Personalizing Atomoxetine Dosing in Children with ADHD: What Can We Learn from Current Supporting Evidence

Abstract

Atomoxetine is the first non-stimulant medication approved by the US Food and Drug Administration for the treatment of attention deficit/hyperactivity disorder (ADHD). It can significantly improve ADHD symptoms, with good efficacy and tolerability. However, its efficacy was not consistent among all patients, especially for pediatric population. Due to marked heterogeneity in treatment response, a precision therapy should be developed and evaluated to guide treatment planning at the individual level. We have gained a better understanding of the pharmacokinetic profile. This review summarized some factors affecting peak concentrations of atomoxetine, including food, CYP2D6 and CYP2C19 phenotypes, and drug-drug interactions. The association between response and genetic polymorphisms of genes encoding the pharmacological targets such as norepinephrine transporter (NET/SLC6A2) and dopamine β hydroxylase (DBH) was also discussed. Based on the well-developed and validated assays for monitoring plasma concentrations of atomoxetine, the therapeutic reference range in pediatric patients with ADHD proposed by several studies was summarized. However, supporting evidence on the relationship between systemic atomoxetine exposure levels and clinical response is far from sufficient. We have to create evidence to characterize clearly the dose-exposure relationship, to establish clinically relevant metric for systemic exposure, to define a therapeutic exposure range, and to provide a dose-adaptation strategy before implementing personalized dosing for atomoxetine in children with ADHD. Personalizing atomoxetine dosage may be even more complex than we anticipated, but we can be optimistic about the future based on the remarkable advances in understanding the nature and causes of ADHD, as well as environmental stressors.

Growing evidence of pharmacotherapy effectiveness in managing attention-deficit/hyperactivity disorder in young children with or without autism spectrum disorder: a minireview

“…Adverse events during atomoxetine treatment tend to occur more frequently in preschool children than in older children, and this may be due to developmental differences in pharmacokinetics (52). Furthermore, there is broad heterogeneity in response to atomoxetine in terms of efficacy and tolerability, and this is likely attributable in large part to atomoxetine being mainly metabolized by the highly polymorphic enzyme, Cytochrome P450 2D6 (52,53). Ultra-rapid metabolizers may experience reduced efficacy, and poor metabolizers may have a higher risk of adverse events.…”