CYP2D6 predicted metabolizer status and safety in adult patients with attention-deficit hyperactivity disorder participating in a large placebo-controlled atomoxetine maintenance of response clinical trial.
Atomoxetine, which is indicated for treatment of attention-deficit hyperactivity disorder (ADHD), is predominantly metabolized by genetically polymorphic cytochrome P450 2D6 (CYP2D6). Based on identified CYP2D6 genotypes, individuals can be categorized into 4 phenotypic metabolizer groups as ultrarapid, extensive, intermediate, and poor. Previous studies have focused on observed differences between poor and extensive metabolizers, but it is not well understood whether the safety profile of intermediate metabolizers differs from that of ultrarapid and extensive metabolizers. This study compared safety and tolerability among the different CYP2D6 metabolizer groups in the 12-week open-label phase of an atomoxetine study in adult patients with ADHD. Genotyping identified 1039 patients as extensive/ultrarapid metabolizers, 780 patients as intermediate metabolizers, and 117 patients as poor metabolizers. Common (≥5% frequency) treatment-emergent adverse events did not significantly differ between extensive/ultrarapid and intermediate metabolizers (odds ratios were <2.0 or >0.5). Poor metabolizers had higher frequencies of dry mouth, erectile dysfunction, hyperhidrosis, insomnia, and urinary retention compared with the other metabolizer groups. There were no significant differences between extensive/ultrarapid and intermediate metabolizers in changes from baseline in vital signs. These results suggest that data from CYP2D6 intermediate and extensive/ultrarapid metabolizers can be combined when considering safety analyses related to atomoxetine.
Eli Lilly and Company, Indianapolis, IN, USA.
Bonnie A
BA
Fijal
Eli Lilly and Company, Indianapolis, IN, USA.
Yingying
Y
Guo
BioStatSolutions, Inc., Frederick, MD, USA.
Si G
SG
Li
Eli Lilly and Company, Indianapolis, IN, USA.
Jonna
J
Ahl
Eli Lilly Japan KK, Kobe, Japan.
Taro
T
Goto
Eli Lilly and Company, Indianapolis, IN, USA.
Yoko
Y
Tanaka
Eli Lilly and Company, Indianapolis, IN, USA.
Laura K
LK
Nisenbaum
Eli Lilly and Company, Indianapolis, IN, USA.
Himanshu P
HP
Upadhyaya
D018759:Adrenergic Uptake Inhibitors / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use; D000328:Adult; D000069445:Atomoxetine Hydrochloride / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use; D001289:Attention Deficit Disorder with Hyperactivity / Q000188:drug therapy* / Q000235:genetics; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D010641:Phenotype; D055815:Young Adult
D018759:Adrenergic Uptake Inhibitors; D000069445:Atomoxetine Hydrochloride; D019389:Cytochrome P-450 CYP2D6
ADHD; CYP2D6 metabolizer; atomoxetine