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.