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 本项目旨在定义和验证工作流程，以使用计算机模拟技术证明生物等效性。 机械模型报价人决定专注于PBBM-PBPK模型，并将使用两个独立的 用于进行分析的软件：GastroPlus ®和PK-SIM ®。通过这样做，优势，局限性和差距 将在用于描述API的ADME的领先平台中确定。 这一目标将通过以下三个方面实现：（1）确定哥伦比亚大学的案例研究， 马里兰州和其他合作伙伴的数据库;（2）验证GastroPlus和PK-SIM预测 受试者间和受试者内变异性;（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PBBM-PBPK模型的开发和验证， 两个平台上的API。然后，将虚拟群体模拟与观察到的个体PK进行比较 浓度时间过程，以评估两个平台描述临床观察到的 受试者间变异性根据结果，将制定可量化的验证标准。这些可以 在进行任何虚拟生物等效性研究之前，将其作为工作流程中的检查点。PBBM-PBPK模型 然后将用于进行多项虚拟生物等效性研究，并将结果与 从合作者的数据集中进行正面或负面的案例研究。将模拟信息性情景 为了支持基于药品特性的工作流程的开发（例如，高可变性，窄 治疗指数）。此外，还将测试工作流程中受试者内变异性的整合。 该项目的结果将支持仿制药产品的监管评估。的 制定和验证的工作流程将有助于建立科学和监管标准， 创新开发和执行这些仿制药产品的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.