Predicting the Required Water Intake for Oral Drug Administration Based on Drug and Formulation Properties Using Physiologically Based Biopharmaceutics Modeling: Immediate-Release Formulations Containing Weakly Acidic or Neutral Drugs

The effect of water intake on oral drug absorption is critically important for both appropriate medication use and drug development. Although systematic evaluation of water intake effects across all orally administered drugs would provide valuable insights, conducting comprehensive clinical studies in humans is impractical. It has been reported that, in real-world setting, patients typically take medications with less water than the volumes recommended in regulatory guidances (e.g., ICH M13A, US FDA). Therefore, this study aimed to predict the water volume required for adequate drug absorption under fasting conditions for immediate-release formulations of weakly acidic and neutral drugs using physiologically based biopharmaceutics modeling (PBBM). Differential equations describing water transport and absorption in the stomach and small intestine were developed and integrated into a PBBM framework. Using this model, drug absorption was simulated across a wide range of physicochemical and formulation properties, including solubility, membrane permeability, dose, and dissolution rate. To assess model performance and identify appropriate initial gastrointestinal fluid conditions, absorption was predicted for drugs with reported human fraction absorbed (Fa) values using different initial fluid volumes. In addition, for drugs with documented changes in human AUC associated with altered water intake, predicted changes in Fa were compared with observed AUC ratios. The developed PBBM successfully captured the influence of water intake on drug absorption and enabled identification of appropriate modeling conditions for prediction. The results demonstrated that absorption of poorly soluble drugs is particularly sensitive to water intake, whereas formulations exhibiting rapid particle-level dissolution showed minimal dependence on drinking volume. These findings provide a mechanistic basis for estimating the water volume required for drug administration in clinical practice. Furthermore, application of this framework during drug discovery and formulation development may support the design of pharmaceutical products with stable absorption profiles across diverse administration conditions.