From Empirical Correlation to Mechanistic Modeling: The Changing Landscape of IVIVC Approaches for Oral Modified-Release Drug Products

In vitro–in vivo correlation (IVIVC) is an important tool in the development, quality evaluation, and regulatory assessment of oral modified-release (MR) drug products. By establishing a quantitative relationship between in vitro dissolution and in vivo drug absorption, IVIVC provides a scientific basis for formulation optimization, bioequivalence evaluation, and the establishment of clinically relevant dissolution specifications. Conventional IVIVC approaches, which are primarily based on empirical correlations, have been widely applied in relatively simple MR systems. However, their predictive capability and extrapolation potential remain limited due to the lack of mechanistic understanding of drug release, absorption processes, and physiological factors. With the advancement of physiologically based biopharmaceutics modeling (PBBM), IVIVC is expanding from empirical correlation toward mechanistic modeling, providing a novel framework for evaluating the in vitro–in vivo relationship of oral MR drug products. This review summarizes the development and limitations of conventional IVIVC approaches, with particular emphasis on the principles, workflow, and recent applications of PBBM-driven mechanistic IVIVC in various oral MR formulations. Furthermore, commonly used modeling platforms and regulatory applications are discussed. Finally, current challenges and future perspectives of PBBM-IVIVC are highlighted. Unless otherwise specified, the term “modified-release (MR) drug products” in this review refers to oral modified-release drug products.