Application of Physiologically Based Pharmacokinetic Modeling to Optimize Assessment of Age‐Related Fluoxetine Accumulation in the Elderly

Abstract

ABSTRACT This study quantified age‐related differences in fluoxetine pharmacokinetics and evaluated the influence of CYP2D6 phenotype using physiologically based pharmacokinetic (PBPK) modeling integrated with clinical therapeutic drug monitoring data. A PBPK model for fluoxetine and its active metabolite norfluoxetine was implemented in the Simcyp Simulator and verified using published pharmacokinetic studies. Simulations of repeated fluoxetine administration (20 mg once daily) were performed in younger adults (18–65 years) and elderly individuals (65–98 years). Model predictions were compared with therapeutic drug monitoring data from Korean 47 patients (18–88 years) receiving fluoxetine for at least 5 weeks. Simulations demonstrated delayed steady‐state attainment and reduced clearance in elderly individuals, resulting in approximately two‐fold higher fluoxetine exposure after prolonged dosing and 1.5‐fold higher total active moiety exposure than in younger adults. Clinical observations supported these findings, with significantly higher dose‐normalized trough concentrations in elderly patients. Although CYP2D6 phenotype affected parent‐drug exposure, total active moiety exposure varied only modestly across phenotypes, suggesting that CYP2D6 phenotyping may not be necessary when titrating fluoxetine doses in elderly patients. These findings demonstrate that aging may enhance fluoxetine accumulation during chronic therapy, supporting cautious dose titration and extended monitoring in the elderly population.