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: 8922803
• 负责人: P. Worth Longest
• 金额: $ 4.76万
• 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 2016-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8922803
• 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.

一些用于治疗呼吸系统疾病(如哮喘和慢性阻塞性肺病)的吸入性药物将很快被 由于现有专利到期而成为仿制药的候选药物。如果这些药物可以作为 仿制药，在保持安全性和有效性的同时降低成本是可能的，这将使消费者受益 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以用来证明等效性。然而，一个更好的 需要了解局部和局部药物在肺部的沉积模式。 本研究的目的是促进现有口服吸入剂CFD模型的发展。 可以解释吸入器特征(喷雾或喷气动量)的药物产品、药物 物理化学特性(气动尺寸分布、蒸发和冷凝、 溶解)和生理参数(呼吸模式、几何形状、疾病状态) 呼吸道内的区域性药物沉积。在之前的一项研究中(由美国食品和药物管理局赞助) 提出的CFD模型准确地预测了口腔-喉咙(MT)和上段气管、支气管(TB)的沉积 商用MDI和DPI吸入器，基于同时进行的体外实验的验证，模型是 展示了对整个结核病地区药物沉积的预测。在这项新提出的研究中， 现有的CFD模型将扩展到预测整个肺(结核和肺泡区)的沉积 包括壁面运动。将开发能够在以下方面解释学科间差异的模型 几何波形和吸入波形都有。当前项目的重点是将两者进行比较 肺给药的体外实验和体内研究的CFD预测 以及药物在呼吸道内的沉积分布。为实现这一总体目标，应采取以下措施 提出了具体的目标。 具体目标1：典型人体气道延伸几何图形的开发和网格生成 从口咽部到肺泡区 具体目标2：开发可提供射程的特征几何形状和吸入条件 可以评估总体的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#年整个呼吸道中的传输和沉积 健康的小型、中型和大型受试者有不同的呼吸模式，并评估受试者之间的变异性 具体目标4：模拟多分散药物颗粒在#年的整个呼吸道中的传输和沉积 不同呼吸参数的哮喘患者 本研究开发的CFD模型将在吸入器的设计、选型等领域发挥重要作用 适当的吸入装置和吸入流动条件，以实现最佳的肺输送，并确定 设备之间的生物等效性。基于前一年的模型开发，很有趣 标准MDI和DPI吸入器与正确吸入器和DPI吸入器在结核病和肺泡输送方面的差异 显示了不正确的吸入曲线。开发的CFD模型和体外测试都将是 与体内数据进行了广泛的比较，将为研究人员提供两种快速预测药物的方法 在整个人群的呼吸道内的分布。这是一种测定药物在体内沉积的新方法 结合低成本PK数据的肺部最终可用于建立仿制药和非专利药之间的生物等效性 创新者产品不需要昂贵和难以解释的药效学研究。此外, 所提出的方法与治疗类别无关，因此将作为通用方法适用。 方法适用于所有口服吸入性药品。