Evaluating the Impact of CYP2D6 Phenotype on Fluvoxamine Pharmacokinetics in Geriatric Patients Using Physiologically Based Pharmacokinetic Modeling

Abstract

Background/Objectives: Fluvoxamine is commonly prescribed for depressive disorders in elderly patients, a population that frequently exhibits variable drug responses and increased susceptibility to adverse effects due to age-related physiological changes. CYP2D6 polymorphisms may further affect fluvoxamine pharmacokinetics in elderly patients, complicating dose optimization for this group. Previous pharmacogenetic studies examining the impact of CYP2D6 phenotype on fluvoxamine treatment outcomes have primarily focused on younger adults, leaving a gap in understanding its effects on the elderly. Methods: The impact of CYP2D6 phenotypes on fluvoxamine exposure in geriatrics was evaluated using a physiologically based pharmacokinetic (PBPK) modeling approach incorporating geriatric-specific physiological parameters. Results: The fluvoxamine PBPK model was verified using clinical pharmacokinetic data from younger and older adults, along with phenotype-dependent exposure differences between CYP2D6 poor metabolizers (PMs) and extensive metabolizers (EMs). Simulations showed that steady-state exposure in elderly patients was 1.8-fold higher than those in younger adults, and 2.1-fold higher in CYP2D6 PMs compared with EMs. Based on these simulations, doses of approximately 50 mg/day for PMs, 50-100 mg/day for intermediate metabolizers (IMs), 100 mg/day for EMs, and 150-200 mg/day for ultrarapid metabolizers (UMs) may be appropriate for elderly patients, accompanied by cautious dose escalation and clinical monitoring. Conclusions: These findings suggest that CYP2D6 genotype-guided dosing may be a useful strategy for optimizing fluvoxamine therapy in elderly patients, with the potential to improve treatment outcomes while minimizing the risk of adverse drug reactions in this high-risk population.