Population pharmacokinetics of paroxetine in the pediatric population

Aims: The aim of this work was to develop a population pharmacokinetic model for Paroxetine in pediatric patients and to use this model to assess individual exposure in pediatric patients enrolled in clinical trials for Major Depressive Disorder, Social Anxiety Disorder and Obsessive Compulsive Disorder for which only sparse plasma samples were collected.

Methods: The model structure was selected according to the PK profile obtained in 62 pediatric patients (27 children and 35 adolescents) in an intensive PK sampling study (8 PK samples per occasion) with paroxetine administered at 10 mg/day for the first 2 weeks 20 mg/day for the next 2 weeks, and 30 mg/day for the final 2 weeks, with PK assessment at the end of each dosing period. The effects of age, weight and gender on paroxetine pharmacokinetics were evaluated in this population. The resulting model was than used as a prior to obtain individual PK parameters in 131 pediatric patients for which only sparse (n=199) samples were available. Population pharmacokinetic analysis was performed on the data pooled from all studies using the nonlinear mixed-effects modelling program NONMEM Version V.

Results: The best model retained was single compartment with first order absorption and saturable first-pass effect and elimination. Both clearance and volume of distribution were found to be dependent on body weight according to the allometric model. The model enabled to assess individual paroxetine exposure in sparsely sampled children and adolescent patients.