Association of Atomoxetine Discontinuation Patterns with CYP2D6 Phenotype in Children and Adolescents with Attention Deficit Hyperactivity Disorder.

CYP2D6 metabolizes atomoxetine; the activity score (adjusted for phenoconversion under inhibitors) drives exposure, efficacy and tolerability.

This electronic health record review assessed the association between CYP2D6 phenotype and atomoxetine treatment outcomes in 108 patients aged 21 or younger with ADHD, after adjusting activity scores for phenoconversion from CYP2D6 inhibitors (13 poor, 30 intermediate, 61 normal, 4 ultrarapid metabolizers). Normal/ultrarapid metabolizers were more likely to discontinue atomoxetine due to lack of efficacy (sHR = 1.9; p = 0.04), whereas poor/intermediate metabolizers more often stopped due to toxicity (sHR = 0.4; p = 0.03). A nonlinear effect of adjusted activity score on discontinuation for lack of efficacy (p < 0.001) and for toxicity (p < 0.001) was identified. When CYP2D6 genotype was available before prescribing in intermediate/poor metabolizers, lower median initial doses were used (0.5 vs 0.8 mg/kg/day).

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

This study strengthens the clinical actionability of CYP2D6 for atomoxetine, already covered by a CPIC recommendation, by linking phenotype to discontinuation reason in a pediatric population. The phenoconversion adjustment is methodologically exemplary and reminds us that genotype alone is insufficient without accounting for drug interactions. The retrospective design and limited sample warrant caution, but preemptive genotype use already translates into adapted starting doses.

Analysis by Dr Thibaut Benquey