Pharmacokinetics, safety, and tolerability of atomoxetine and effect of CYP2D6*10/*10 genotype in healthy Japanese men

J Clin Pharmacol. 2012 Mar;52(3):388-403. doi: 10.1177/0091270011398657. Epub 2011 May 4.

Abstract

Atomoxetine is a cytochrome P4502D6 (CYP2D6) substrate. The reduced-activity CYP2D6*10 allele is particularly prevalent in the Japanese population and may contribute to known ethnic differences in CYP2D6 metabolic capacity. The purpose of this study was to examine atomoxetine pharmacokinetics, safety, tolerability, and the effect of the CYP2D6*10/*10 genotype after single-stepped dosing (10, 40, 90, or 120 mg) and at steady state (40 or 60 mg twice a day for 7 days) in 49 healthy Japanese adult men. Dose proportionality was shown and tolerability confirmed at all doses studied. Comparison of pharmacokinetics, safety, and tolerability between Japanese and US subjects showed no clinically meaningful ethnic differences. The CYP2D6*10/*10 subjects had 2.1- to 2.2-fold and 1.8-fold higher area under the plasma concentration-time curve values relative to the CYP2D6*1/*1 and *1/*2 subjects and the CYP2D6*1/*10 and *2/*10 subjects, respectively. The adverse events reported by CYP2D6*10/*10 subjects were indistinguishable from those of other Japanese participants. The higher mean exposure in CYP2D6*10/*10 subjects is not expected to be clinically significant.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic Uptake Inhibitors / adverse effects
  • Adrenergic Uptake Inhibitors / pharmacokinetics
  • Adult
  • Area Under Curve
  • Asian Continental Ancestry Group / genetics*
  • Atomoxetine Hydrochloride
  • Cytochrome P-450 CYP2D6 / genetics*
  • Cytochrome P-450 CYP2D6 / metabolism*
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Gene Expression Regulation, Enzymologic
  • Genotype
  • Half-Life
  • Humans
  • Male
  • Propylamines / adverse effects*
  • Propylamines / pharmacokinetics*
  • Young Adult

Substances

  • Adrenergic Uptake Inhibitors
  • Propylamines
  • Atomoxetine Hydrochloride
  • Cytochrome P-450 CYP2D6