Machine Learning in Bioequivalence: Towards Identifying an Appropriate Measure of Absorption Rate

Abstract

In this study, the modern tool of machine learning is used to address an old problem from a new perspective. Traditionally, the scientific basis for determining bioequivalence is based on a pharmacokinetic comparison, specifically the rate and extent of absorption between two products. Even though it is generally agreed that the peak plasma concentration (Cmax) should be used to measure the rate of absorption, several studies have raised concerns. Thus, alternative pharmacokinetic metrics have been proposed to address Cmax shortcomings. The aim of this study is to utilize unsupervised (principal component analysis) and supervised (random forest) machine learning algorithms to uncover the relationships among the pharmacokinetic parameters and identify the most suitable metric for absorption rate. One actual and three simulated donepezil bioequivalence datasets were utilized. For the needs of this study, a population pharmacokinetic model of donepezil was also developed and further used for the simulation of BE datasets with different absorption kinetics. Among the pharmacokinetic metrics explored, the newly proposed Cmax/Tmax ratio is also investigated. The latter was found to better reflect the absorption rate, regardless of the kinetic properties of absorption. This is one of the first studies utilizing machine learning in the field of bioequivalence.