Background and objective: Fexofenadine is commonly used as a probe substrate to assess P-glycoprotein (Pgp) activity. While its use in healthy volunteers is well documented, data in older adult and polymorbid patients are lacking. Age- and disease-related physiological changes are expected to affect the pharmacokinetics of fexofenadine. This study aims to investigate the pharmacokinetics of fexofenadine in hospitalized older adult patients as a potential marker of Pgp activity, using data from the OptimAT study (ClinicalTrials.gov identifier: NCT03477331).

Methods: Population pharmacokinetic (popPK) modeling was conducted using data from 449 hospitalized patients with a median age of 71 years (range: 25-97) and 10 healthy volunteers (median age: 23 years, range: 20-36). Fexofenadine plasma concentrations were analyzed using a refined two-compartment model with sequential zero/first-order absorption, while investigating the impact of covariates such as age, renal function, and Pgp inhibitors on fexofenadine pharmacokinetics.

Results: Age, renal insufficiency, and Pgp inhibitors significantly influenced fexofenadine exposure. Renal function was a key factor, with AUC_0-6 increasing by 79% in mild-to-moderate and by 154% in moderate-to-severe renal impairment compared with normal renal function. Co-administration of Pgp inhibitors led to a 35% increase in AUC_0-6 . Across chronic kidney disease (CKD) stages, age, and Pgp inhibitor status, fexofenadine AUC_0-6 ratio ranged from 1.15 (stage 1, 20-30 years) to 4.59 (stage 5, 91-100 years, with Pgp inhibitors), relative to a reference subject of 20 years, normal renal function, and no Pgp inhibitors.

Conclusion: Clinicians should consider the risk of Pgp substrate accumulation in older adults, particularly those with advanced renal impairment. We propose typical values stratified by age and renal function to assist in interpreting Pgp phenotyping using fexofenadine exposure, thereby supporting drug optimization in this population. Further studies are needed to explore underlying mechanisms, such as reduced Pgp activity or expression.