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. METHOD: 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.
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. METHOD: 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.
Authors: Jacob T Brown; Jeffrey R Bishop; Katrin Sangkuhl; Erika L Nurmi; Daniel J Mueller; Jean C Dinh; Andrea Gaedigk; Teri E Klein; Kelly E Caudle; James T McCracken; Jose de Leon; J Steven Leeder Journal: Clin Pharmacol Ther Date: 2019-04-13 Impact factor: 6.875
Authors: Cynthia A Prows; Todd G Nick; Shannon N Saldaña; Sanjeev Pathak; Chunyan Liu; Kejian Zhang; Zachary S Daniels; Alexander A Vinks; Tracy A Glauser Journal: J Child Adolesc Psychopharmacol Date: 2009-08 Impact factor: 2.576
Authors: Silvana Borges; Zeruesenay Desta; Yan Jin; Azzouz Faouzi; Jason D Robarge; Sanosh Philips; Santosh Philip; Anne Nguyen; Vered Stearns; Daniel Hayes; James M Rae; Todd C Skaar; David A Flockhart; Lang Li Journal: J Clin Pharmacol Date: 2010-01-15 Impact factor: 3.126