Sex-Related Differences in Physiologically-Based Biopharmaceutics Modeling

Physiologically based pharmacokinetic (PBPK) and physiologically-based biopharmaceutics (PBBM) modeling are valuable tools in drug development, allowing mechanistic predictions of drug absorption and disposition. However, sex-related differences in gastrointestinal physiology are often underrepresented in virtual populations, potentially limiting prediction accuracy. This study aimed to evaluate how sex-related physiological differences are incorporated into commonly used PBPK platforms and to illustrate their impact on pharmacokinetic predictions using ketoprofen as a case study. Three PBPK platforms were systematically reviewed to assess predefined sex-specific gastrointestinal parameters. All three platforms incorporated sex-related differences in general anatomy and physiology but overlooked sex-specific variability in gastrointestinal tract parameters. In addition, three PBBM models of ketoprofen were developed and verified in males and subsequently extrapolated to females using default and refined sex-specific parameters. Under default female settings, the models overpredicted Cmax and underestimated Tmax, resulting in concentration–time profiles that were nearly indistinguishable from those of males. Refining gastrointestinal tract parameters for females population improved prediction performance and better reflected observed sex differences. These findings indicate that current PBPK platforms may require user-defined adjustments to adequately represent sex-specific gastrointestinal physiology and that incorporating such parameters could lead to more representative PBBM applications.