Understanding Atomoxetine Exposure Variability in Children and Adolescents With ADHD Through Population Pharmacokinetics

Atomoxetine, a selective norepinephrine reuptake inhibitor, is a nonstimulant alternative to treat attention-deficit/hyperactivity disorder in children and adolescents. Atomoxetine exposure is highly variable due to cytochrome P450 polymorphism; however, the impact of these genetic variations has not been adequately characterized in the pediatric population. A population pharmacokinetic (PK) model was developed to evaluate steady-state atomoxetine exposures after oral administration in a large, heterogeneous population of children and adolescents with different metabolic phenotypes. Due to the highly variable and complex absorption between subjects and occasions, a two-stage approach was implemented, treating each participant/occasion as a separate individual. First, the individual atomoxetine parameters were estimated using a one-compartment distribution model with zero-order duration into a depot compartment followed by first-order absorption into the central compartment with linear elimination. Next, population-level parameters were obtained, and covariate analysis was performed. Using actual body weight, relative bioavailability based on CYP2D6 or CYP2C19 phenotype, and CYP2D6 clearance effects in the model reduced the variability from 81.6% to 64.5% and 92.4% to 75.5% for apparent volume and apparent clearance, respectively. The final model showed adequate precision in PK parameters and accuracy in exposure metrics. Following prospective validation, this model could be used to provide clinicians with individualized dosing targets when prescribing atomoxetine to children and adolescents based on their genetic disposition.