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

    Di Fu,Hong-Li Guo,Ya-Hui Hu,Wei-Rong Fang,Qian-Qi Liu,Jing Xu,Dan-Dan Wu,Feng Chen

    European Journal of Clinical Pharmacology（2023）SCI 3区

    Children’s Hospital of Nanjing Medical University

    Cited 3|Views5
    Abstract
    There is marked heterogeneity in treatment response of atomoxetine in patients with attention deficit/hyperactivity disorder (ADHD), especially for the pediatric population. This review aims to evaluate current evidence to characterize the dose-exposure relationship, establish clinically relevant metrics for systemic exposure to atomoxetine, define a therapeutic exposure range, and to provide a dose-adaptation strategy before implementing personalized dosing for atomoxetine in children with ADHD. A comprehensive search was performed across electronic databases (PubMed and Embase) covering the period of January 1, 1985 to July 10, 2022, to summarize recent advances in the pharmacokinetics, pharmacogenomics/pharmacogenetics (PGx), therapeutic drug monitoring (TDM), physiologically based pharmacokinetics (PBPK), and population pharmacokinetics (PPK) of atomoxetine in children with ADHD. Some factors affecting the pharmacokinetics of atomoxetine were summarized, including food, CYP2D6 and CYP2C19 phenotypes, and drug‒drug interactions (DDIs). The association between treatment response and genetic polymorphisms of genes encoding pharmacological targets, such as norepinephrine transporter (NET/SLC6A2) and dopamine β hydroxylase (DBH), was also discussed. Based on 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 was far from sufficient. Personalizing atomoxetine dosage may be even more complex than anticipated thus far, but elucidating the best way to tailor the non-stimulant to a patient’s individual need will be achieved by combining two strategies: detailed research in linking the pharmacokinetics and pharmacodynamics in pediatric patients, and better understanding in nature and causes of ADHD, as well as environmental stressors.
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    Key words
    ADHD,Atomoxetine,Children,CYP2D6,Pharmacogenetics,Therapeutic drug monitoring
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    【要点】：该论文旨在评估现有证据，以个性化儿童ADHD患者 atomoxetine 的用药剂量，探讨剂量-暴露关系，并提出剂量调整策略。
    

    【方法】：通过综合电子数据库（PubMed和Embase）检索，总结atomoxetine在儿童ADHD患者中的药代动力学、药物基因组学/药物遗传学、治疗药物监测、生理基础药代动力学和群体药代动力学等方面的最新进展。
    

    【实验】：研究未具体描述实验过程，但梳理了影响atomoxetine药代动力学的因素，包括食物、CYP2D6和CYP2C19表型以及药物相互作用，并讨论了治疗反应与基因多态性的关联。基于多项研究，提出了儿童ADHD患者的atomoxetine治疗参考范围，但关于系统暴露水平与临床反应关系的数据仍不足。研究指出，个性化剂量调整需要结合儿童药代动力学和药效学的研究以及更好地理解ADHD的本质和原因。