Development of Hybrid CFD-PBPK Models for Absorption of Intranasal Corticosteroids

鼻炎的有效治疗方法是鼻腔注射皮质类固醇(ICSS)。这个 ICS给药的主要优点是足够浓度的药物可以 通过鼻腔喷雾装置将其直接输送到作用部位。尽管 ICS的治疗效果是通过局部给药引起的，值得关注 保持这些药剂可以足够的量到达体循环 产生不利影响。皮质类固醇小滴在鼻腔内的局部沉积 文章是评估后续课程时需要考虑的一个重要因素 局部或全身给药鼻腔喷雾剂的药代动力学。这项提议将 介绍一种混合计算流体力学的发展和评估- 以生理为基础的药代动力学(CFD-PBPK)模型 吸收鼻腔给药产品，以支持和促进仿制药指导 开发、产品开发和应用程序审查。三大名牌ICSS 一系列的溶解度(氟龙酶、威拉米斯特和Rhinocort Aqua)将用于 研究它们的喷雾液滴大小分布、鼻腔内局部剂量以及 吸收特性。CFD方法和基于CT扫描的鼻腔重建 鼻腔正常的受试者和鼻炎的受试者将被用来 模拟和表征这三种皮质类固醇的颗粒沉积 鼻腔喷雾。这些信息将与本地化药物的PBPK模型相关联 在鼻黏膜中吸收。建议通过使用CFD模拟 鼻腔喷雾剂和PBPK模型模拟药物吸收，那是准确的 对ICSS吸收特性的估计可以用来估计鼻腔 组织浓度和血液PK谱。这项建议的具体目标是： 1.描述飞沫在鼻腔中的区域分布模式 从三个商业ICS排放。每种鼻腔喷雾剂的液滴大小分布 产品将用激光衍射法进行测定。然后这些大小分布将是 用于使用健康和鼻炎受试者的CFD模型进行鼻腔喷雾模拟。在……里面 每个受试者，鼻腔喷雾模拟的剂量将在解剖学上进行分析 感兴趣的区域。 2.建立ICS鼻腔吸收的生理吸收模型 粘膜。CFD模拟的区域剂量估计将与PBPK联系起来 模拟鼻腔的溶解、吸收和粘液纤毛的模型 ICSS的通关。 3.刻画了PBPK模型模拟的不确定性和总体变异性 ICS吸收。模型参数将通过分布来表征，而不是 单个参数值。蒙特卡罗模拟将使用PBPK进行 ICSS患者鼻腔组织和血液浓度差异的模型研究 由于模型参数值的变化而产生。

Rhinitis is effectively treated by administration of intranasal corticosteroids (ICSs). The major advantage of ICS administration is that sufficient concentrations of the drug can be directly delivered to the site of action by means of a nasal spray device. Although the therapeutic effect of an ICS is elicited by local action via topical delivery, concerns remain that these agents may reach the systemic circulation in sufficient quantities to produce adverse effects. The regional deposition of corticosteroid droplets in the nasal passages is an important factor to consider when evaluating subsequent pharmacokinetics of nasal sprays for topical or systemic delivery. This proposal will address the development and evaluation of a hybrid computational fluid dynamics- physiologically based pharmacokinetic (CFD-PBPK) model for the distribution and absorption of nasally delivered products to support and facilitate generic drug guidance development, product development, and application review. Three brand-name ICSs with a range of solubilities (Flonase, Veramyst, and Rhinocort Aqua) will be used to study their spray droplet size distribution, localized dose in the nasal passages, and absorption characteristics. CFD methods and CT scan-based sinonasal reconstructions from a subject with normal nasal passages and a subject with rhinitis will be used to simulate and characterize particle deposition delivered by these three corticosteroid nasal sprays. This information will be linked with a PBPK model for localized drug absorption in the nasal mucosa. It is proposed that through the use of CFD simulations of nasal sprays and PBPK model simulations of drug absorption, that accurate estimates of the absorption characteristics of ICSs can be determined to estimate nasal tissue concentrations and blood PK profiles. The specific aims of the proposal are: 1. Characterize the regional distribution patterns in the nasal passages of droplets emitted from three commercial ICSs. Droplet size distributions from each nasal spray product will be determined using laser diffraction. These size distributions will then be used in nasal spray simulations using CFD models of a healthy and rhinitic subject. In each subject, the dose from the nasal spray simulation will be analyzed in anatomical regions of interest. 2. Develop physiologically based absorption models of ICS absorption in the nasal mucosa. Regional dose estimates from the CFD simulations will be linked to PBPK models of the nasal passages to simulate the dissolution, absorption, and mucociliary clearance of ICSs. 3. Characterize the uncertainty and population variability of PBPK model simulations of ICS absorption. Model parameters will be characterized by distributions instead of single parameter values. Monte Carlo simulations will be performed using the PBPK model to characterize differences in nasal tissue and blood concentrations of ICSs resulting from changes in model parameter values.