Population Pharmacokinetics of Sertraline in Healthy Subjects: a Model-Based Meta-analysis

Sertraline pharmacokinetics is poorly understood and highly variable due to large between-subject variability with inconsistent reports for oral bioavailability. The study objective was to characterize sertraline pharmacokinetics by developing and validating a sertraline population pharmacokinetic (PK) model in healthy subjects using published clinical PK data. We carried a systematic literature search in PubMed in October 2015 and identified 27 pharmacokinetic studies of sertraline conducted in healthy adult subjects and reported in the English language. Sixty mean plasma concentration-time profiles made of 748 plasma concentrations following IV, single, and multiple oral doses ranging from 5 to 400 mg were extracted and analyzed for dose proportionality by a log-linear model and fitted to a 2-compartment pharmacokinetic model in NONMEM using a model-based meta-analysis (MBMA) approach. After a single oral dose, sertraline C_max and AUC_∞ increased with dose proportionally between 50 and 200 mg, and bioavailability increased nonlinearly with dose from 5 to 50 mg and plateaued afterwards while T_max and t_1/2 did not change with dose. Following multiple oral doses, C_max and AUC_∞ increased proportionally with dose across the entire dose range (5-200 mg) while bioavailability, T_max, and t_1/2 remained constant with dose. Sertraline absorption was time-dependent and best described by a sigmoidal E_max function of time after dose. Study findings indicate that sertraline PK is linear in healthy adult subjects at doses ≥ 50 mg, and exposures were nonlinear only after single oral doses < 50 mg likely due to reduced bioavailability.