PBPK Modeling Addresses Oral Absorption-Mediated Drug Interactions.

Absorption is the first and imperative step to understanding the pharmacokinetics (PK) and ADME (absorption, distribution, metabolism, and excretion) of a drug product. Drug interactions also occur during the absorption process and have the potential to alter the PK of a drug, causing safety and efficacy concerns. Physiologically based pharmacokinetic (PBPK) modeling has emerged as a powerful tool to assess these interactions, supporting drug development and regulatory decisions. This review explores key mechanisms underlying oral absorption-mediated DDIs, including alterations in gastric pH, gastric emptying, gastrointestinal transit, and food effects. While interactions involving intestinal transporters and enzymes are reviewed in other articles of this special issue, this work emphasizes changes in gastrointestinal factors that influence drug absorption. Applications of PBPK modeling are illustrated through case examples predicting pH-dependent interactions, gastric transit alterations, and food effects. Regulatory acceptance of PBPK-based DDI assessments is discussed with reference to recent U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) case studies. Finally, future directions highlight the integration of machine learning and global harmonization of regulatory expectations. PBPK modeling offers a mechanistic approach for assessing absorption-mediated DDI risk, enhancing decision-making in drug development and regulatory science.