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

开发PBBM框架以支持局部作用的生物等效性评估 健康受试者和患者胃肠道中的药物-项目总结 本项目的目标是提出一种新的、经过验证的模型集成方法， 评价局部作用药物生物等效性（BE）时的比较临床终点生物等效性（BE）研究 产品在胃肠道（GIT）。 这一目标将通过两个配对要素实现：体外组件和计算机组件。 目前已批准上市的GIT局部作用制剂的体外溶出度将在 代表健康和患病肠道生理学的生物相关溶出介质。此外，配方 将为三（3）个API创建变体。将在相同的体外试验中检测其溶出特性。 这项工作将首次表明产品质量属性对API溶出度/放行的影响， 患者同时，高级房室吸收和转运（ACAT™）模型， GastroPlus©生理药代动力学（PBPK）平台将适用于GIT 疾病状况。结合目前获批的GIT局部作用药物的体外溶出度结果 将建立具有增强ACAT模型的产品的体外与体内关系，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 以区分产品质量属性和病理生理学属性的相对重要性 局部和全身浓度时间过程的参数。最后，将使用虚拟BE方法 以将试验制剂变体与其各自的参比品进行比较。研究中心的相应PK指标 将比较供试制剂和参比制剂的作用和血浆中的BE，以评估两个生物相中的BE。 该项目的结果将支持对当地代理药品的监管评估， GIT疾病，提出了一种新的，模型集成的方法，代替目前的BE做法。这 方法将有助于建立科学和监管标准，以支持创新发展 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.