Optimizing Mirtazapine Initial Dosing: A Population Analysis of the Effects of BMI, Paroxetine and Fluvoxamine

This study aimed to develop a population pharmacokinetic (PPK) model of mirtazapine (MTZ) in Chinese patients with depression and to optimize initial dosing regimens by systematically evaluating the impact of body mass index (BMI) and concomitant medications (paroxetine and fluvoxamine).

A retrospective analysis was conducted using 210 serum concentration observations from 105 inpatients. A one-compartment model was developed using nonlinear mixed-effects modeling (NONMEM). Potential covariates, including demographic characteristics and drug-drug interactions, were investigated. The final model was evaluated using goodness-of-fit plots, bootstrap analysis, normalized prediction distribution errors (NPDE), and external validation with independent clinical data (n = 49) and literature data. Monte Carlo simulations were performed to recommend individualized dosing regimens for different subgroups.

The final PPK model estimated the typical apparent clearance (CL/F) and apparent volume of distribution (V/F) as 29.3 L/h and 348 L, respectively. BMI, paroxetine, and fluvoxamine were identified as significant covariates affecting CL/F. Specifically, obesity (BMI ≥ 28 kg/m²), co-administration of paroxetine, and co-administration of fluvoxamine reduced CL/F by 29.4%, 26.9%, and 51.1%, respectively. Simulation results indicated that while a daily dose of 30-37.5 mg is appropriate for typical patients, dose reductions are necessary for specific subgroups to avoid drug accumulation and toxicity. The recommended dose is 22.5-30 mg/d for obese patients or those co-medicated with paroxetine and 15 mg/d for those co-medicated with fluvoxamine.

The developed PPK model accurately characterizes the pharmacokinetics of MTZ in Chinese patients, identifying BMI, paroxetine, and fluvoxamine as main factors influencing clearance. These findings provide a valuable reference for optimizing individualized MTZ dosing.