A mechanism-based computational toolkit to optimize age-specific pediatric pulmonary drug delivery

基于机制的计算工具包，用于优化特定年龄的儿科肺部药物输送

基本信息

批准号：
9909367
负责人：
NARENDER SINGH
金额：
$ 22.49万
依托单位：
CFD RESEARCH CORPORATION
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-18 至 2021-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9909367
关键词：
3-Dimensional 8 year old Adrenal Cortex Hormones Adult Aerosols Affect Age Air Movements Anatomy Appearance Arkansas Asthma Biochemical Process Biological Availability Biological Products Biophysics Birth Blood Caliber Calibration Child Childhood Childhood Asthma Collaborations Computer Models Computer software Coupled Data Deposition Development Devices Dimensions Disease Dose Drug Combinations Drug Delivery Systems Drug Kinetics Formulation Geometry Goals Guidelines Human Image Inhalation Inhalation Device Inhalation Therapy Inhalators Liquid substance Literature Lung Mechanics Medicine Metered Dose Inhaler Device Methodology Modeling Modernization National Institute of Child Health and Human Development Nebulizer Organ Pathologic Patients Pattern Pharmaceutical Preparations Phase Physiological Physiology Population Powder dose form Publishing Pulmonology Radiology Specialty Reporting Research Research Personnel Research Project Grants Resolution Respiration Disorders Respiratory Mechanics Respiratory System Safety Scanning Standardization Structure System Testing Therapeutic Effect Toxic effect United States National Institutes of Health Universities Validation Water Work X-Ray Computed Tomography absorption age group appropriate dose asthmatic base clinical practice college computational platform computer framework computerized tools constriction cost design drug development drug inhalation effective therapy evaluation/testing image reconstruction improved novel pediatric department pharmacokinetic model pressure programs respiratory response simulation virtual

项目摘要

A mechanism-based computational toolkit to optimize age-specific pediatric pulmonary drug delivery Project Summary/Abstract: The selection of the most age-appropriate combination of drug, device, and interface is critical for the effective administration of any prescribed therapy. This is especially relevant in pediatric cases of respiratory disorders that require inhalation therapy. However, in spite of all the modern advancements in inhalation therapies, the fraction of drugs reaching the lungs for maximal therapeutic effects remains low while increasing the dose causes an increase in systemic concentration and subsequent toxicity. The lack of approved age-appropriate drug/device combinations has been limited by experimental constraints in children and the plasticity of pediatric airway structures that continuously evolves from birth to adulthood, influencing airflow dynamics and respiratory mechanics. Motivated by such shortcomings, which cannot be solved by experimental strategies alone, we propose to develop a novel multiscale computational toolkit to simulate deposition, dissolution, absorption, transport, clearance, and actions of inhaled drug products. The core of this toolkit will be an integral framework of computational fluid dynamics (CFD) and whole-body physiology-based pharmacokinetic (PBPK) models, specific to selected age groups. In Phase I, we will (1) develop image-based and anatomically-faithful 3D CFD models of pediatric airway geometry to calculate age-, drug-, and device-specific deposition patterns; (2) extend the CFD models to account for various physiological and pathological settings, such as constriction of airway geometry; and (3) integrate CFD deposition models with PBPK models to estimate systemic concentration of the inhaled drugs. This workflow, in collaboration with Department of Pediatrics, Pulmonology Division at the University of Arkansas College of Medicine, and Department of Radiology at Duke University, will primarily focus on modeling two test subjects for corticosteroid inhalation using two commonly used pediatric inhalation devices. In Phase II, we will further improve our computational tools by model validation on additional pediatric age-groups, drugs and drug combinations, and other pediatric inhalation devices, such as, nebulizers and soft mist inhalers. Our goal of using these computational strategies is to develop a product that will aim to facilitate drug development by identifying key biopharmaceutical factors affecting efficacy and safety of inhaled drugs that help guide age-appropriate dosing, device, and interface selection to better inform clinical practice. The final deliverable will be a commercial quality software package with graphical and instant response abilities to estimate regional and global deposition of inhaled drugs in the human respiratory tract and their fate through its appearance in the systemic blood until eliminated from the body. The software with pre-loaded test cases will be made available at no cost to NIH/FDA researchers for evaluation and testing.

基于机制的计算工具包，以优化特异性小儿肺部药物输送项目摘要/摘要：选择最适合年龄的药物，设备和界面的组合对于有效给予任何处方疗法。这在呼吸系统疾病的小儿病例中尤其重要这需要吸入疗法。但是，尽管吸入疗法的所有现代进步，但达到肺部最大治疗作用的药物的一部分仍然很低，同时增加剂量全身浓度和随后的毒性增加。缺乏批准的年龄药物/设备组合受到儿童的实验限制和小儿的可塑性的限制气道结构从出生到成年后不断发展，影响气流动态和呼吸系统力学。由于这种缺点无法通过实验策略解决的动机，我们建议开发一种新型的多尺度计算工具包，以模拟沉积，溶解，吸收，吸入药品的运输，清除和作用。该工具包的核心将是一个整体框架计算流体动力学（CFD）和全身生理学的药代动力学（PBPK）模型，特定于选定的年龄组。在第一阶段，我们将（1）开发基于图像和解剖学的小儿气道3D CFD模型计算年龄，药物和设备特异性沉积模式的几何形状；（2）将CFD模型扩展到帐户用于各种生理和病理环境，例如气道几何学的收缩；（3）整合具有PBPK模型的CFD沉积模型估计吸入药物的全身浓度。这工作流程，与阿肯色大学儿科系肺科学系合作杜克大学医学院和放射学系将主要集中于建模两个测试使用两个常用的儿科吸入装置吸入皮质类固醇的受试者。在第二阶段，我们将通过模型验证其他小儿年龄段，药物和药物，进一步改善了我们的计算工具组合以及其他儿科吸入装置，例如雾化器和软雾吸入器。我们使用的目标这些计算策略是开发一种旨在通过识别来促进药物开发的产品关键的生物制药因素影响吸入药物的功效和安全性，以帮助指导适合年龄的药物剂量，设备和界面选择，以更好地为临床实践提供信息。最终可交付的将是具有图形和即时响应能力的商业质量软件包估计吸入药物在人类呼吸道中的区域和全球沉积及其命运它的出现在系统性血液中，直到被消除。带有预加载测试用例的软件将无需向NIH/FDA研究人员免费提供评估和测试。