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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.

一个基于机制的计算工具包，以优化特定年龄的儿科肺部药物输送项目概要/摘要：选择最适合年龄的药物、器械和接口组合对于有效治疗至关重要。给予任何规定的治疗。这在儿科呼吸系统疾病病例中尤其重要需要吸入疗法的病人然而，尽管吸入疗法的所有现代进步，当增加剂量时，到达肺部以达到最大治疗效果的药物比例仍然很低，全身浓度增加和随后的毒性。缺乏经批准的适龄药物/器械组合受到儿童实验限制和儿童的可塑性的限制，气道结构从出生到成年不断演变，影响气流动力学和呼吸力学由于这些缺点，不能单独通过实验策略解决，我们建议开发一种新的多尺度计算工具包来模拟沉积，溶解，吸收，吸入性药品的运输、清除和作用。该工具包的核心将是一个完整的框架计算流体动力学（CFD）和基于全身生理学的药代动力学（PBPK）模型，针对特定年龄组。在第一阶段，我们将（1）开发基于图像和解剖学上忠实的小儿气道3D CFD模型几何形状，以计算年龄、药物和器械特定的沉积模式;（2）扩展CFD模型，用于各种生理和病理设置，例如气道几何形状的收缩;以及（3）整合 CFD沉积模型与PBPK模型估计吸入药物的全身浓度。这工作流程，与阿肯色州大学儿科、肺科合作医学院和杜克大学放射学系将主要集中在模拟两个测试受试者使用两种常用的儿科吸入装置吸入皮质类固醇。在第二阶段，我们将通过对其他儿科年龄组、药物和药物的模型验证，进一步改进我们的计算工具组合和其它儿科吸入装置，例如喷雾器和软雾吸入器。我们的目标是利用这些计算策略的目的是开发一种产品，影响吸入性药物疗效和安全性的关键生物制药因素，有助于指导适合年龄的剂量、设备和接口选择，以更好地为临床实践提供信息。最终交付的将是一个商业质量的软件包与图形和即时响应能力估计吸入药物在人体呼吸道中的区域和全球沉积及其结局，它在全身血液中的出现，直到从体内消除。带有预加载测试用例的软件将免费提供给NIH/FDA研究人员进行评估和测试。