In vitro fluid capacity-limited dissolution testing and its kinetic relation to i

体外液体容量限制溶出试验及其与 i 的动力学关系

• 批准号: 8690239
• 负责人: Masahiro Sakagami
• 金额: $ 20万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-15 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8690239
• 关键词: vitro; fluid; capacity; limited; dissolution

PROJECT SUMMARY While being indispensable in the therapeutic management of many lung diseases, orally inhaled drug products (OIDPs) constitute a significant healthcare cost burden in the United States and worldwide. Thus, their generic development and entry are being sought, yet regulatory methods/paths to assess generic bioequivalence with the reference (innovator) product have not yet been established. The FDA Office of Generic Drug (OGD) initiated a study to evaluate the sensitivity of pharmacokinetics to differences in the aerodynamic particle size distribution (APSD) for three different, investigational dry powder inhaler (DPI) formulations of a poorly soluble inhaled corticosteroid (ICS), fluticasone propionate (FP) [RFA-FD-13-014]. This is to identify key drug and formulation variables and device performances to establish proper equivalency limits and design a possible path forward for generic bioequivalence. Accordingly, this cooperative research agreement project with FDA is to assist this OGD's study by developing an in vitro dissolution test method for OIDPs, capable of predicting APSD-dependent lung deposition and absorption following inhalation in humans, when aerosol drug dissolution is rate-determining in the lung. We hypothesize that such in vitro aerosol drug dissolution rates can be used in a newly developed semi-physiological lung deposition and disposition kinetics model to explain or extrapolate APSD-dependent pharmacokinetics of the FP aerosols for OGD's three investigational DPIs. In Aim 1, we will validate our modified in vitro fluid capacity-limited Transwell(R)-based aerosol dissolution system using reference OIDPs, Flovent HFA(R) and Diskus(R) to identify the experimental setup variables to best predict in vivo pulmonary dissolution rates, and to assess the sensitivity of differentiating APSD-dependent dissolution rates. In Aim 2, using the dissolution system, established in Aim 1, we will determine the dissolution rates (i.e., kdiss values) for the "respirable" (d 5.8 or 6.5 mm) drug aerosols generated from OGD's three investigational FP-DPIs and commercial ICS-OIDPs. The kdiss values will be correlated with the "respirable" doses and/or APSDs provided or measured in this project for their use in Aim 3, in addition to the solubility. In Aim 3, using the semi- physiological lung deposition and disposition kinetics model, we will attempt to predict the FP pharmacokinetics following inhalation of OGD's three FP-DPIs from the in vitro kdiss values experimentally determined in Aim 2, and to fit the observed FP plasma concentration-time profiles provided by OGD, together with the compendial APSD data, in order to derive the best estimates for the in vivo clinical kdiss values to be correlated with the in vitro kdiss values. The proposed study will be completed in one year with three personnel and our Bioanalytical Share Resource Laboratory. If successful, as proposed, this novel systems and approach could prospectively supplement or supplant the formal in vivo bioequivalence assessment, i.e., pharmacokinetic equivalence studies in humans, as a part of their bioequivalence demonstration for poorly soluble ICSs such as FP, and possibly mometasone furoate and fluticasone furoate.

项目摘要 在许多肺部疾病的治疗管理中，口服吸入药品必不可少 （OIDP）在美国和全球构成了重大的医疗费用负担。因此，他们的通用 正在寻求开发和进入，但使用监管方法/途径来评估一般的生物等效性 参考（创新者）产品尚未建立。 FDA通用药物办公室（OGD） 开始了一项研究，以评估药代动力学对空气动力学粒径差异的敏感性 分布（APSD），用于三种不同的研究干粉吸入器（DPI）公式的分布 吸入皮质类固醇（ICS），丙酮酸氟替卡松（FP）[RFA-FD-13-014]。这是确定关键药物和 配方变量和设备性能，以建立适当的当量限制并设计可能 通用生物等效性的前进。因此，与FDA的该合作研究协议项目是 通过为OIDP开发体外溶解测试方法来帮助这项OGD的研究，能够预测 吸入后，气溶胶药物溶解后吸入后，依赖APSD的肺沉积和吸收 是肺中的速率确定。我们假设这种体外气溶胶药物溶解速率可用于 新开发的半生理肺沉积和性动力学模型，以解释或推断 OGD的三个研究DPI的FP气溶胶的APSD依赖性药代动力学。在AIM 1中，我们将 使用参考来验证我们修饰的体外流体容量受限型Transwell（R）的气溶胶溶解系统 OIDP，Flovent HFA（R）和圆盘（R）识别实验设置变量，以最好地预测体内肺 溶解速率，并评估区分APSD依赖性溶解速率的灵敏度。在AIM 2中， 使用AIM 1中建立的溶出系统，我们将确定溶解速率（即KDISS值） OGD的三个研究FP-DPI和 商业ICS-oidps。 KDISS值将与提供的“可呼吸”剂量和/或APSD相关 除了溶解度外，在本项目中测量了它们在AIM 3中的使用。在AIM 3中，使用半 生理肺沉积和处置动力学模型，我们将尝试预测FP药代动力学 从AIM 2中确定的体外KDIS值中吸入OGD的三个FP-DPI后 并符合OGD提供的观察到的FP血浆浓度谱图 APSD数据，为了得出与IN相关的体内临床kdiss值的最佳估计值 体外kdiss值。拟议的研究将在一年内完成三名人员和我们的生物分析 共享资源实验室。如果按照提议成功，这种新颖的系统和方法可以前瞻性地 补充或取代正式的体内生物等效性评估，即药代动力学等效性 在人类中的研究，作为其生物等效性的一部分，用于易溶的ICS，例如FP和 可能有芒替索斯狂热和氟替卡松狂。