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

鼻内皮质类固醇（ICS）可有效治疗鼻炎。的 ICS给药的主要优点是足够浓度的药物可以 通过鼻喷雾装置直接递送至作用部位。虽然 ICS的治疗效果是通过局部给药的局部作用引起的， 仍然认为这些药剂可以以足够的量到达体循环， 产生不良影响。皮质类固醇小滴在鼻腔的局部沉积 段落是评估后续段落时要考虑的重要因素。 用于局部或全身递送的鼻喷雾剂的药代动力学。这项建议会 解决混合计算流体动力学的开发和评估- 基于生理学的药代动力学（CFD-PBPK）模型的分布和 鼻内给药产品的吸收，以支持和促进仿制药指导 开发、产品开发和应用审查。三个名牌ICS 将使用具有一系列溶解度的（Flonase、Veramyst和Rhinocort Aqua） 研究他们的喷雾液滴大小分布，鼻腔局部剂量， 吸收特性计算流体力学方法和基于CT扫描的鼻窦重建 将使用来自具有正常鼻道的受试者和患有鼻炎的受试者的样品， 模拟和表征由这三种皮质类固醇递送颗粒沉积 鼻喷剂这些信息将与本地化药物的PBPK模型相关联 在鼻粘膜中吸收。建议通过使用CFD模拟 鼻喷雾剂和药物吸收的PBPK模型模拟， 可以确定ICS的吸收特性的估计， 组织浓度和血液PK特征。该提案的具体目标是： 1.描述飞沫在鼻道中的区域分布模式 从三个商业ICSs排放。每种鼻喷雾剂的液滴粒度分布 将使用激光衍射测定产物。这些尺寸分布将是 用于使用健康和鼻炎受试者的CFD模型进行鼻喷雾模拟。在 每例受试者，将在解剖学中分析鼻喷雾模拟的剂量 感兴趣的区域。 2.开发鼻内ICS吸收的生理学吸收模型 粘膜CFD模拟的区域剂量估计值将与PBPK相关联 鼻道模型，以模拟溶解、吸收和粘膜纤毛 清除ICS。 3.描述PBPK模型模拟的不确定性和群体变异性， ICS吸收。模型参数将由分布表征，而不是 单参数值。将使用PBPK进行蒙特卡罗模拟 描述鼻组织和ICS血液浓度差异的模型 由模型参数值的变化引起。

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.