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

一种基于机理的儿科肺部给药优化工具包 项目摘要/摘要： 选择最适合年龄的药物、设备和接口的组合对于有效 接受任何处方治疗。这在儿科呼吸系统疾病的病例中尤其相关。 需要吸入疗法。然而，尽管吸入疗法取得了所有的现代进步， 在增加剂量的同时，到达肺部以获得最大治疗效果的药物比例仍然很低 全身浓度的增加和随后的毒性。缺乏经批准的适龄儿童 药物/装置的组合受到儿童实验限制和儿童的可塑性的限制 从出生到成年期持续进化的呼吸道结构，影响气流动力学和呼吸 机械师。受这些不足的驱使，单靠实验策略是无法解决的，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、 吸入性药物产品的运输、清关和行动。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， 特定于选定的年龄组。 在第一阶段，我们将(1)开发基于图像的、符合解剖学原理的儿科呼吸道三维CFD模型 用于计算特定于年龄、药物和设备的沉积模式的几何图形；(2)扩展CFD模型以考虑 用于各种生理和病理环境，如气道几何形状狭窄；以及(3)整合 CFD沉积模型与PBPK模型用于估算吸入药物的全身浓度。这 工作流程，与阿肯色大学肺病学部儿科合作 医学院和杜克大学放射学系将主要专注于模拟两种测试 受试者使用两种常用的儿科吸入器吸入皮质类固醇。在第二阶段，我们会 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 其他儿科吸入器，如喷雾器和软雾吸入器。我们的目标是使用 这些计算策略是开发一种产品，旨在通过识别 影响吸入性药物疗效和安全性的关键生物制药因素 剂量、设备和接口选择，以更好地向临床实践提供信息。 最终的交付成果将是一个具有图形和即时响应能力的商业质量软件包 通过以下途径估计吸入性药物在人类呼吸道的区域和全球沉积及其去向 它出现在全身血液中，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的研究人员进行评估和测试。

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.