Evaluation of the Potential Drug-Drug Interaction Between Aspirin and Fexuprazan in Healthy Subjects Using Mechanism-Based PK/PD Modeling

Background and objective : Long-term aspirin therapy requires gastroprotection with acid suppressants such as fexuprazan, a novel potassium-competitive acid blocker (P-CAB), which raises theoretical concerns about altered absorption kinetics due to elevated gastric pH. This study aimed to quantitatively evaluate the potential drug-drug interaction (DDI) between aspirin and fexuprazan using a mechanism-based pharmacokinetic/pharmacodynamic (PK/PD) modeling approach.Methods : A mechanism-based PK/PD model was developed using clinical data from healthy subjects administered a single oral dose of aspirin (500 mg) alone or in combination with fexuprazan (80 mg). The model linked fexuprazan-induced intragastric pH dynamics to the absorption kinetics of aspirin and its subsequent irreversible inhibition of platelet aggregation. Based on this established model, simulations were performed to predict the PK and PD profiles of clinically relevant low-dose aspirin (100 mg) combined with therapeutic maintenance doses of fexuprazan (20 mg and 40 mg).Results: Fexuprazan co-administration elevated gastric pH, which slightly delayed the absorption rate of aspirin. However, it did not significantly alter the total systemic exposure () of aspirin or its major metabolite, salicylic acid. Regarding pharmacodynamics, a minor statistical difference was observed for the high-dose regimen. However, simulations predicted that the antiplatelet efficacy of low-dose aspirin would remain virtually unchanged when combined with therapeutic doses of fexuprazan under steady-state conditions.Conclusions: Although fexuprazan may delay the initial absorption kinetics of aspirin by elevating gastric pH, this kinetic interaction is not expected to clinically compromise the therapeutic antiplatelet effect of aspirin. The proposed mechanism-based PK/PD model successfully elucidates this dissociation between PK delay and PD maintenance, supporting the safe concomitant use of these agents.