Buccal drug delivery relies on prolonged mucosal contact for absorption, sensitive to interindividual chemical and physical variability within the oral microenvironment (Hua, 2019; Shipp et al., 2022). The oral microbiome, which varies with diet, host genetics, and disease state, is a key modulator of local pH, epithelial integrity, and salivary composition, which may influence systemic drug exposure (Lamont et al., 2023; Rajasekaran et al., 2024; Shipp et al., 2022). However, the pharmacokinetic impact of the oral microbiome remains poorly characterized, leaving a potentially significant determinant of buccal drug absorption unaccounted for and limiting optimization of buccal drug therapy. Therefore, we developed a physiologically based pharmacokinetic (PBPK) model using GastroPlus® to evaluate how microbiome-relevant parameters influence buccal midazolam absorption.