Pharmacogenetic, Clinical, Prescribing, and Demographic Predictors of Sertraline Pharmacokinetics

Background: Interindividual variability in sertraline pharmacokinetics remains substantial, but the relative contributions of pharmacogenetic (PGx), demographic, clinical, and prescribing determinants have not been comprehensively evaluated in routine clinical practice. The study aimed to evaluate PGx, demographic, clinical, and prescribing determinants of sertraline plasma concentrations, sertraline plasma concentration-to-dose ratio (C/D), and non-dose-normalized sertraline-to-norsertraline metabolic ratio (MR), with log₁₀-transformed dose-normalized sertraline/norsertraline metabolic ratio (LogMR_DN) and log₁₀-transformed MR (LogMR) evaluated as exploratory derived pharmacokinetic outcomes in real-world clinical settings. Methods: This prospective real-world PGx study included 153 patients receiving sertraline therapy who participated in the MedeA clinical PGx implementation program. Associations of genotype-predicted phenotypes for CYP2C19, CYP2B6, CYP2D6, CYP2C9, and CYP3A4, CYP2C:TG haplotype status, demographic, clinical, and prescribing characteristics with sertraline concentration, C/D, MR, and LogMR_DN were evaluated using univariable analyses. Separate multivariable linear regression models were fitted for these outcomes and LogMR using 140 complete cases. Results: CYP2C19 gPM status was associated with higher sertraline concentrations (β = 72.10, 95% CI: 21.36-122.84; p = 0.01). Although a higher sertraline C/D ratio was observed in the conventional multivariable model with CYP2C19 gPM (β = 1.46, 95% CI: 0.85-2.08; p < 0.001), this association was not retained after HC3 heteroscedasticity-robust standard errors were applied (β = 1.46, 95% CI: -0.09-3.02; p = 0.07). In a small exploratory subgroup analysis, patients with combined CYP2C19 and CYP2B6 poor-metabolizer status (n = 2) had sertraline concentrations exceeding 150 ng/mL. Conclusions: The study findings provide further insights into the relevance of CYP2C19 in sertraline pharmacokinetics.