Model-informed precision dosing of paroxetine to optimize individualized therapy in patients with mental disorders

Paroxetine exhibits significant inter-individual variability in concentrations due to nonlinear pharmacokinetics and metabolic differences, particularly at higher doses. The therapeutic reference range recommended by the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP; 20-65 μg/L) was derived primarily from studies in patients receiving 20-40 mg daily, which may not adequately reflect drug exposure at higher clinical doses. This study integrated literature data analysis and population pharmacokinetic (PPK) simulations, revealing that the mean concentration reported in the literature was 173.13 μg/L at 60 mg/d, significantly exceeding the AGNP range, while PPK simulations indicated a mean concentration of 235.94 μg/L in females at 60 mg/d, nearly twice that in males. Considering that sex and dosage significantly influence paroxetine concentrations, sex-specific exploratory therapeutic reference ranges for 60 mg/d were proposed: 85-180 μg/L for males and 150-290 μg/L for females. Based on clinical data and reported toxicity cases, a laboratory alert concentration of 350 μg/L is suggested to ensure an adequate safety margin. Overall, this study refines the paroxetine therapeutic reference range by incorporating dose- and sex-specific guidance to support more precise therapeutic drug monitoring (TDM) and promote individualized treatment, particularly at a dosage of 60 mg.