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：
10459595
负责人：
Jing Li
金额：
$ 37.32万
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/10459595
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.

抽象的向大脑的药物传递受到血脑屏障（BBB）的限制，该障碍物是物理和生化障碍将大脑与循环系统分开。小分子药物主要通过跨细胞无源扩散和转运蛋白介导的活性转运。脑肿瘤中的BBB被破坏在不同的程度上，导致药物肿瘤暴露的大大和个体间差异。机理了解和预测异质药物渗透到完整的BBB中，并破坏了血液脑肿瘤屏障（BBTB）至关重要，对大脑的理性药物开发和治疗至关重要癌症。考虑到跨BBB的药物渗透率和程度由两者确定的事实生物系统特征和药物特性，人类BBB/BBTB渗透性的预测临床前的体外或动物模型因生物系统差异而复杂。因此，创新的方法是必须的。体内体内外推 - 基于生理学的药代动力学（ivive-pbpk）模型提供了一个独特的平台，可以同时合并药物和系统 - 特定参数到PK模型，并实现基于体内动力学过程的单个基于体内动力学过程的先验预测关于体外数据的机械缩放（例如体外酶和转运蛋白动力学）。总体目标项目是开发基于机制的PBPK模型平台，用于预测异质药物渗透进入人脑和脑肿瘤。我们将采用综合翻译研究方法来实现该目标利用体外药理学研究，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。这些药物已经或在我们的临床试验计划中，正在胶质母细胞瘤患者中评估。观察到的临床血浆和脑肿瘤 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BBB转运蛋白丰度的知识，这对于建立预测的ivive缩放因素至关重要转运蛋白介导的人BBB和BBTB的主动清除率，AIM 1是确定转运蛋白的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。 AIM 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吸收药物转运蛋白的相互作用。目标3是开发和验证小说 7室渗透率受限的大脑（7Brain）PBPK模型，该模型解释了大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模型是用于预测异质药物的首个基于机制的模型平台穿透人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。