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
Pharmaceutical Sciences Research Center, Department of Pharmacy, Children's Hospital of Nanjing Medical University, Nanjing 210008, China
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.
FU Di,GUO Hong-Li,HU Ya-Hui et al. A precision medication study of atomoxetine in children with attention deficit hyperactivity disorder: CYP2D6 genetic testing and therapeutic drug monitoring[J]. CJCP, 2023, 25(1): 98-103.
FU Di,GUO Hong-Li,HU Ya-Hui et al. A precision medication study of atomoxetine in children with attention deficit hyperactivity disorder: CYP2D6 genetic testing and therapeutic drug monitoring[J]. CJCP, 2023, 25(1): 98-103.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.