorubicin disposition in rats and human,Drug Delivery and Translational Research

当前位置： X-MOL 学术 › Drug Deliv. Transl. Res. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

A physiologically based pharmacokinetic model to predict pegylated liposomal doxorubicin disposition in rats and human
Drug Delivery and Translational Research ( IF 5.7 ) Pub Date : 2022-05-13 , DOI: 10.1007/s13346-022-01175-w
Maiara Camotti Montanha ₁ , Alice Howarth ₁ , Doaa Ahmed Mohamed ₁ , Estelle Loier ₁ , Lauren Main ₁ , Matthias Rösslein ₂ , Christiaan Delmaar ₃ , Adriele Prina-Mello _{4,

5} , Marco Siccardi ₁

Affiliation

The use of nanoparticles (NPs) can support an enhancement of drug distribution, resulting in increased drug penetration into key tissues. Experimental in vitro data can be integrated into computational approaches to simulate NP absorption, distribution, metabolism and elimination (ADME) processes and provide quantitative pharmacokinetic predictions. The aim of this study is to develop a novel mechanistic and physiologically based pharmacokinetic (m-PBPK) model to predict the biodistribution of NPs focusing on Doxil. The main processes underpinning NPs ADME were represented considering molecular and cellular mechanisms such as stability in biological fluids, passive permeability and uptake activity by macrophages. A whole-body m-PBPK rat and human models were designed in Simbiology v. 9.6.0 (MATLAB R2019a). The m-PBPK models were successfully qualified across doxorubicin and Doxil^® in both rat and human since all PK parameters AUC_0-inf, C_max, t_1/2, Vd and Cl were within twofold, with an AUC_0-inf absolute average-fold error (AAFE) value of 1.23 and 1.16 and 1.76 and 1.05 for Doxorubicin and Doxil^® in rat and human, respectively. The time to maximum concentration in tissues for doxorubicin in both rat and human models was before 30 min of administration, while for Doxil^®, the t_max was after 24 h of administration. The organs that accumulate most NP are the spleen, liver and lungs, in both models. The m-PBPK represents a predictive platform for the integration of in vitro and formulation parameters in a physiological context to quantitatively predict the NP biodistribution.

Graphical abstract

Schematic diagram of the whole-body m-PBPK models developed for Doxil^® in rat and human physiology.

中文翻译：

预测大鼠和人类聚乙二醇化脂质体多柔比星分布的基于生理的药代动力学模型

纳米粒子 (NPs) 的使用可以支持药物分布的增强，从而增加药物对关键组织的渗透。体外实验数据可以集成到计算方法中，以模拟 NP 吸收、分布、代谢和消除 (ADME) 过程并提供定量药代动力学预测。本研究的目的是开发一种新的基于机械和生理的药代动力学 (m-PBPK) 模型来预测以 Doxil 为重点的 NPs 的生物分布。考虑分子和细胞机制，例如生物体液中的稳定性、被动渗透性和巨噬细胞的摄取活性，代表了支撑 NPs ADME 的主要过程。在 Simbiology v. 9.6.0 (MATLAB R2019a) 中设计了全身 m-PBPK 大鼠和人体模型。^®在大鼠和人类中，因为所有 PK 参数 AUC _0-inf、C _max、t _1/2、Vd 和 Cl 都在两倍以内，AUC _0-inf绝对平均倍数误差 (AAFE) 值为 1.23 和 1.16，并且多柔比星和 Doxil ^®在大鼠和人体内分别为 1.76 和 1.05。在大鼠和人类模型中，阿霉素在组织中达到最大浓度的时间是在给药 30 分钟之前，而对于 Doxil ^®，t _max给药24小时后。在两种模型中，积累最多 NP 的器官是脾脏、肝脏和肺脏。m-PBPK 代表了在生理环境中整合体外和制剂参数以定量预测 NP 生物分布的预测平台。