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

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.