title: Recognition of impaired atomoxetine metabolism because of low CYP2D6 activity.
abstract: Ten out of 100 children treated for attention deficit hyperactivity disorder with standard doses of atomoxetine were selected by a neurologist for cytochrome P450 2D6 and cytochrome P450 2C19 genotyping, based on late response (>9 weeks) and adverse effects (gastrointestinal problems, sleeping disorders, malaise, inactivity, and mood instabilities). After genotyping, eight children were confirmed to have compromised cytochrome P450 2D6 activity because of at least one nonfunctional or less functional allele. Cytochrome P450 C19 is a minor pathway in atomoxetine metabolism and therefore of less importance. Tailored therapeutic advice was given to the neurologist. Four children with compromised cytochrome P450 2D6 activity responded better after decreasing their atomoxetine dose. The other four ceased treatment because of initial adverse effects. These cases indicate that compromised atomoxetine metabolism can be recognized, based on adverse effects and late response to atomoxetine. Physicians should be aware of the typical pattern of adverse effects and late response in atomoxetine treatment, possibly indicating compromised cytochrome P450 2D6 activity. Cytochrome P450 2D6 genotyping before atomoxetine treatment may be beneficial in preventing overdosing or early cessation. Further research is needed to establish the cost versus benefit ratio of prospective cytochrome P450 2D6 genotyping in atomoxetine treatment.
authors.affiliation: Department of Clinical Pharmacy, Amphia Hospital, Breda, The Netherlands. mtlaak@tsz.nl
authors.forename: Maureen A
authors.initials: MA
authors.lastname: ter Laak
authors.forename: Alphons H
authors.initials: AH
authors.lastname: Temmink
authors.forename: Ankie
authors.initials: A
authors.lastname: Koeken
authors.forename: Nils E
authors.initials: NE
authors.lastname: van 't Veer
authors.forename: Paul R M
authors.initials: PR
authors.lastname: van Hattum
authors.forename: Christa M
authors.initials: CM
authors.lastname: Cobbaert
mesh_terms: D000293:Adolescent; D018759:Adrenergic Uptake Inhibitors / Q000009:adverse effects*; D000069445:Atomoxetine Hydrochloride; D001289:Attention Deficit Disorder with Hyperactivity / Q000188:drug therapy* / Q000235:genetics*; D002648:Child; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D005838:Genotype; D006801:Humans; D010597:Pharmacogenetics; D011437:Propylamines / Q000009:adverse effects* / Q000378:metabolism; D012189:Retrospective Studies
chemical_list: D018759:Adrenergic Uptake Inhibitors; D011437:Propylamines; D000069445:Atomoxetine Hydrochloride; D019389:Cytochrome P-450 CYP2D6