Project Summary/ Abstract In the field of biopharmaceutics, virtual bioequivalence (VBE) trial simulations have the potential to increase the speed of drug development, lower its cost and reduce exposure of human volunteers and patients to unneeded therapies. VBE is based on the proven ability of mechanistic physiologically-based pharmacokinetic (PBPK) models to simulate realistic virtual cohorts of patients which can replace full clinical trials. However, well-defined and verified workflows and examples of VBE applications are not yet fully established. Having well-defined workflows in a seamless, user- friendly, and widely accessible modeling platform tested with multiple case studies will ensure a wider adoption VBE by industry and regulatory bodies. This project proposes to develop an integrated VBE platform yielding optimal decisions for a matter directly related to the health and safety of patients, and their optimal and cost-effective treatment. The capacity to integrate various streams of data (in vitro information on drug and formulations, physiological knowledge of what conditions the ability of a drug to reach its site of action, variability physiology and metabolism across patients) is not just a software production exercise but requires deep knowledge of each area and expertise in the field. This needs to be complemented by rigorous statistical analyses, as applied to real clinical data, of the VBE simulations. Our overall objectives are to • Develop a software platform allowing for flexible, fit-for-purpose, VBE workflows taking advantage of existing tools and adding user-defined modules. • Provide guidance on VBE workflow design (how to solve particular questions, pitfalls to avoid, help with the design of supporting experiments and trials) for regulatory agencies/industries. • Make maximum use of the capabilities of existing in vitro data analysis and modeling tools to extract key parameters values relevant to formulation differences for selected routes of administration (e.g., oral, intra-muscular injection). • Conduct six in-depth VBE case studies, very close to real life cases, where individualized BE clinical data are available to the team through literature reports or internal investigations; Experimental in vitro data is already available or will be generated as required. • Create automated default reporting templates that clearly document the workflow and its results and are easily understood by non-users for assessment purpose (with flexibility to modify default templates when needed). Our specific aims are divided in workflow design, software implementation and case studies. We anticipate that the proposed research will result in a wider patient centric application of population PBPK models in generic drug development and regulatory reviews, but also for innovators’ drugs, enhancing drug efficacy, availability and safety for all the world’s population.

Project Narrative Virtual bioequivalence (VBE) uses mechanistic physiologically-based pharmacokinetic models to simulate realistic virtual cohorts of patients which can replace full clinical trials. However, well-defined workflows and examples of VBE applications are lacking; this study will develop an integrated VBE platform yielding optimal decisions for a matter directly related to the health and safety of patients, and their optimal treatment. Our software platform will help generic drug development and regulatory reviews, but also innovators’ drug development, enhancing drug efficacy, availability and safety for all the world’s population.