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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.

摘要