Influence of CYP2D6, CYP2C19, and CYP2C9 Pharmacogenetics and Clinical Factors on Dose-Normalized Venlafaxine/O-Desmethylvenlafaxine Metabolic Ratio in Spanish Patients

<b>Background/Objectives</b>: Venlafaxine has been reported to exhibit significant interindividual pharmacokinetic heterogeneity across populations, which has been linked to cytochrome P450 polymorphisms and clinical factors. This study aimed to assess the impact of pharmacogenetic (PGx) and clinical determinants on the dose-normalized venlafaxine/O-desmethylvenlafaxine (ODV) metabolic ratios (MRs) in routine clinical settings in Spain. <b>Methods</b>: 29 adult patients receiving venlafaxine were prospectively recruited through the MedeA PGx Implementation Strategy into clinical practice (Extremadura, Spain). <i>CYP2D6</i>, <i>CYP2C19</i>, and <i>CYP2C9</i> genotypes were determined using TaqMan^® assays, and <i>CYP2D6</i> activity scores were assigned based on allele functionality. Steady-state trough plasma concentration of venlafaxine and ODV were measured using a validated high-performance liquid chromatography method. Dose-normalized venlafaxine/ODV MRs were compared across <i>CYP2D6</i>-, <i>CYP2C19</i>-, and <i>CYP2C9</i>-genotype-predicted metabolizer groups. The influence of demographic and clinical variables on dose-normalized venlafaxine/ODV MR was also assessed. <b>Results</b>: Significant variability in dose-normalized venlafaxine/ODV MRs was observed across <i>CYP2D6</i> (<i>p</i> = 0.019) and <i>CYP2C19</i> (<i>p</i> = 0.008) metabolizer groups. Among clinical variables, sex was significantly associated with differences in dose-normalized venlafaxine/ODV MR (<i>p</i> = 0.0006). <b>Conclusions</b>: <i>CYP2D6</i> and <i>CYP2C19</i> genotypes and sex significantly contribute to variability in venlafaxine metabolism in patients treated in routine clinical settings. These results highlight the value of combining PGx and clinical data with drug plasma concentration measurement to optimize venlafaxine therapy within PGx implementation programs.