Effects of paroxetine on the pharmacokinetics of atomoxetine and its metabolites in different CYP2D6 genotypes

Jung, Eui Hyun; Lee, Yun Jeong; Kim, Dong‐Hyun; Kang, Pureum; Lim, Chang Woo; Cho, Chang‐Keun; Jang, Choon‐Gon; Lee, Seok‐Yong; Bae, Jung‐Woo

doi:10.1007/s12272-020-01300-8

Cited by 16 publications

(3 citation statements)

References 34 publications

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“…In addition, our study subjects also did not involve the combined use of traditional Chinese herbs, so there was no need to concern potential herb-drug interactions either. Impressively, Belle et al found that inhibition of CYP2D6 by paroxetine markedly affected the atomoxetine disposition in healthy adults, resulting in pharmacokinetics similar to PMs of CYP2D6 substrates [ 43 ], which was line with a very recent study reported by Jung et al [ 44 ]. Therefore, the possibility of changes in systemic exposure to atomoxetine should be given adequate attention when co-administered with other medications, particularly CYP2D6 inhibitors, due to comorbidity treatment.…”

Section: Discussionsupporting

confidence: 74%

Individualized atomoxetine response and tolerability in children with ADHD receiving different dosage regimens: the need for CYP2D6 genotyping and therapeutic drug monitoring to dance together

Guo,

Wu,

et al. 2024

Transl Psychiatry

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Integrating CYP2D6 genotyping and therapeutic drug monitoring (TDM) is crucial for guiding individualized atomoxetine therapy in children with attention-deficit/hyperactivity disorder (ADHD). The aim of this retrospective study was (1) to investigate the link between the efficacy and tolerability of atomoxetine in children with ADHD and plasma atomoxetine concentrations based on their CYP2D6 genotypes; (2) to offer TDM reference range recommendations for atomoxetine based on the CYP2D6 genotypes of children receiving different dosage regimens. This retrospective study covered children and adolescents with ADHD between the ages of 6 and <18, who visited the psychological and behavioral clinic of Children’s Hospital of Nanjing Medical University from June 1, 2021, to January 31, 2023. The demographic information and laboratory examination data, including CYP2D6 genotype tests and routine TDM of atomoxetine were obtained from the hospital information system. We used univariate analysis, Mann-Whitney U nonparametric test, Kruskal-Wallis test, and the receiver operating characteristic (ROC) curve to investigate outcomes of interest. 515 plasma atomoxetine concentrations of 385 children (325 boys and 60 girls) with ADHD between 6 and 16 years of age were included for statistical analysis in this study. Based on genotyping results, >60% of enrolled children belonged to the CYP2D6 extensive metabolizer (EM), while <40% fell into the intermediate metabolizer (IM). CYP2D6 IMs exhibited higher dose-corrected plasma atomoxetine concentrations by 1.4-2.2 folds than those CYP2D6 EMs. Moreover, CYP2D6 IMs exhibited a higher response rate compare to EMs (93.55% vs 85.71%, P = 0.0132), with higher peak plasma atomoxetine concentrations by 1.67 times than those of EMs. Further ROC analysis revealed that individuals under once daily in the morning (q.m.) dosing regimen exhibited a more effective response to atomoxetine when their levels were ≥ 268 ng/mL (AUC = 0.710, P < 0.001). In addition, CYP2D6 IMs receiving q.m. dosing of atomoxetine were more likely to experience adverse reactions in the central nervous system and gastrointestinal system when plasma atomoxetine concentrations reach 465 and 509 ng/mL, respectively. The findings in this study provided promising treatment strategy for Chinese children with ADHD based on their CYP2D6 genotypes and plasma atomoxetine concentration monitoring. A peak plasma atomoxetine concentration higher than 268 ng/mL might be requisite for q.m. dosing. Assuredly, to validate and reinforce these initial findings, it is necessary to collect further data in controlled studies with a larger sample size.

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Section: Discussionsupporting

confidence: 74%

Individualized atomoxetine response and tolerability in children with ADHD receiving different dosage regimens: the need for CYP2D6 genotyping and therapeutic drug monitoring to dance together

Guo,

Wu,

et al. 2024

Transl Psychiatry

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“…We have gained a better understanding of the pharmacokinetic profile of atomoxetine. This review summarizes some factors affecting peak concentrations of atomoxetine, including food, CYP2D6 phenotypes, and drug-drug interactions (Brown, Abdel-Rahman, van Haandel, Gaedigk, Lin & Leeder, 2016;Brown et al, 2019b;Jung et al, 2020;Sauer, Ring & Witcher, 2005;Yu, Li & Markowitz, 2016). Food fails to affect the absolute bioavailability of atomoxetine, but reduces its rate of absorption.…”

Section: Conclusion and Future Perspectivementioning

confidence: 99%

“…It is worth noting that atomoxetine is mainly metabolized by CYP2D6, and its genetic polymorphism has effects on the efficacy and safety by affecting its metabolic process (Brown, Abdel-Rahman, van Haandel, Gaedigk, Lin & Leeder, 2016;Brown et al, 2019b). Meanwhile, the metabolic phenotype of CYP2D6 also affectsT max and half-life (t 1/2 ) of atomoxetine therapy (Brown, Abdel-Rahman, van Haandel, Gaedigk, Lin & Leeder, 2016;Jung et al, 2020). Additionally, physiologically-based pharmacokinetic (PBPK) and population pharmacokinetics (PPK) models will also serve as valuable tools for predicting atomoxetine exposure and determining optimal atomoxetine doses for future clinical trials and in clinical practice.…”

Section: Introductionmentioning

confidence: 99%

Personalizing Atomoxetine Dosing in Children with ADHD: What Can We Learn from Current Supporting Evidence

Guo

et al. 2022

Preprint

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Atomoxetine is the first non-stimulant medication approved by the US Food and Drug Administration for the treatment of attention deficit/hyperactivity disorder (ADHD). It can significantly improve ADHD symptoms, with good efficacy and tolerability. However, its efficacy was not consistent among all patients, especially for pediatric population. Due to marked heterogeneity in treatment response, a precision therapy should be developed and evaluated to guide treatment planning at the individual level. We have gained a better understanding of the pharmacokinetic profile. This review summarized some factors affecting peak concentrations of atomoxetine, including food, CYP2D6 and CYP2C19 phenotypes, and drug-drug interactions. The association between response and genetic polymorphisms of genes encoding the pharmacological targets such as norepinephrine transporter (NET/SLC6A2) and dopamine β hydroxylase (DBH) was also discussed. Based on the well-developed and validated assays for monitoring plasma concentrations of atomoxetine, the therapeutic reference range in pediatric patients with ADHD proposed by several studies was summarized. However, supporting evidence on the relationship between systemic atomoxetine exposure levels and clinical response is far from sufficient. We have to create evidence to characterize clearly the dose-exposure relationship, to establish clinically relevant metric for systemic exposure, to define a therapeutic exposure range, and to provide a dose-adaptation strategy before implementing personalized dosing for atomoxetine in children with ADHD. Personalizing atomoxetine dosage may be even more complex than we anticipated, but we can be optimistic about the future based on the remarkable advances in understanding the nature and causes of ADHD, as well as environmental stressors.

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Personalizing atomoxetine dosing in children with ADHD: what can we learn from current supporting evidence

Guo

et al. 2023

Eur J Clin Pharmacol

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Effects of paroxetine on the pharmacokinetics of atomoxetine and its metabolites in different CYP2D6 genotypes

Cited by 16 publications

References 34 publications

Individualized atomoxetine response and tolerability in children with ADHD receiving different dosage regimens: the need for CYP2D6 genotyping and therapeutic drug monitoring to dance together

Individualized atomoxetine response and tolerability in children with ADHD receiving different dosage regimens: the need for CYP2D6 genotyping and therapeutic drug monitoring to dance together

Personalizing Atomoxetine Dosing in Children with ADHD: What Can We Learn from Current Supporting Evidence

Personalizing atomoxetine dosing in children with ADHD: what can we learn from current supporting evidence

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