A precision medication study of atomoxetine in children with attention deficit hyperactivity disorder: CYP2D6 genetic testing and therapeutic drug monitoring

FU Di; GUO Hong-Li; HU Ya-Hui; CHEN Feng

doi:10.7499/j.issn.1008-8830.2208092

PDF(666 KB)

Chinese Journal of Contemporary Pediatrics ›› 2023, Vol. 25 ›› Issue (1) : 98-103. DOI: 10.7499/j.issn.1008-8830.2208092

REVIEW

A precision medication study of atomoxetine in children with attention deficit hyperactivity disorder: CYP2D6 genetic testing and therapeutic drug monitoring

FU Di, GUO Hong-Li, HU Ya-Hui, CHEN Feng

Author information +

History +

Abstract

Atomoxetine is the first non-stimulant drug for the treatment of children and adults with attention deficit hyperactivity disorder (ADHD), and its safety and efficacy show significant differences in the pediatric population. This article reviews the genetic factors influencing the pharmacokinetic differences of atomoxetine from the aspect of the gene polymorphisms of the major metabolizing enzyme CYP2D6 of atomoxetine, and then from the perspective of therapeutic drug monitoring, this article summarizes the reference ranges of the effective concentration of atomoxetine in children with ADHD proposed by several studies. In general, there is an association between the peak plasma concentration of atomoxetine and clinical efficacy, but with a lack of data from the Chinese pediatric population. Therefore, it is necessary to establish related clinical indicators for atomoxetine exposure, define the therapeutic exposure range of children with ADHD in China, and combine CYP2D6 genotyping to provide support for the precision medication of atomoxetine.

Key words

Attention deficit hyperactivity disorder / Atomoxetine / CYP2D6 / Precision medication / Child

Cite this article

EndNote

Ris (Procite)

Bibtex

Download Citations

FU Di, GUO Hong-Li, HU Ya-Hui, CHEN Feng. A precision medication study of atomoxetine in children with attention deficit hyperactivity disorder: CYP2D6 genetic testing and therapeutic drug monitoring[J]. Chinese Journal of Contemporary Pediatrics. 2023, 25(1): 98-103 https://doi.org/10.7499/j.issn.1008-8830.2208092

References

1 Fu D, Wu DD, Guo HL, et al. The mechanism, clinical efficacy, safety, and dosage regimen of atomoxetine for ADHD therapy in children: a narrative review[J]. Front Psychiatry, 2022, 12: 780921. PMID: 35222104. PMCID: PMC8863678. DOI: 10.3389/fpsyt.2021.780921.
2 Cutler AJ, Mattingly GW, Jain R, et al. Current and future nonstimulants in the treatment of pediatric ADHD: monoamine reuptake inhibitors, receptor modulators, and multimodal agents[J]. CNS Spectr, 2022, 27(2): 199-207. PMID: 33121553. DOI: 10.1017/S1092852920001984.
3 Cortese S, Adamo N, Del Giovane C, et al. Comparative efficacy and tolerability of medications for attention-deficit hyperactivity disorder in children, adolescents, and adults: a systematic review and network meta-analysis[J]. Lancet Psychiatry, 2018, 5(9): 727-738. PMID: 30097390. PMCID: PMC6109107. DOI: 10.1016/S2215-0366(18)30269-4.
4 刘靖, 郑毅. 《中国注意缺陷多动障碍防治指南》第二版解读[J]. 中华精神科杂志, 2016, 49(3): 132-135. DOI: 10.3760/cma.j.issn.1006-7884.2016.03.002.
5 中华医学会儿科学分会发育行为学组. 注意缺陷多动障碍早期识别、规范诊断和治疗的儿科专家共识[J]. 中华儿科杂志, 2020, 58(3): 188-193. PMID: 32135589. DOI: 10.3760/cma.j.issn.0578-1310.2020.03.006.
6 Newcorn JH, Sutton VK, Weiss MD, et al. Clinical responses to atomoxetine in attention-deficit/hyperactivity disorder: the integrated data exploratory analysis (IDEA) study[J]. J Am Acad Child Adolesc Psychiatry, 2009, 48(5): 511-518. PMID: 19318988. DOI: 10.1097/CHI.0b013e31819c55b2.
7 Brown JT, Bishop JR, Sangkuhl K, et al. Clinical pharmacogenetics implementation consortium guideline for cytochrome P450 (CYP)2D6 genotype and atomoxetine therapy[J]. Clin Pharmacol Ther, 2019, 106(1): 94-102. PMID: 30801677. PMCID: PMC6612570. DOI: 10.1002/cpt.1409.
8 Ruppert K, Geffert C, Clement HW, et al. Therapeutic drug monitoring of atomoxetine in children and adolescents with attention-deficit/ hyperactivity disorder: a naturalistic study[J]. J Neural Transm (Vienna), 2022, 129(7): 945-959. PMID: 35391568. PMCID: PMC9217867. DOI: 10.1007/s00702-022-02483-8.
9 Hiemke C, Bergemann N, Clement HW, et al. Consensus guidelines for therapeutic drug monitoring in neuropsychopharmacology: update 2017[J]. Pharmacopsychiatry, 2018, 51(1-02): 9-62. PMID: 28910830. DOI: 10.1055/s-0043-116492.
10 Sauer JM, Ring BJ, Witcher JW. Clinical pharmacokinetics of atomoxetine[J]. Clin Pharmacokinet, 2005, 44(6): 571-590. PMID: 15910008. DOI: 10.2165/00003088-200544060-00002.
11 Yu G, Li GF, Markowitz JS. Atomoxetine: a review of its pharmacokinetics and pharmacogenomics relative to drug disposition[J]. J Child Adolesc Psychopharmacol, 2016, 26(4): 314-326. PMID: 26859445. PMCID: PMC4876529. DOI: 10.1089/cap.2015.0137.
12 Brown JT, Abdel-Rahman SM, van Haandel L, et al. Single dose, CYP2D6 genotype-stratified pharmacokinetic study of atomoxetine in children with ADHD[J]. Clin Pharmacol Ther, 2016, 99(6): 642-650. PMID: 26660002. PMCID: PMC4862932. DOI: 10.1002/cpt.319.
13 Protti M, Mandrioli R, Marasca C, et al. New-generation, non-SSRI antidepressants: drug-drug interactions and therapeutic drug monitoring. Part 2: NaSSAs, NRIs, SNDRIs, MASSAs, NDRIs, and others[J]. Med Res Rev, 2020, 40(5): 1794-1832. PMID: 32285503. DOI: 10.1002/med.21671.
14 Michelson D, Read HA, Ruff DD, et al. CYP2D6 and clinical response to atomoxetine in children and adolescents with ADHD[J]. J Am Acad Child Adolesc Psychiatry, 2007, 46(2): 242-251. PMID: 17242628. DOI: 10.1097/01.chi.0000246056.83791.b6.
15 Li Q, Wu YE, Wang K, et al. Developmental pharmacogenetics of CYP2D6 in Chinese children: loratadine as a substrate drug[J]. Front Pharmacol, 2021, 12: 657287. PMID: 34295246. PMCID: PMC8292113. DOI: 10.3389/fphar.2021.657287.
16 Alali M, Ismail Al-Khalil W, Rijjal S, et al. Frequencies of CYP2D6 genetic polymorphisms in Arab populations[J]. Hum Genomics, 2022, 16(1): 6. PMID: 35123571. PMCID: PMC8817534. DOI: 10.1186/s40246-022-00378-z.
17 Caudle KE, Sangkuhl K, Whirl-Carrillo M, et al. Standardizing CYP2D6 genotype to phenotype translation: consensus recommendations from the clinical pharmacogenetics implementation consortium and Dutch pharmacogenetics working group[J]. Clin Transl Sci, 2020, 13(1): 116-124. PMID: 31647186. PMCID: PMC6951851. DOI: 10.1111/cts.12692.
18 Zhou W, Jiang Y, Xu Y, et al. Comparison of adverse drug reactions between tamoxifen and toremifene in breast cancer patients with different CYP2D6 genotypes: a propensity-score matched cohort study[J]. Int J Cancer, 2022, 150(10): 1664-1676. PMID: 34957551. DOI: 10.1002/ijc.33919.
19 王玉文, 周国岭, 刘艳, 等. CYP2D6基因多态性与托莫西汀治疗ADHD疗效的关联性研究进展[J]. 中国现代医生, 2018, 56(20): 165-168.
20 Byeon JY, Kim YH, Lee CM, et al. CYP2D6 allele frequencies in Korean population, comparison with East Asian, Caucasian and African populations, and the comparison of metabolic activity of CYP2D6 genotypes[J]. Arch Pharm Res, 2018, 41(9): 921-930. PMID: 30191460. DOI: 10.1007/s12272-018-1075-6.
21 Gaedigk A, Simon SD, Pearce RE, et al. The CYP2D6 activity score: translating genotype information into a qualitative measure of phenotype[J]. Clin Pharmacol Ther, 2008, 83(2): 234-242. PMID: 17971818. DOI: 10.1038/sj.clpt.6100406.
22 Teh LK, Bertilsson L. Pharmacogenomics of CYP2D6: molecular genetics, interethnic differences and clinical importance[J]. Drug Metab Pharmacokinet, 2012, 27(1): 55-67. PMID: 22185816. DOI: 10.2133/dmpk.DMPK-11-RV-121.
23 Cui YM, Teng CH, Pan AX, et al. Atomoxetine pharmacokinetics in healthy Chinese subjects and effect of the CYP2D6*10 allele[J]. Br J Clin Pharmacol, 2007, 64(4): 445-449. PMID: 17610534. PMCID: PMC2048549. DOI: 10.1111/j.1365-2125.2007.02912.x.
24 Byeon JY, Kim YH, Na HS, et al. Effects of the CYP2D6*10 allele on the pharmacokinetics of atomoxetine and its metabolites[J]. Arch Pharm Res, 2015, 38(11): 2083-2091. PMID: 26254792. DOI: 10.1007/s12272-015-0646-z.
25 Kim SH, Byeon JY, Kim YH, et al. Physiologically based pharmacokinetic modelling of atomoxetine with regard to CYP2D6 genotypes[J]. Sci Rep, 2018, 8(1): 12405. PMID: 30120390. PMCID: PMC6098032. DOI: 10.1038/s41598-018-30841-8.
26 方妍彤, 陈敏, 吉宁, 等. CYP2D6基因多态与托莫西汀治疗儿童注意缺陷多动障碍反应的关联研究[J]. 中国心理卫生杂志, 2015, 29(6): 401-405. DOI: 10.3969/j.issn.1000-6729.2015.06.001.
27 Ramsey LB, Brown JT, Vear SI, et al. Gene-based dose optimization in children[J]. Annu Rev Pharmacol Toxicol, 2020, 60: 311-331. PMID: 31283429. DOI: 10.1146/annurev-pharmtox-010919-023459.
28 Xia Y, Guo HL, Hu YH, et al. Determination of atomoxetine levels in human plasma using LC-MS/MS and clinical application to Chinese children with ADHD based on CPIC guidelines[J]. Anal Methods, 2021, 13(21): 2434-2441. PMID: 33998618. DOI: 10.1039/d1ay00521a.
29 Sugimoto A, Suzuki Y, Orime N, et al. The lowest effective plasma concentration of atomoxetine in pediatric patients with attention deficit/hyperactivity disorder: a non-randomized prospective interventional study[J]. Medicine (Baltimore), 2021, 100(27): e26552. PMID: 34232195. PMCID: PMC8270591. DOI: 10.1097/MD.0000000000026552.
30 Shi C, Xiao Y, Mao Y, et al. Voriconazole: a review of population pharmacokinetic analyses[J]. Clin Pharmacokinet, 2019, 58(6): 687-703. PMID: 30687893. DOI: 10.1007/s40262-019-00735-7.
31 Jing Y, Kong Y, Hou X, et al. Population pharmacokinetic analysis and dosing guidelines for tacrolimus co-administration with Wuzhi capsule in Chinese renal transplant recipients[J]. J Clin Pharm Ther, 2021, 46(4): 1117-1128. PMID: 33768546. DOI: 10.1111/jcpt.13407.