Development of PBBM Framework to Support an Assessment of Bioequivalence for Locally-Acting Drugs in the Gastrointestinal Tract in Healthy Subjects and Patients

支持局部用药生物等效性评价的PBBM框架的开发 健康受试者和患者的胃肠道药物--项目摘要 该项目的目标是提出一种新的、经过验证的模型集成方法，作为 比较临床终点生物等效性研究评价局部作用药物的生物等效性 胃肠道(GIT)中的产品。 这一目标将通过两种配对元素实现：一种是体外成分，一种是硅成分。 目前批准上市的Git局部作用药物产品的体外溶出度将在 代表健康和疾病肠道生理的生物悬浮溶解介质。此外，配方 将为三(3)个API创建变体。它们的溶出性能将在相同的体外试验中进行测试。 这项工作将首次表明产品质量属性对原料药溶解/释放的影响 病人。同时，先进的隔室吸收和转运(ACAT™)模型，在 基于生理的药代动力学(PBPK)平台，将适用于GIT 疾病状况。结合目前批准的Git局部作用药物的体外释放结果 具有增强的ACAT模型的产品，体外和体内的关系将被建立，以评估 PBPK模型预测局部和全身暴露的能力。参数敏感性分析(PSA)将 用来区分产品质量属性和病理生理的相对重要性 局部和全身集中时间进程的参数。最后，将使用虚拟BE方法 将试验配方变体与其各自的参考文献进行比较。站点的相应PK指标 将在血药浓度和血药浓度两个阶段进行比较，以评估BE在两个生物相中的作用。 这个项目的发现将支持对当地作用药物产品的监管评估 通过提出一种新的、模型集成的方法来取代目前的BE实践，Git疾病。这 方法论将有助于建立支持创新发展的科学和监管标准 并对这些复杂的仿制药产品进行BE评价。

Development of PBBM Framework to Support an Assessment of Bioequivalence for Locally-Acting Drugs in the Gastrointestinal Tract in Healthy Subjects and Patients – Project Summary The goal of this project is to propose a new, validated model-integrated approach as an alternative to comparative clinical endpoint bioequivalence (BE) studies when evaluating the BE of locally acting drug products in the gastrointestinal tract (GIT). This goal will be achieved through two paired elements: an in vitro component and an in silico component. In vitro dissolution of GIT locally acting drug products currently approved on the market will be measured in biorelevant dissolution media representing the healthy and diseased gut physiology. Additionally, formulation variants will be created for three (3) APIs. Their dissolution properties will be tested in the same in vitro assays. This effort will provide a first indication of the impact of product quality attributes on API dissolution/release in patients. In parallel, the Advanced Compartmental Absorption and Transit (ACAT™) model, within GastroPlus© physiologically based pharmacokinetic (PBPK) platform, will be adapted to account for GIT disease conditions. Combining the in vitro dissolution results from currently approved GIT locally acting drug products with the enhanced ACAT model, in vitro to in vivo relationships will be established to assess the ability of the PBPK model to predict local and systemic exposures. Parameter sensitivity analysis (PSA) will be performed to differentiate the relative importance of product quality attributes and pathophysiological parameters on the local and systemic concentration time courses. Finally, a virtual BE approach will be used to compare the test formulation variants with their respective references. Respective PK metrics at the site of action and in plasma for the test and reference drug products will be compared to assess BE in both biophases. The findings from this project will support the regulatory assessment of locally acting drug products for GIT diseases by proposing a novel, model-integrated approach in lieu of the current BE practices. This methodology will help to establish scientific and regulatory standards for supporting innovative development and performing BE evaluation of these complex generic drug products.