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.

许多用于治疗呼吸系统疾病（例如哮喘和COPD）的吸入药物很快将是 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，同时保持安全性和功效，这将使消费者受益 和医疗保健系统。有人提出，低成本药代动力学（PK）研究 血液或尿液中的浓度可用于证明等效性。但是，更好 需要了解肺中区域和局部药物沉积模式。 这项研究的目的是提高现有的口服CFD模型的开发 可以说明吸入器特征（喷雾或喷射动量），药物的药品 物理化学特性（空气动力学尺寸分布，蒸发和凝结， 溶解）和生理参数（呼吸模式，几何形状，疾病状态）在局部和 整个气道的区域药物沉积。在先前的研究中（由美国FDA赞助） 拟议的CFD模型准确预测了口throat（MT）和上流气管（TB）沉积 商业MDI和DPI吸入器，基于同时进行体外实验的验证，模型为 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模型将扩展以预测整个肺部的沉积（结核病和肺泡区域） 包括墙运动。将开发模型，可以说明以主体间的可变性 几何和吸入波形。当前项目的重点将是比较 在体外实验和CFD预测，并在肺部药物递送方面具有可用的体内研究 和气道中的药物沉积分布。为了实现这一总体目标，以下 提出了具体目标。 特定目的1：开发和网格生成代表性的人类气道几何形状扩展 从喉头刺到肺泡区域 特定目的2：开发特征性的几何和吸入条件，可以提供范围 可以评估人口间可变性的参数 特定目的3：模拟整个呼吸道中多分散DPI气溶胶的传输和沉积 具有不同呼吸模式的健康小型，中，大受试者并评估受试者间的可变性 特定目标4：在整个气道中的多分散药物颗粒的传输和沉积模拟 具有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领域发挥重要作用，选择 适当的吸入设备和吸入流量条件，可用于最佳肺输送和确定 设备之间的生物等效性。根据前一年的模型开发，有趣 标准MDI和DPI吸入器与正确和DPI吸入器之间的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是 与体内数据相比广泛比较，将为研究人员提供两种快速预测药物的方法 气道内部分布在人群中。这种确定药物沉积的新方法 结合低成本PK数据的肺最终可用于在通用和 创新产品无需昂贵且难以解释药效研究。此外， 提出的方法独立于治疗类别，因此适用于通用 所有口服吸入药品的方法。