An In Silico Approach toward the Appropriate Absorption Rate Metric in Bioequivalence

Abstract

In bioequivalence, the maximum plasma concentration (Cmax) is traditionally used as a metric for the absorption rate, despite the fact that there are several concerns. The idea of “average slope” (AS) was recently introduced as an alternative metric to reflect absorption rate. This study aims to further extend the previous findings and apply an in silico approach to investigate the kinetic sensitivity of AS and Cmax. This computational analysis was applied to the C-t data of hydrochlorothiazide, donepezil, and amlodipine, which exhibit different absorption kinetics. Principal component analysis (PCA) was applied to uncover the relationships between all bioequivalence metrics. Monte Carlo simulations of bioequivalence trials were performed to investigate sensitivity. The appropriate programming codes were written in Python for the PCA and in MATLAB® for the simulations. The PCA verified the desired properties of AS and the unsuitability of Cmax to reflect absorption rate. The Monte Carlo simulations showed that AS is quite sensitive to detecting differences in absorption rate, while Cmax has almost negligible sensitivity. Cmax fails to reflect absorption rate, and its use in bioequivalence gives only a false impression. AS has the appropriate units, is easily calculated, exhibits high sensitivity, and has the desired properties of absorption rate.

Virtual Bioequivalence in Pharmaceuticals: Current Status and Future Prospects

“…It is shown to be more sensitive in detecting differences in absorption rate than Cmax, which is less suitable for accurately reflecting absorption rate. The findings suggest that using Cmax alone may provide a false impression of bioequivalence, while AS offers a more reliable alternative [68].…”