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

基于生理学的药物渗透到人脑和脑肿瘤的药代动力学模型

基本信息

批准号：
10298016
负责人：
Jing Li
金额：
$ 39.43万
依托单位：
WAYNE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10298016
关键词：
Active Biological Transport Affect Animal Model Antineoplastic Agents Area Biochemical Biological Models Blood - brain barrier anatomy Brain Brain Neoplasms Cardiovascular system Carrier Proteins Cerebral cortex Characteristics Clinical Clinical Pharmacology Clinical Trials Collaborations Computer Models Data Data Set Decision Making Development Diffusion Dose Drug Delivery Systems Drug Formulations Drug Kinetics Drug Modelings Drug usage Enzymes Glioblastoma Goals Health Personnel Heterogeneity Human In Vitro Individual Kinetics Knowledge Malignant neoplasm of brain Mediating Metabolism Methods Modeling Necrosis Neuraxis Oncology Outcome Patients Penetration Permeability Pharmaceutical Preparations Pharmacology Pharmacology Study Pharmacotherapy Physiological Plasma Predictive Factor Process Property Proteins Proteomics Regimen SDZ RAD Specimen Structure System Translational Research Validation base biological systems blood perfusion blood-brain barrier function blood-brain barrier permeabilization blood-brain tumor barrier brain parenchyma clinical development comparative contrast enhanced design drug development effective therapy improved in vitro Assay in vitro Model in vivo innovation inter-individual variation inter-institutional model development novel novel therapeutics pharmacokinetic model physiologically based pharmacokinetics pre-clinical predictive modeling programs small molecule tool translational research program tumor uptake

项目摘要

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.

抽象的药物向大脑的输送受到血脑屏障（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移动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差异。机械论了解和预测异质药物在完整 BBB 和破坏的血液中的渗透脑肿瘤屏障（BBTB）对于合理的脑肿瘤药物开发和治疗至关重要癌症。鉴于药物穿过血脑屏障的速度和程度由两者决定生物系统特征和药物特性，预测人体 BBB/BBTB 通透性临床前体外或动物模型因生物系统差异而变得复杂。因此，发展创新方法势在必行。基于生理学的体外体内外推法药代动力学 (IVIVE-PBPK) 模型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纳入 PK 模型，并能够基于个体体内动力学过程进行先验预测体外数据的机械尺度（例如体外酶和转运蛋白动力学）。本次活动的总体目标项目旨在开发基于机制的 PBPK 模型平台，用于预测异质药物渗透进入人脑和脑肿瘤。我们将采用综合转化研究方法来实现这一目标利用了体外药理学研究、PK 建模和临床试验。三种药物（AZD1775、 Ceritinib 和 ribociclib）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。这些药物已经或正在我们的临床试验计划中对胶质母细胞瘤患者进行评估。血浆和脑肿瘤的临床观察 PK 数据可用于模型开发和验证。作为解决我们之间差距的第一步关于 BBB 转运体丰度的知识，这对于建立用于预测的 IVIVE 缩放因子至关重要转运蛋白介导的人类 BBB 和 BBTB 主动清除，目标 1 是确定转运蛋白非癌性皮质的孤立微血管以及对比度增强和非增强的丰度胶质母细胞瘤标本。目标 2 是确定代谢、被动跨细胞的药物特异性参数渗透性以及与外排和摄取药物转运蛋白的相互作用。目标 3 是开发并验证一部小说 7室通透性受限脑（7Brain）PBPK模型，考虑了脑和肿瘤区域血液灌注、pH、BBB/BBTB 完整性和转运蛋白表达的生理差异。 7脑 PBPK模型是首个基于机制的异质药物预测模型平台渗透人类 BBB 和 BBTB。它有望成为协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。