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

开发和验证使用 PBBM-PBPK 模型进行虚拟生物等效性研究的工作流程

• 批准号: 10786889
• 负责人: Frederico Martins
• 金额: $ 24.96万
• 依托单位: SIMULATIONS PLUS, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-05 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10786889
• 关键词: Development; validation; workflow; conduct; virtual

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.

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。 – 项目概要 该项目旨在定义和验证工作流程，以在计算机中使用来演示生物等效性 机械模型。报价方决定专注于 PBBM-PBPK 模型，并将使用两个独立的模型 执行分析的软件：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 的领先平台上进行识别。 这一目标将通过三个要素来实现：（1）确定英国大学的案例研究 马里兰州和其他合作伙伴的数据库； (2)验证GastroPlus和PK-SIM预测的能力 受试者间和受试者内的变异性； (3) 模拟信息情景，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多个 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 集中时间课程来评估两个平台描述临床观察到的情况的能力 主体间变异性。根据结果​​，将制定可量化的验证标准。那些将服务 作为进行任何虚拟生物等效性研究之前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 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（例如，高变异性、窄 治疗指数）。此外，还将测试工作流程中受试者内部变异性的整合。 该项目的研究结果将支持仿制药产品的监管评估。这 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。