Simple pharmacokinetic models accounting for drug monitoring results of atomoxetine and its 4-hydroxylated metabolites in Japanese pediatric patients genotyped for cytochrome P450 2D6

• Published in: Drug metabolism and pharmacokinetics Vol. 35; no. 2; pp. 191 - 200
• Main Authors: Notsu, Yuki, Shimizu, Makiko, Sasaki, Tatsuro, Nakano, Ayane, Ota, Miki, Yoshida, Sayaka, Yamazaki, Hiroshi
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.04.2020
• Subjects: Adolescent; Asian Continental Ancestry Group; Atomoxetine Hydrochloride - blood; Atomoxetine Hydrochloride - pharmacokinetics; Attention Deficit Disorder with Hyperactivity - diagnosis; Attention Deficit Disorder with Hyperactivity - drug therapy; Attention Deficit Disorder with Hyperactivity - metabolism; Child; Compartment model; CYP2D6; Cytochrome P-450 CYP2D6 - genetics; Cytochrome P-450 CYP2D6 - metabolism; Drug Monitoring; Female; Genotype; Humans; Male; Models, Biological; PBPK model; Pharmacokinetics; Phenols - blood; Phenols - pharmacokinetics; Propylamines - blood; Propylamines - pharmacokinetics; Compartment model; Genotype; Pharmacokinetics; CYP2D6; PBPK model
• ISSN: 1347-4367; 1880-0920; 1880-0920
• DOI: 10.1016/j.dmpk.2019.08.005

Atomoxetine is an approved medicine for attention-deficit/hyperactivity disorder and a cytochrome P450 2D6 (CYP2D6) probe substrate. Simple physiologically based pharmacokinetic (PBPK) models and compartment models were set up to account for drug monitoring results of 33 Japanese patients (6–15 years of age) to help establish the correct dosage for the evaluation of clinical outcomes. The steady-state one-point drug monitoring data for the most participants indicated the extensive biotransformation of atomoxetine to 4-hydroxyatomoxetine under individually prescribed doses of atomoxetine. However, 5 participants (with impaired CYP2D6 activity scores based on the CYP2D6 genotypes) showed high plasma concentrations of atomoxetine (0.53–1.5 μM) compared with those of total 4-hydroxyatomoxetine (0.49–1.4 μM). Results from full PBPK models using the in-built Japanese pediatric system of software Simcyp, one-compartment models, and new simple PBPK models (using parameters that reflected the subjects' small body size and normal/reduced CYP2D6-dependent clearance) could overlay one-point measured drug/metabolite plasma concentrations from almost common 28 participants within threefold ranges. Validated one-compartment or simple PBPK models can be used to predict steady-state plasma concentrations of atomoxetine and/or its primary metabolites in Japanese pediatric patients (>6 years) who took a variety of individualized doses in a clinical setting. [Display omitted]