J Thromb Haemost. 2025 Jul 3:S1538-7836(25)00412-X. doi: 10.1016/j.jtha.2025.06.023. Online ahead of print.
ABSTRACT
BACKGROUND: Atrial fibrillation affects nearly half of geriatric inpatients, with edoxaban frequently used for stroke prevention. However, geriatric patients are underrepresented in drug trials with edoxaban. The limited data and high pharmacokinetic variability result in using this high-risk medication without a full understanding of its exposure in this population.
OBJECTIVES: To characterize the dose-exposure relationship and predict the sufficiency of current fixed-dose guideline for geriatric patients.
METHODS: We conducted a single-center prospective PK study in geriatric inpatients. We built a population pharmacokinetics (popPK) model and used it to simulate various dosing strategies (n=1000 simulations).
RESULTS: Seventeen frail geriatric patients (median age 87 years, IQR 83-90) receiving routine edoxaban contributed a total of 85 steady-state PK samples. A two-compartment popPK model best described the edoxaban and M4 metabolite concentrations, with proton pump inhibitors (PPI) reducing relative bioavailability by 24%. Key parameters included absorption rate constant 0.104 h-1, clearance 9.02 L/h, and central and peripheral volumes 47.4 L and 42.7 L. Edoxaban concentrations correlated with factor-Xa inhibitor concentrations (ρ=0.966). Nearly half of the patients had Cmin >43 ng/mL, with no difference between PPI and non-PPI groups. Simulations showed a 6.75% probability of overexposure with 15 mg, 42.4% with 30 mg, and 84.25% with 60 mg.
CONCLUSION: Estimated PK parameters in geriatric patients differed from those reported in pivotal trial populations, suggesting increased exposure thereby potentially influencing bleeding risk. The impact of PPI was not clinically relevant. Further investigation is needed to assess the benefits of alternative dosing in this population.
PMID:40617502 | DOI:10.1016/j.jtha.2025.06.023