Bridging Literature and Real-World Evidence: External Evaluation and Development of Fluoxetine Population Pharmacokinetics Model

Background: Fluoxetine is widely prescribed to treat depression but exhibits high inter-individual and inter-ethnic pharmacokinetic (PK) variability. Most published population pharmacokinetic (PopPK) models were derived from Western patients, and their applicability to Chinese patients remains uncertain. Methods: A systematic review of the published fluoxetine PopPK models was carried, and the relevant demographic and model parameters were extracted. A retrospective real-world dataset from Chinese psychiatric patients was then collected. External evaluation was conducted to assess the model’s predictive performance. Subsequently, a joint parent–metabolite PopPK model was developed to better characterize fluoxetine and its active metabolite norfluoxetine in Chinese patients. Finally, Monte Carlo simulations were performed to evaluate once-daily dosing regimens of 10–60 mg for 30 days, focusing on the probability of achieving target (PTA) steady-state trough concentrations (Cmin,ss). Results: Two published PopPK models were identified and externally evaluated using data from 198 Chinese patients with 241 fluoxetine and 241 norfluoxetine plasma concentrations. Both models were shown to have prediction discrepancy. The parent drug–metabolite model was used to describe the characteristics of fluoxetine and norfluoxetine in the Chinese population. Sex was identified as the significant covariate, and males exhibited a 16.5% higher clearance than females. The simulation results indicate that the maximum effective dose for females is 30 mg once daily, and for males, it is 40 mg once daily. Conclusions: This study provides the first comprehensive external evaluation of published fluoxetine PopPK models and establishes a tailored joint model that incorporates sex effects to explain trough variability in Chinese psychiatric patients. The findings support 30–40 mg once daily as a practical dosing range for Chinese adults and adolescents, with males more likely to require the higher dose.