CYP2D6 and clinical response to atomoxetine in children and adolescents with ADHD.
BACKGROUND
Atomoxetine, a selective norepinephrine reuptake inhibitor effective in the treatment of attention-deficit/hyperactivity disorder (ADHD), is metabolized through the cytochrome P-450 2D6 (CYP2D6) enzyme pathway, which is genetically polymorphic in humans. Variations in plasma atomoxetine exposures can occur because of genetic variation or as a consequence of coadministration with drugs that inhibit CYP2D6.


METHODS
We examined the effects of CYP2D6 on the efficacy, safety, and tolerability of atomoxetine in children and adolescents using pooled data from atomoxetine clinical trials.


RESULTS
At endpoint, poor metabolizers had markedly greater reductions in mean symptom severity scores compared with extensive metabolizers (p < .05). Poor metabolizers had greater increases in heart rate and diastolic blood pressure (p < .001) and smaller increases in weight (p < .05) than extensive metabolizers. Several adverse events, including decreased appetite and tremor, were more frequent in poor metabolizers (p < .05).


CONCLUSIONS
These results suggest that CYP2D6 poor metabolizers taking atomoxetine in doses up to 1.8 mg/kg/day are likely to have greater efficacy, greater increases in cardiovascular tone, and some differences in tolerability compared with CYP2D6 extensive metabolizers taking similar doses.
Michelson
David
D
Lilly Research Laboratories, Indianapolis, USA. david_michelson@merck.com
Read
Holly A
HA
Ruff
Dustin D
DD
Witcher
Jennifer
J
Zhang
Shuyu
S
McCracken
James
J
D000293:Adolescent; D018759:Adrenergic Uptake Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D000069445:Atomoxetine Hydrochloride; D001289:Attention Deficit Disorder with Hyperactivity / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D001711:Biotransformation / Q000235:genetics; D002648:Child; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D015201:Meta-Analysis as Topic; D011110:Polymorphism, Genetic / Q000235:genetics*; D011437:Propylamines / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D016032:Randomized Controlled Trials as Topic; D016896:Treatment Outcome
D018759:Adrenergic Uptake Inhibitors; D011437:Propylamines; D000069445:Atomoxetine Hydrochloride; D019389:Cytochrome P-450 CYP2D6