Development and validation of a workflow to conduct virtual bioequivalence studies using PBBM-PBPK models

开发和验证使用PBBM进行虚拟生物等效性研究的工作流程 PBPK模型。-项目摘要 该项目旨在定义和验证工作流程，以证明在硅胶中使用的生物等效性 机械论模型。发起人决定将重点放在PBBM-PBPK模型上，并将使用两个独立的 执行分析的软件：GstroPlus？和PK-SIM？？通过这样做，优势、限制和差距 将在用于描述API的ADME的领先平台上标识。 这一目标将通过三个要素来实现：(1)确定联合国大学的案例研究 马里兰和其他合作伙伴的数据库；(2)验证GstroPlus和PK-SIM预测 对象间和对象内的可变性；(3)模拟信息情景，以支持建立 与FDA科学家合作的虚拟生物等效性工作流程。 案例研究的数据集将支持开发和验证PBBM-PBPK模型 两个平台上的API。然后，将虚拟种群模拟与观察到的个体PK进行比较 评估两个平台描述临床观察的能力的集中时间进程 研究对象间的可变性。根据结果，将制定可量化的验证标准。这些将会服务于 作为工作流程中的检查点，然后进行任何虚拟生物等效性研究。PBBM-PBPK模型 然后将用于进行多个虚拟生物等效性研究，并将结果与 来自合作者数据集的正面或负面案例研究。将模拟信息丰富的场景 支持基于药品特性的工作流程的开发(例如，高可变性、狭义 治疗指数)。此外，还将测试工作流中主题内可变性的整合。 该项目的发现将支持对仿制药产品的监管评估。这个 开发和验证的工作流程将有助于建立科学和监管标准，以支持 对这些仿制药产品进行创新开发和虚拟生物等效性评价。

Development and validation of a workflow to conduct virtual bioequivalence studies using PBBM- PBPK models. – Project Summary This project aims to define and validate a workflow to demonstrate bioequivalence using in silico mechanistic models. The offerors decided to focus on PBBM-PBPK models and will use two separate software to perform the analysis: GastroPlus© and PK-SIM©. By doing so, advantages, limitations, and gaps will be identified across leading platforms used to describe the ADME of APIs. This goal will be achieved through three elements: (1) identification of case studies in the University of Maryland and other partners’ databases; (2) validation of the ability of GastroPlus and PK-SIM to predict the inter- and intrasubject variability; (3) simulation of informative scenario to support the establishment of the virtual bioequivalence workflow in collaboration with FDA scientist. Case studies’ datasets will support the development and validation of PBBM-PBPK models for multiple APIs on both platforms. Then, virtual populations simulation will be compared with observed individual PK concentration time courses to assess the ability of both platforms to describe the clinically observed intersubject variability. Based on the results, quantifiable validation criteria will be developed. Those will serve as a checkpoint in the workflow before conducting any virtual bioequivalence study. The PBBM-PBPK models will then be used to perform multiple virtual bioequivalence studies, and the results will be compared with either positive or negative case studies from collaborators’ datasets. Informative scenarios will be simulated to support the development of the workflow based on drug product characteristics (e.g., high variability, narrow therapeutic index). Furthermore, the integration of intrasubject variability in the workflow will be tested. The findings from this project will support the regulatory assessment of generic drug products. The developed and validated workflow will help to establish scientific and regulatory standards for supporting innovative development and performing virtual bioequivalence evaluation of these generic drug products.