(T-108) Right Dose, Wrong Patient? Clinical Perspectives on Atomoxetine Nonresponse in ADHD
Tuesday, October 21, 2025
7:00 AM - 1:45 PM MDT
Location: Colorado A
Kevin Tobin – University of Maryland; Addison Leabo – Children’s Mercy Kansas City; Steve Leeder – Children’s Mercy Kansas City; Allison Dunn – University of Maryland
Post-Doctoral Researcher University of Maryland Baltimore, Maryland, United States
Disclosure(s):
Kevin V. Tobin, PhD: No financial relationships to disclose
Objectives: Atomoxetine (ATX) is a non-stimulant selective norepinephrine reuptake inhibitor approved for attention-deficit/hyperactivity disorder (ADHD) treatment with highly variable systemic exposure due to polymorphic CYP2D6 metabolism. Poor metabolizers may experience >10-fold higher ATX exposures than normal metabolizers when at equivalent weight-based doses1. A target pediatric ATX exposure (400 ng/mL) is based on the relationship between peak ATX concentrations and change in ADHD-RS scores 2,3. However, 40% of patients do not respond to treatment, regardless of dose4. This study aims to evaluate ATX exposures and clinical response across a metabolically diverse pediatric population to inform individualized dosing and identify predictors of treatment success.
Methods: A population pharmacokinetic (popPK) model was developed using pooled data from three prospective clinical studies (86 patients, ages 6–17), with CYP2D6 activity phenotyping. ATX concentrations were characterized using nonlinear mixed effects modeling. Structural models were selected based on goodness of fit and covariates were assessed to explain interindividual variability. Model performance was evaluating using bootstrapped populations and predictive checks. In one of the three clinical studies (31 patients), ADHD subtype and clinical response were assessed at baseline and weeks 6, 12, and 18. Response was defined as >40% reduction in total symptom score from baseline. Exposure-response relationships were explored using observed and model-simulated ATX concentrations, including a comparison of responses at visits in which the target Cmax of ≥400 ng/mL was achieved. Predictors of treatment success were explored by stratifying response rate by various demographics including ADHD subtypes, comorbidities, CYP2D6 phenotypes, body composition, sex, and ethnicity. All analyses were performed in Pumas v2.5.1 and R 4.2.3.
Results: ATX PK was best described by a one-compartment distribution model with zero-order absorption into a depot, followed by first-order absorption and first-order elimination. Typical Vc/F and CL/F were estimated as 173 L and 38.9 L/hr, respectively. Poor and ultra rapid metabolizers exhibited -81% and +34% changes in CL/F, respectively, compared to normal metabolizers. The final qualified model was reliably used to derive exposure metrics. The target Cmax of ≥400 ng/mL was observed in 43 of 88 visits, however, 16 of these visits (37%) did not show a response. Despite similar exposures between responders and non-responders, 32% of the patients did not respond at least once throughout the study, suggesting clinical response is influenced by intrinsic patient characteristics. When evaluating ATX response and patient demographics, only inattentive ADHD subtype patients showed a significantly higher response rate (92%).
Conclusions: A popPK model was developed to describe the ATX exposures in children and adolescents across a range of CYP2D6 phenotypes. While no consistent exposure–response relationship was observed, patients with predominantly inattentive symptoms appeared more likely to benefit from ATX treatment.
Citations: [1] Brown JT, Abdel-Rahman SM, van Haandel L, Gaedigk A, Lin YS, Leeder JS. Single dose, CYP2D6 genotype-stratified pharmacokinetic study of atomoxetine in children with ADHD. Clin Pharmacol Ther. 2016;99(6):642-650. doi:10.1002/cpt.319 [2] Michelson D, Read HA, Ruff DD, Witcher J, Zhang S, McCRACKEN J. CYP2D6 and Clinical Response to Atomoxetine in Children and Adolescents With ADHD. Journal of the American Academy of Child & Adolescent Psychiatry. 2007;46(2):242-251. doi:10.1097/01.chi.0000246056.83791.b6 [3] Brown JT, Bishop JR, Sangkuhl K, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6 Genotype and Atomoxetine Therapy. Clin Pharmacol Ther. 2019;106(1):94-102. doi:10.1002/cpt.1409 [4] Newcorn JH, Sutton VK, Weiss MD, Sumner CR. Clinical Responses to Atomoxetine in Attention-Deficit/Hyperactivity Disorder: The Integrated Data Exploratory Analysis (IDEA) Study. Journal of the American Academy of Child & Adolescent Psychiatry. 2009;48(5):511-518. doi:10.1097/CHI.0b013e31819c55b2
