Predictive Lung Deposition Models for Safety and Efficacy of Orally Inhaled Drug

口服吸入药物安全性和有效性的预测肺沉积模型

• 批准号: 8485977
• 负责人: P. Worth Longest
• 金额: $ 29.97万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-15 至 2015-09-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8485977
• 关键词: Predictive; Lung; Deposition; Models; Safety

A number of inhaled medications used to treat respiratory diseases (such as asthma and COPD) will soon be candidates for generic drugs due to the expiration of existing patents. If these drugs can be offered as generics, reduced costs may be possible while maintaining safety and efficacy, which will benefit consumers and the health care system. It has been suggested that low-cost pharmacokinetic (PK) studies, which monitor concentrations in the blood or urine, could be used to demonstrate equivalence. However, a better understanding of regional and local drug deposition patterns in the lung is required. The objective of this study is to advance the development of an existing CFD model of orally inhaled drug products that can account for inhaler characteristics (spray or air-jet momentum), drug physicochemical properties (aerodynamic size distribution, evaporation and condensation, dissolution) and physiological parameters (breathing pattern, geometry, disease state) on local and regional drug deposition throughout the airways. In a previous study (sponsored by the US FDA) the proposed CFD model accurately predicted mouth-throat (MT) and upper tracheobronchial (TB) deposition from commercial MDI and DPI inhalers, based on validation with concurrent in vitro experiments, and the model was demonstrated to predict drug deposition throughout the entire TB region. In this newly proposed study, the existing CFD model will be extended to predict deposition throughout the lungs (TB and alveolar regions) with the inclusion of wall motion. Models will be developed that can account for intersubject variability in terms of both geometry and inhalation waveforms. An emphasis of the current project will be on comparing both in vitro experiments and CFD predictions with available in vivo studies in terms of lung drug delivery and drug depositional distribution within the airways. To achieve this overall objective, the following specific aims are proposed. Specific Aim 1: Development and mesh generation of representative human airway geometries extending from the mouth-throat to the alveolar region Specific Aim 2: Development of characteristic geometries and inhalation conditions that can provide a range of parameters within which inter-subject variability can be assessed for a population Specific Aim 3: Simulation of transport and deposition of polydisperse DPI aerosols in the entire airways of healthy small, medium, and large subjects with different breathing patterns and assess intersubject variability Specific Aim 4: Simulation of transport and deposition of polydisperse drug particles in the entire airways of asthmatic patients with different breathing parameters The CFD model developed in this study will play a valuable role in the areas of inhaler design, selecting appropriate inhalation devices and inhalation flow conditions for optimal lung delivery, and determining bioequivalence between devices. Based on the previous first year of model development, interesting differences in the TB and alveolar delivery between standard MDI and DPI inhalers used with correct and incorrect inhalation profiles were demonstrated. Both the developed CFD model and in vitro tests will be extensively compared with in vivo data and will give researchers two methods for rapidly predicting drug distribution within the airways across a population. This new approach for determining drug deposition in the lungs coupled with low-cost PK data can ultimately be used to establish bioequivalence between generic and innovator products without the need for costly and difficult to interpret pharmacodynamic studies. In addition, the methods proposed are independent of therapeutic class and therefore would be applicable as a universal method for all orally inhaled drug products.

许多用于治疗呼吸道疾病（如哮喘和COPD）的吸入药物将很快被 由于现有专利到期，仿制药的候选人。如果这些药物可以作为 仿制药，降低成本可能是可能的，同时保持安全性和有效性，这将有利于消费者 和医疗保健系统。有人建议，低成本的药代动力学（PK）研究，监测 血液或尿液中的浓度，可用于证明等效性。然而，更好的 需要了解肺中的区域和局部药物沉积模式。 本研究的目的是推进现有的经口吸入的CFD模型的发展 可以解释吸入器特性（喷雾或喷气动量）的药品，药物 物理化学性质（空气动力学粒度分布、蒸发和冷凝， 溶解）和生理参数（呼吸模式、几何形状、疾病状态）对局部和 区域性药物沉积在整个呼吸道。在之前的一项研究（由美国FDA申办）中， 提出的CFD模型准确地预测了口腔咽喉（MT）和上气管支气管（TB）沉积， 商业MDI和DPI吸入器，基于同时进行的体外实验的验证， 证明可以预测整个结核病地区的药物沉积。在这项新研究中， 现有的计算流体动力学模型将扩展到预测整个肺部（肺结核和肺泡区域）的沉积， 包括室壁运动。将开发能够解释受试者间差异的模型 几何形状和吸入波形。本项目的重点将是比较两者 体外实验和CFD预测，以及肺药物输送方面的体内研究 和气道内的药物沉积分布。为实现这一总体目标， 提出了具体目标。 具体目标1：开发和网格生成代表性的人体气道几何形状， 从咽喉到肺泡区 具体目标2：开发能够提供一系列 可评估人群受试者间变异性的参数 具体目标3：模拟多分散DPI气溶胶在人的整个气道中的传输和沉积 具有不同呼吸模式的健康小型、中型和大型受试者，并评估受试者间变异性 具体目标4：模拟多分散药物颗粒在大鼠整个气道中的转运和沉积 不同呼吸参数的哮喘患者 本研究所建立的CFD模型对吸入器的设计、选择和使用具有一定的指导意义 用于最佳肺递送的适当吸入装置和吸入流动条件，以及确定 器械之间的生物等效性。基于之前第一年的模型开发，有趣的是， 使用正确和适当剂量的标准MDI和DPI吸入器之间TB和肺泡输送的差异， 证明了不正确的吸入曲线。开发的CFD模型和体外试验都将 与体内数据进行了广泛的比较，并将为研究人员提供两种快速预测药物的方法。 分布在整个人群的气道内。这种新的方法，用于确定药物沉积在 肺再加上低成本的PK数据，最终可用于建立仿制药和非仿制药之间的生物等效性。 创新产品，而无需昂贵且难以解释的药效学研究。此外，本发明还提供了一种方法， 所提出的方法与治疗类别无关，因此可作为通用的 所有经口吸入制剂的方法。