Atomoxetine pharmacokinetics in healthy Chinese subjects and effect of the CYP2D6*10 allele

Abstract

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.

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

“…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.…”

“…The oral clearance of the homozygous CYP2D6*10 Japanese subjects were significantly lower than those of the CYP2D6*1/*1, *1/*2, *1/*10 and *2/*10 subjects, and were clearly distinguished from PMs, with the most profound effects noted on clearance in homozygous CYP2D6*10 subjects relative to CYP2D6*1/ *1 and *1/*2 genotypes (Matsui et al 2012). In Chinese subjects, homozygous CYP2D6*10 subjects had, on average, a two-fold higher systemic exposure than the heterozygous CYP2D6*10 and the homozygous CYP2D6*1 subjects (Table 3), as a result of 50% reduction in oral clearance (Cui et al 2007). Likewise, systemic atomoxetine exposure in Korean CYP2D6*10/*10 individuals was approximately threefold greater than that observed in Korean CYP2D6*wt/*wt (*wt = *1 or *2) and *wt/*10 subjects (Byeon et al 2015).…”

“…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).…”

Effect of 24 Cytochrome P450 2D6 Variants Found in the Chinese Population on Atomoxetine Metabolism in vitro

“…Atomoxetine [7], a highly selective noradrenergic reuptake inhibitor with little affinity for other neurotransmitter systems, is widely used as a drug to treat attention deficit hyperactivity disorder (ADHD) [8] in children, adolescents and adults, which was proved in the United States in 2002. Studies have shown that the prevalence of ADHD was 4.31-5.83% in our country.…”

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.…”