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

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European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

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.

Methods

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.

Results

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.

Conclusion

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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Abbreviations

ADHD:

Attention deficit/hyperactivity disorder

AGNP:

Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie

AS:

Activity score

AUC:

Area under the time curve

CD:

Conduct disorder

CL/F:

Apparent oral clearance

C max :

Peak concentration

CPIC:

Clinical Pharmacogenetic Implementation Consortium

CYP2D6:

Cytochrome P450 2D6

DA:

Dopamine

DBH:

Dopamine β hydroxylase

DDIs:

Drug–drug interactions

DPWG:

Dutch Pharmacogenetics Working Group

EM:

Extensive metabolizer

EMs:

Extensive metabolizers

HLMs:

Human liver microsomes

IM:

Intermediate metabolizer

LD:

Linkage imbalance

NAD:

Naive average data approach

NDA:

N‐desmethylatomoxetine

NE:

Norepinephrine

N-desmethyl-4-OH-atomoxetine:

N-desmethyl-4-hydroxyatomoxetine

NET:

Norepinephrine transporter

NET/SLC6A2:

Norepinephrine transporter

NONMEM:

Nonlinear mixed-effects modeling approach

NPD:

Naive pooled data analysis

ODD:

Oppositional defiant disorder

PBPK:

Physiologically based pharmacokinetics

PFC:

Prefrontal cortex

PGx:

Pharmacogenomics

PM:

Poor metabolizers

PMs:

Poor metabolizers

PPK:

Population pharmacokinetics

TDM:

Therapeutic drug monitoring

T max :

Time to maximum plasma concentration

t 1/2 :

Half-life

UM:

Ultrarapid metabolizer

2-CH2OH-atomoxetine:

2‐Hydroxymethylatomoxetine

4-OH-atomoxetine:

4-Hydroxyatomoxetine

4-OH-atomoxetine-O-glucuronide:

4-Hydroxyatomoxetine-O-glucuronide

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Acknowledgements

This research was supported by the Specially Appointed Medical Expert Project of the Jiangsu Commission of Health (2019), the Talent Project established by the Chinese Pharmaceutical Association Hospital Pharmacy department (NO. CPA-Z05-ZC-2022-003), a grant from Jiangsu Research Hospital Association for Precision Medication (JY2022).

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Authors and Affiliations

  1. Pharmaceutical Sciences Research Center, Department of Pharmacy, Children’s Hospital of Nanjing Medical University, Nanjing, China

    Di Fu, Hong-Li Guo, Ya-Hui Hu, Jing Xu & Feng Chen

  2. School of Basic Medical Sciences and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China

    Di Fu & Wei-Rong Fang

  3. Department of Children Health Care, Children’s Hospital of Nanjing Medical University, 72 Guangzhou Road, Nanjing, 210008, China

    Qian-Qi Liu & Dan-Dan Wu

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Contributions

Conceptualization, J.X., D.D.W., and F.C.; writing—original draft preparation, D.F.; writing—review and editing, D.F., F.C., H.-L.G., Y.-H.H., W.-R.F., and Q.-Q.L.; critical revision of the manuscript, F.C; funding acquisition, F.C. All authors have read and agreed to the submitted version of the manuscript.

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Fu, D., Guo, HL., Hu, YH. et al. Personalizing atomoxetine dosing in children with ADHD: what can we learn from current supporting evidence. Eur J Clin Pharmacol 79, 349–370 (2023). https://doi.org/10.1007/s00228-022-03449-1

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