Atomoxetine pharmacokinetics in healthy Chinese subjects and effect of the CYP2D610 allele

• Published in: British journal of clinical pharmacology Vol. 64; no. 4; pp. 445 - 449
• Main Authors: Cui, Yi M., Teng, Choo H., Pan, Alan X., Yuen, Eunice, Yeo, Kwee P., Zhou, Ying, Zhao, Xia, Long, Amanda J., Bangs, Mark E., Wise, Stephen D.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.10.2007
• Subjects: Adrenergic Uptake Inhibitors - administration & dosage; Adrenergic Uptake Inhibitors - pharmacokinetics; Adult; Asian Continental Ancestry Group - genetics; atomoxetine; Atomoxetine Hydrochloride; China; Chinese; CYP2D6; CYP2D610; Cytochrome P-450 CYP2D6 - genetics; Cytochrome P-450 CYP2D6 - metabolism; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Male; Pharmacokinetics; Propylamines - administration & dosage; Propylamines - pharmacokinetics; China
• ISSN: 0306-5251; 1365-2125
• DOI: 10.1111/j.1365-2125.2007.02912.x

What is already known about this subject • Atomoxetine is a cytochrome P450 2D6 (CYP2D6) substrate and its pharmacokinetics has been characterized in a predominantly White population during clinical development. • There are scant East Asian pharmacokinetic data available. • The CYP2D6*10 allele is particularly prevalent in East Asian populations and may contribute to the known ethnic differences in CYP2D6 metabolic capacity. What this study adds • The pharmacokinetics of multiple‐dose 80 mg daily atomoxetine observed in Chinese healthy subjects appears comparable to previous data in other ethnic populations. • Homozygous CYP2D6*10 subjects appear to have higher exposures, but are not a clearly distinct group compared with other CYP2D6 extensive metabolizers. Aims To characterize atomoxetine pharmacokinetics, explore the effect of the homozygous CYP2D6*10 genotype on atomoxetine pharmacokinetics and evaluate the tolerability of atomoxetine, in healthy Chinese subjects. Methods Twenty‐four subjects, all CYP2D6 extensive metabolizers (EM), were randomized to receive atomoxetine (40 mg qd for 3 days, then 80 mg qd for 7 days) or matching placebo (2 : 1 ratio) in a double‐blind fashion. Atomoxetine serum concentrations were measured following single (40 mg) and multiple (80 mg) doses. Adverse events, clinical safety laboratory data and vital signs were assessed during the study. Results Atomoxetine was rapidly absorbed with median time to maximum serum concentrations of approximately 1.5 h after single and multiple doses. Atomoxetine concentrations appeared to decrease monoexponentially with a mean apparent terminal half‐life (t1/2) of approximately 4 h. The apparent clearance, apparent volume of distribution and t1/2 following single and multiple doses were similar, suggesting linear pharmacokinetics with respect to time. Homozygous CYP2D6*10 subjects had 50% lower clearances compared with other EM subjects, resulting in twofold higher mean exposures. No clinically significant changes or abnormalities were noted in laboratory data and vital signs. Conclusions The pharmacokinetics of atomoxetine in healthy Chinese subjects appears comparable to other ethnic populations. Multiple dosing of 80 mg qd atomoxetine was well tolerated in this study.