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

基本信息

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
项目类别：
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

项目摘要

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.

许多用于治疗呼吸系统疾病（例如哮喘和慢性阻塞性肺病）的吸入药物很快就会上市。由于现有专利到期而成为仿制药的候选者。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可能会降低成本，这将使消费者受益和医疗保健系统。有人建议进行低成本药代动力学 (PK) 研究，监测血液或尿液中的浓度可用于证明等效性。然而，一个更好的需要了解肺部区域和局部药物沉积模式。本研究的目的是推进现有口服吸入 CFD 模型的开发可以解释吸入器特性（喷雾或空气喷射动量）的药品、药物物理化学特性（空气动力学尺寸分布、蒸发和冷凝、溶解）和局部和生理参数（呼吸模式、几何形状、疾病状态）整个气道的局部药物沉积。在之前的一项研究（由美国 FDA 赞助）中提出的 CFD 模型准确预测了口腔 (MT) 和上气管支气管 (TB) 沉积物商业 MDI 和 DPI 吸入器，基于同步体外实验的验证，模型为被证明可以预测整个结核病区域的药物沉积。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部（结核病和肺泡区域）的沉积包括室壁运动。将开发可以解释主体间变异性的模型几何波形和吸气波形。当前项目的重点是比较两者肺部药物输送方面的体外实验和 CFD 预测以及可用的体内研究以及药物在气道内的沉积分布。为实现这一总体目标，提出了具体目标。具体目标 1：代表性人类气道几何形状的开发和网格生成从口腔到肺泡区域具体目标 2：开发可提供一系列特性的几何形状和吸入条件可以评估人群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整个气道中的运输和沉积不同呼吸参数的哮喘患者本研究中开发的 CFD 模型将在吸入器设计、选择等领域发挥重要作用。适当的吸入装置和吸入流量条件以实现最佳的肺部输送，并确定设备之间的生物等效性。基于之前第一年的模型开发，有趣正确和正确使用的标准 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 模型和体外测试都将与体内数据进行广泛比较，将为研究人员提供两种快速预测药物的方法人群气道内的分布。这种确定药物沉积的新方法肺结合低成本 PK 数据最终可用于建立仿制药和仿制药之间的生物等效性创新产品，无需进行昂贵且难以解释的药效学研究。此外，所提出的方法独立于治疗类别，因此可作为通用方法使用适用于所有口服吸入药品的方法。