Impact of <scp>CYP2C19</scp> Phenotype on Escitalopram Response in Geriatrics: Based on Physiologically‐Based Pharmacokinetic Modeling and Clinical Observation

Escitalopram is commonly prescribed for depressive and anxiety disorders in elderly patients, who often show variable drug responses and face higher risks of side effects due to age-related changes in organ function. The CYP2C19 polymorphism may further affect escitalopram pharmacokinetics in elderly patients, complicating dose optimization for this group. Previous pharmacogenetic studies examining the impact of CYP2C19 phenotype on escitalopram treatment outcomes have primarily focused on younger adults, leaving a gap in understanding its effects on the elderly. The aim of this investigation is to determine the impact of CYP2C19 phenotypes on escitalopram exposure in geriatrics using a physiologically-based pharmacokinetic (PBPK) model with geriatric-specific parameters and our clinical sample of 88 elderly patients with major depressive disorder. Based on PBPK simulations, the exposure of escitalopram in CYP2C19 poor metabolizers (PMs) was 2.1-fold higher compared with CYP2C19 extensive metabolizers (EMs). In line with PBPK results, the dose-normalized trough concentration in our clinical sample varied according to CYP2C19 phenotype (P = 0.0132), with PMs having a 1.6-fold higher concentration than EMs. Based on simulated and observed results, it is suggested that an escitalopram dose of 10 mg/day maybe appropriate for PMs, while a maximum dose of 20 mg/day could be used for EMs and IMs who do not achieve therapeutic responses at 10 mg/day. These findings suggest that CYP2C19 genotyping in elderly patients could be beneficial for tailoring dosing regimens in clinical practice, potentially improving treatment outcomes and reducing the risk of adverse drug reactions associated with escitalopram in this vulnerable group.