Atomoxetine is a cytochrome P450 (P450) 2D6 probe substrate and an approved medicine for attention deficit/hyperactivity disorder. In this humanized liver mouse study, interactions between atomoxetine and the P450 2D6 probe drug paroxetine were observed. Human physiologically based pharmacokinetic (PBPK) models were established by scaling up humanized liver mouse data obtained in the absence or presence of paroxetine. These models could explain the drug monitoring results of atomoxetine and its primary 4-hydroxylated and N-demethylated metabolites in Japanese children aged 8–14 years and could be used to help establish the correct dosage and for the evaluation of clinical outcomes. The results of simple PBPK models (using input parameters that reflected the subjects’ small body size and normal or reduced P450 2D6–dependent clearance) were in general agreement with one-point measured plasma concentrations of atomoxetine and its 4-hydroxylated and N-demethylated metabolites in 13 pediatric participants. Unexpectedly high hepatic exposure, possibly in intermediate-metabolizer patients harboring CYP2D6*10 or 2D6*36 alleles, might in part explain the adverse effects of atomoxetine prescribed alone recorded in a Japanese adverse-event database. The steady-state, one-point drug monitoring data from the participants indicated extensive biotransformation of atomoxetine to 4-hydroxyatomoxetine under individually prescribed doses of atomoxetine. These results also suggest that a relatively narrow range of 4-hydroxyatomoxetine and N-desmethylatomoxetine concentration ratios in spot urine and/or plasma samples from pediatric patients could be a simple semiquantitative determinant factor for P450 2D6 intermediate metabolizers compared with the wide range of concentrations of the two primary metabolites and substrate in extensive metabolizers.

SIGNIFICANCE STATEMENT Validated simple pharmacokinetic models can predict steady-state plasma concentrations of the approved medicine atomoxetine and its primary metabolites in the majority of pediatric patients. The package insert advises careful dose escalation, especially for poor metabolizers; however, no simple way exists to determine cytochrome P450 (P450) 2D6 phenotypes. A relatively narrow range ratio of 4-hydroxyatomoxetine and N-desmethylatomoxetine in spot urine/plasma samples could be a simple semiquantitative determinant factor for P450 2D6 intermediate metabolizers to optimize or confirm the correct dosage.

This work was supported in part by the Japan Society for the Promotion of Science Grant-in-Aid for Scientific Research [Grant 23K06217] and the Japan Agency for Medical Research and Development (AMED) [Grant 23mk0101253h0102].

The authors declare that they have no conflicts of interest with the contents of this article.

dx.doi.org/10.1124/dmd.123.001481.