The effect of CYP2D6 genotype on the dose-exposure relationship for atomoxetine has not been well characterized in children. Children 6-17 years of age diagnosed with attention-deficit hyperactivity disorder (ADHD) were stratified by CYP2D6 genotype into groups with 0 (poor metabolizers [PMs], n = 4), 0.5 (intermediate metabolizers [IMs], n = 3), one (extensive metabolizer [EM]1, n = 8) or two (EM2, n = 8) functional alleles and administered a single 0.5 mg/kg oral dose of atomoxetine (ATX). Plasma and urine samples were collected for 24 (IM, EM1, and EM2) or 72 hours (PMs). Dose-corrected ATX systemic exposure (area under the curve [AUC]0-) varied 29.6-fold across the study cohort, ranging from 4.4 ± 2.7 μMh in EM2s to 5.8 ± 1.7 μMh, 16.3 ± 2.9 μMh, and 50.2 ± 7.3 μMh in EM1s, IMs, and PMs, respectively (P < 0.0001). Simulated steady state profiles at the maximum US Food and Drug Administration (FDA)-recommended dose suggest that most patients are unlikely to attain adequate ATX exposures. These data support the need for individualized dosing strategies for more effective use of the medication.
Bibliographical noteFunding Information:
Support was provided by grants from the National Institutes of Health's Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) grant 1R01HD058556 (Leeder, Lin, co-PIs). J.T.B. was supported by grant T32 HD069038 "Postdoctoral Training in Pediatric Clinical Pharmacology" from the National Institutes of Health's Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) (Kearns, PD).