Advancements in Virtual Bioequivalence: A Systematic Review of Computational Methods and Regulatory Perspectives in the Pharmaceutical Industry

Abstract

Background/objectives: The rise of virtual bioequivalence studies has transformed the pharmaceutical landscape, enabling more efficient drug development processes. This systematic review aims to explore advancements in physiologically based pharmacokinetic (PBPK) modeling, its regulatory implications, and its role in achieving virtual bioequivalence, particularly for complex drug formulations.

Methods: We conducted a systematic review of clinical trials using computational methods, particularly PBPK modeling, to carry out bioequivalence assessments. Eligibility criteria are emphasized during in silico modeling and pharmacokinetic simulations. Comprehensive literature searches were performed across databases such as PubMed, Scopus, and the Cochrane Library. A search strategy using key terms and Boolean operators ensured that extensive coverage was achieved. We adhered to the PRISMA guidelines in regard to the study selection, data extraction, and quality assessment, focusing on key characteristics, methodologies, outcomes, and regulatory perspectives from the FDA and EMA.

Results: Our findings indicate that PBPK modeling significantly enhances the prediction of pharmacokinetic profiles, optimizing dosing regimens, while minimizing the need for extensive clinical trials. Regulatory agencies have recognized this utility, with the FDA and EMA developing frameworks to integrate in silico methods into drug evaluations. However, challenges such as study heterogeneity and publication bias may limit the generalizability of the results.

Conclusions: This review highlights the critical need for standardized protocols and robust regulatory guidelines to facilitate the integration of virtual bioequivalence methodologies into pharmaceutical practices. By embracing these advancements, the pharmaceutical industry can improve drug development efficiency and patient outcomes, paving the way for innovative therapeutic solutions. Continued research and adaptive regulatory frameworks will be essential in navigating this evolving field.

Keywords: pharmaceutical industry; physiologically based pharmacokinetic (PBPK) modelling; regulatory guidelines; virtual bioequivalence.

Figure 1

PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) flow diagram illustrating the study selection process, from identification through to inclusion, outlining the number of records screened, excluded, and included in the final scoping review.

Figure 2

Pie chart depicting the distribution of in silico modeling tools used in virtual bioequivalence studies, as identified in the systematic review. The chart highlights the percentage utilization of each tool, including SimCYP^®, PK-Sim^®, GastroPlus™, Phoenix WinNonlin™, and MATLAB^®.

Figure 3

Prevalence of disease types in virtual bioequivalence research (2014–2024). This figure illustrates the distribution of various disease types investigated in studies utilizing virtual bioequivalence over the past decade.