title: Single dose, CYP2D6 genotype-stratified pharmacokinetic study of atomoxetine in children with ADHD.
abstract: 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.
authors.affiliation: Department of Pharmacy Practice and Pharmaceutical Sciences, University of Minnesota College of Pharmacy, Duluth, Minnesota, USA.
authors.forename: J T
authors.initials: JT
authors.lastname: Brown
authors.affiliation: Division of Clinical Pharmacology, Toxicology, and Therapeutic Innovation, Department of Pediatrics, Children's Mercy Kansas City and University of Missouri-Kansas City, Kansas City, Missouri, USA.
authors.forename: S M
authors.initials: SM
authors.lastname: Abdel-Rahman
authors.affiliation: Division of Clinical Pharmacology, Toxicology, and Therapeutic Innovation, Department of Pediatrics, Children's Mercy Kansas City and University of Missouri-Kansas City, Kansas City, Missouri, USA.
authors.forename: L
authors.initials: L
authors.lastname: van Haandel
authors.affiliation: Division of Clinical Pharmacology, Toxicology, and Therapeutic Innovation, Department of Pediatrics, Children's Mercy Kansas City and University of Missouri-Kansas City, Kansas City, Missouri, USA.
authors.forename: A
authors.initials: A
authors.lastname: Gaedigk
authors.affiliation: Department of Pharmaceutics, University of Washington School of Pharmacy, Seattle, Washington, USA.
authors.forename: Y S
authors.initials: YS
authors.lastname: Lin
authors.affiliation: Division of Clinical Pharmacology, Toxicology, and Therapeutic Innovation, Department of Pediatrics, Children's Mercy Kansas City and University of Missouri-Kansas City, Kansas City, Missouri, USA.
authors.forename: J S
authors.initials: JS
authors.lastname: Leeder
mesh_terms: D000293:Adolescent; D018759:Adrenergic Uptake Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000483:Alleles; D019540:Area Under Curve; D000069445:Atomoxetine Hydrochloride / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001289:Attention Deficit Disorder with Hyperactivity / Q000188:drug therapy / Q000378:metabolism*; D001711:Biotransformation; D002648:Child; D015331:Cohort Studies; D065731:Cytochrome P-450 CYP2C19 / Q000235:genetics; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D057285:Precision Medicine
chemical_list: D018759:Adrenergic Uptake Inhibitors; D000069445:Atomoxetine Hydrochloride; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6