Physiologically Based Pharmacokinetic Modeling of Drug Penetration into the Human Brain and Brain Tumors

摘要 向大脑输送药物受到血脑屏障(BBB)的限制，血脑屏障是一种物理和生化屏障 将大脑与循环系统分开。小分子药物主要通过血脑屏障转运 跨细胞被动扩散和转运蛋白介导的主动转运。脑肿瘤中的血脑屏障被破坏 在不同程度上，导致药物肿瘤暴露的个体内和个体间的巨大变异性。机械论 了解和预测异质药物通过完整的血脑屏障和破坏的血液的渗透。 脑肿瘤屏障(BBTB)对脑的合理药物开发和治疗至关重要 癌症。鉴于药物通过血脑屏障的速度和程度由两个因素决定 人血脑屏障/血脑屏障通透性的生物系统特征和药物性质预测 临床前的体外或动物模型由于生物系统的差异而变得复杂。因此，中国的发展 创新的方法势在必行。基于生理基础的体内外外推药代动力学研究 (IVE-PBPK)模式提供了一个独特的平台，允许同时合并药物和系统- 将特定参数输入到PK模型中，并允许基于以下条件对个体体内动力学过程进行先验预测 关于体外数据的机械标度(例如，体外酶和转运体动力学)。这个项目的总体目标是 项目是开发一个基于机理的PBPK模型平台，用于预测异质药物的渗透 进入人类的大脑和脑瘤。我们将采用综合翻译研究方法来实现 这一目标利用了体外药理学研究、PK模型和临床试验。三种药物(AZD1775， Ceritinib和Riociclib)将用于初始模型开发和验证，另外3种药物 (everolimus、abemaciclib和LY3214996)将用于进一步的模型验证。这些药物已经或 在我们的临床试验计划中，正在对胶质母细胞瘤患者进行评估。临床血浆和脑肿瘤的观察 PK数据可用于模型开发和验证。作为解决我们的差距的第一步 关于血脑屏障转运体丰度的知识，这对于建立用于预测的IVIVE比例因子是必不可少的 转运蛋白介导的人血脑屏障和血小管蛋白的主动清除，目的1是确定转运蛋白 非癌皮质区离体微血管的丰度及其增强与非增强 胶质母细胞瘤标本。目标2是确定药物特定的代谢参数，被动跨细胞 渗透性，以及与外排和摄取药物转运体的相互作用。目标3是开发和验证一部小说 7室通透性受限脑(7Brain)PBPK模型，该模型考虑了脑和肿瘤区域 血液灌注量、pH、BBB/BBTB完整性和转运体表达的生理学差异。《七脑》 PBPK模型是首个基于机理的异质药物预测模型平台 穿透人体的血脑屏障和血脑屏障。它有望成为一个有价值的工具，帮助开发和 设计改进的药物和给药方案，以更有效地治疗脑癌。

ABSTRACT Drug delivery to the brain is restrained by the blood-brain barrier (BBB), a physical and biochemical barrier separating the brain from the circulatory system. Small molecule drugs move across the BBB mainly via transcellular passive diffusion and transporter-mediated active transport. The BBB in brain tumors is disrupted to varying extent, leading to large intra- and inter-individual variability in drug tumor exposure. Mechanistic understanding and prediction of heterogeneous drug penetration across the intact BBB and disrupted blood- brain tumor barrier (BBTB) is of paramount importance to rational drug development and treatment for brain cancer. Given the fact that the rate and extent of drug penetration across the BBB is determined by both biological system characteristics and drug properties, prediction of human BBB/BBTB permeability from preclinical in vitro or animal models is complicated by biological system differences. Hence, the development of innovative approaches is imperative. The in vitro-in vivo extrapolation-physiologically based pharmacokinetic (IVIVE-PBPK) model offers a unique platform that allows simultaneous incorporation of drug- and system- specific parameters into a PK model and enables a priori prediction of individual in vivo kinetic processes based on mechanistic scaling of in vitro data (e.g., in vitro enzyme and transporter kinetics). The overall goal of this project is to develop a mechanism-based PBPK model platform for predicting heterogeneous drug penetration into the human brain and brain tumors. We will employ an integrated translational research approach to achieve this goal, which leverages in vitro pharmacology studies, PK modeling, and clinical trials. Three drugs (AZD1775, ceritinib, and ribociclib) will be used for initial model development and verification, and additional 3 drugs (everolimus, abemaciclib, and LY3214996) will be used for further model validation. These drugs have been or is being evaluated in glioblastoma patients in our clinical trial program. Observed clinical plasma and brain tumor PK data are available for model development and validation. As the first step towards resolving the gap of our knowledge on BBB transporter abundances, which is essential to establishing IVIVE scaling factors for predicting transporter-mediated active clearance at the human BBB and BBTB, Aim 1 is to determine transporter protein abundances in isolated microvessels of non-cancerous cortex as well as contrast-enhancing and non-enhancing glioblastoma specimens. Aim 2 is to determine drug-specific parameters for metabolism, passive transcellular permeability, and interaction with efflux and uptake drug transporters. Aim 3 is to develop and validate a novel 7-compartment permeability-limited brain (7Brain) PBPK model, which accounts for brain and tumor regional physiological differences in blood perfusion, pH, BBB/BBTB integrity, and transporter expression. The 7Brain PBPK model is the first-of-its kind, mechanism-based model platform for the prediction of heterogeneous drug penetration across the human BBB and BBTB. It promises to be a valuable tool to assist the development and design of improved drugs and dosing regimens for more effective treatment of brain cancer.