Distinct Associations of Age and CYP2D6 Genotype With Parent Venlafaxine Exposure and O‐Demethylation in Japanese Psychiatric Patients

Background Venlafaxine (VEN) is converted to O‐desmethylvenlafaxine (ODV) mainly through CYP2D6‐mediated O‐demethylation. However, age‐related clinical factors may also influence VEN exposure in routine practice. We examined whether age and CYP2D6 genotype show different associations with parent‐drug exposure and metabolic conversion. Methods This retrospective therapeutic drug monitoring analysis included 78 Japanese psychiatric patients with available plasma VEN and ODV concentrations and CYP2D6 genotype data. Two prespecified outcomes were analyzed without body‐weight correction: VEN concentration divided by daily dose (VEN/dose) and the ODV/VEN ratio. CYP2D6*10 and *5 were coded as reduced‐ and no‐function alleles, respectively. Log‐transformed outcomes were analyzed using regression models including age and CYP2D6 reduced/no‐function allele count. Results Nineteen patients (24.4%) were aged 65 years or older. Age was correlated with VEN/dose (Spearman rho = 0.295, p = 0.0086), and older patients had higher VEN/dose than younger patients (median, 0.522 vs. 0.192 [ng/mL]/[mg/day], p = 0.0127). In regression analysis, the incremental R 2 for age was numerically larger than that for CYP2D6 allele count for VEN/dose (incremental R 2 , 0.058 vs. 0.026). Conversely, the ODV/VEN ratio was strongly associated with CYP2D6 allele count (standardized beta = −0.391, p < 0.001; incremental R 2 = 0.145) but not with age. Age‐by‐genotype interactions were not significant for either outcome. Conclusions Age appeared to be more closely related to dose‐corrected parent VEN exposure, whereas CYP2D6 genotype predominantly determined the ODV/VEN metabolic ratio. The relative contribution of age should be interpreted descriptively because no formal comparison of effect sizes was performed. Separating exposure and metabolic‐ratio outcomes may clarify how geriatric and pharmacogenetic factors contribute to VEN disposition.