Single dose, CYP2D6 genotype-stratified pharmacokinetic study of atomoxetine in children with ADHD

• Published in: Clinical pharmacology and therapeutics Vol. 99; no. 6; p. 642
• Main Authors: Brown, J T, Abdel-Rahman, S M, van Haandel, L, Gaedigk, A, Lin, Y S, Leeder, J S
• Format: Journal Article
• Language: English
• Published: United States 01.06.2016
• Subjects: Adolescent; Adrenergic Uptake Inhibitors - administration & dosage; Adrenergic Uptake Inhibitors - pharmacokinetics; Adrenergic Uptake Inhibitors - therapeutic use; Alleles; Area Under Curve; Atomoxetine Hydrochloride - administration & dosage; Atomoxetine Hydrochloride - pharmacokinetics; Atomoxetine Hydrochloride - therapeutic use; Attention Deficit Disorder with Hyperactivity - drug therapy; Attention Deficit Disorder with Hyperactivity - metabolism; Biotransformation; Child; Cohort Studies; Cytochrome P-450 CYP2C19 - genetics; Cytochrome P-450 CYP2D6 - genetics; Female; Genotype; Humans; Longitudinal Studies; Male; Precision Medicine
• ISSN: 1532-6535
• DOI: 10.1002/cpt.319

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 μM*h in EM2s to 5.8 ± 1.7 μM*h, 16.3 ± 2.9 μM*h, and 50.2 ± 7.3 μM*h 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.