Pharmacokinetics, Safety, and Tolerability of Atomoxetine and Effect of CYP2D6*10/*10 Genotype in Healthy Japanese Men

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.

Atomoxetine: A Review of Its Pharmacokinetics and Pharmacogenomics Relative to Drug Disposition

“…Belle et al 2002;Sauer et al 2003;Sauer et al 2004;Cui et al 2007;and Matsui et al 2012. b Data are expressed as mean (% coefficient of variance), unless noted. EM subjects (Matsui et al 2012). Based on the results of a power model analysis, similar dose proportionality relationships of atomoxetine AUC and C max over a dose range of 10-120 mg were observed in both populations (Matsui et al 2012).…”

“…Based on the results of a power model analysis, similar dose proportionality relationships of atomoxetine AUC and C max over a dose range of 10-120 mg were observed in both populations (Matsui et al 2012). Additionally, no significant differences in atomoxetine exposures were documented in Japanese and United States EM subjects (Matsui et al 2012).…”

“…Tables 1 and 2 are compilations of single-and multiple-dose pharmacokinetic parameters of atomoxetine in healthy adults displaying different polymorphisms of CYP2D6 and/or CYP2C19 across various races/ethnicities, which were gleaned from the available published literature. As shown in Table 1, the area under the plasma concentration-time curve (AUC) extrapolated to infinity (AUC inf ) and maximum plasma concentration (C max ) generally increased proportionally to dose in both Japanese and United States References: Chalon et al 2003;Cui et al 2007;Matsui et al 2012;Shang et al 2013;and Choi et al 2014. b Data are expressed as mean (% coefficient of variance), unless noted. Belle et al 2002;Sauer et al 2003;Sauer et al 2004;Cui et al 2007;and Matsui et al 2012. b Data are expressed as mean (% coefficient of variance), unless noted.…”

“…However, neither the predictive methods nor the actual input data used to generate these predictions were provided in that report (Trzepacz et al 2008). Several studies have directly compared the total and peak atomoxetine exposures in homozygous CYP2D6*10 subjects with other CYP2D6 EM subjects (Cui et al 2007;Matsui et al 2012;Byeon et al 2015). As presented within Table 3, an approximately two-fold higher AUC was observed in the homozygous CYP2D6*10 Japanese subjects than in the CYP2D6*1/*1, *1/*2, *1/*10 and *2/*10 subjects (Matsui et al 2012).…”

Characterization of Atomoxetine Biotransformation and Implications for Development of PBPK Models for Dose Individualization in Children

“…Although a predominant role for CYP2D6 in the disposition of ATX has been documented by several studies both in vitro (Ring et al, 2002) and in vivo Cui et al, 2007;Matsui et al, 2012;Brown et al, 2015), other factors also contribute to variability in the dose-exposure relationship, because two-to fivefold variability in apparent oral clearance can be observed within a CYP2D6 genotypepredicted phenotype group in vivo (Matsui et al, 2012;Brown et al, 2015). The objectives of this investigation were threefold: 1) investigate the sources of variability in ATX biotransformation within a CYP2D6 genotype/activity score group; 2) identify other CYP isoforms contributing to ATX biotransformation, particularly in the scenario of lower CYP2D6 activity; and 3) characterize the relative contribution of all pathways of ATX metabolism in a pediatric context, where the influences of CYP genotype, maturation, and development may be evaluated.…”