Physiologically based pharmacokinetic modeling and analysis of administration route-dependent tissue distribution of gold nanoparticles

基于生理学的药代动力学模型和金纳米粒子给药途径依赖性组织分布的分析

• 批准号: 10450369
• 负责人: Zhoumeng Lin
• 金额: $ 7.63万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-10 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10450369
• 关键词: Physiologically; based; pharmacokinetic; modeling; analysis

PROJECT SUMMARY AND ABSTRACT Gold nanoparticles have found promising applications as drug carriers for diagnostic and therapeutic purposes in laboratory animals, but the translation of animal results to clinical success is low. Currently, this field is confronting a dilemma of “so many publications but very few drugs”. There are multiple factors contributing to this. One important factor is a lack of a robust model that can integrate available experimental data to simulate target organ dosimetry and extrapolate pharmacokinetics of gold nanoparticles across different exposure scenarios. Another critical factor is that the traditional pharmacokinetic analysis approaches currently used for small molecules (e.g., drugs and environmental chemicals) are used for nanoparticles, which may not be appropriate because of differences in the pharmacokinetics between small molecules and nanoparticles. Built upon the extensive pharmacokinetic datasets for different sizes of gold nanoparticles in rats after different routes of administration (i.e., intravenous injection, oral gavage, inhalational exposure, or intratracheal instillation) from our collaborator’s laboratory and based on our recently published physiologically based pharmacokinetic (PBPK) model for gold nanoparticles after single route of intravenous administration, here we propose a multi-route whole-body PBPK modeling strategy to address these challenges. The objective of this proposal is to determine whether the traditional route-to-route extrapolation approaches of PBPK models for small molecules are appropriate for gold nanoparticles. We hypothesize that the traditional route-to-route extrapolation approaches of PBPK models for small molecules may not be appropriate for gold nanoparticles. Two Specific Aims were formulated to test this hypothesis. Aim 1: To develop a multi-route PBPK model for gold nanoparticles using traditional PBPK modeling approaches that are typically used for small molecules. Aim 2: To develop a multi- route PBPK model for gold nanoparticles using a new approach particularly designed for nanoparticles. This project is novel and significant because the route-to-route extrapolation of nanoparticle pharmacokinetics has not been rigorously and quantitatively tested before and represents a critical barrier in the field. The proposed research has broad impacts because: (1) if the aims are achieved and our hypothesis is true, then it will establish a rational approach for conducting route-to-route extrapolation that is specifically for nanoparticles; (2) if the results suggest that our hypothesis is false, then at minimal a new robust multi-route PBPK model will be established and our results will greatly improve our fundamental understanding of route-dependent tissue distribution of gold nanoparticles; (3) the proposed PBPK models will be converted to a graphical user interface (GUI) that will be shared with other researchers, thereby making a wide impact in the field by allowing researchers not fully versed in PBPK model coding to be able to use the models to make quantitative simulations and extrapolations. The availability of our collaborator’s extensive datasets and our recently published PBPK modeling framework makes this proposal highly feasible and ideally suitable for the R03 program.

项目概要和摘要 金纳米粒子作为诊断和治疗目的的药物载体具有广阔的应用前景 在实验动物中，但将动物结果转化为临床成功的程度目前还很低。 面临“出版物多而药品少”的困境是多方面因素造成的。 一个重要因素是缺乏一个可以整合可用实验数据来模拟的稳健模型。 不同暴露下金纳米颗粒的靶器官剂量测定和药代动力学外推 另一个关键因素是目前使用的传统药代动力学分析方法。 小分子（例如药物和环境化学品）用于纳米颗粒，这可能不 由于小分子和纳米颗粒之间的药代动力学差异，因此是适当的。 根据不同途径后大鼠体内不同尺寸金纳米颗粒的广泛药代动力学数据集 给药方式（即静脉注射、口服强饲、吸入暴露或气管内滴注） 我们合作者的实验室并基于我们最近发表的基于生理学的药代动力学 (PBPK) 单一途径静脉注射后金纳米粒子的模型，在这里我们提出了多途径 该提案的目标是确定应对这些挑战的全身 PBPK 建模策略。 小分子 PBPK 模型的传统路线到路线外推方法是否有效 我们发现传统的路线到路线外推方法。 小分子的 PBPK 模型可能不适用于金纳米颗粒有两个具体目标。 目的 1：使用金纳米粒子开发多途径 PBPK 模型。 通常用于小分子的传统 PBPK 建模方法 目标 2：开发多分子药物。 使用专为纳米粒子设计的新方法构建金纳米粒子的 PBPK 模型。 该项目新颖且意义重大，因为纳米颗粒药代动力学的路线到路线外推已经 之前没有经过严格的定量测试，是该领域的一个关键障碍。 研究具有广泛的影响，因为：（1）如果目标实现并且我们的假设成立，那么它将建立 一种专门针对纳米粒子进行路径到路径外推的合理方法（2）如果 结果表明我们的假设是错误的，那么至少会出现一个新的稳健的多路径 PBPK 模型 成立，我们的结果将极大地提高我们对途径依赖性组织的基本理解 金纳米颗粒的分布；(3) 所提出的 PBPK 模型将转换为图形用户界面 （GUI）将与其他研究人员共享，从而通过允许在该领域产生广泛的影响 研究人员不完全精通 PBPK 模型编码，无法使用模型进行定量模拟 我们合作者的广泛数据集和我们最近发布的 PBPK 的可用性。 建模框架使该建议高度可行，非常适合 R03 计划。