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Perspectives from the Society for Pediatric Research: pharmacogenetics for pediatricians

Pediatric Research volume 91, pages 529–538 (2022)Cite this article

Abstract

This review evaluates the pediatric evidence for pharmacogenetic associations for drugs that are commonly prescribed by or encountered by pediatric clinicians across multiple subspecialties, organized from most to least pediatric evidence. We begin with the pharmacogenetic research that led to the warning of increased risk of death in certain pediatric populations (“ultrarapid metabolizers”) who are prescribed codeine after tonsillectomy or adenoidectomy. We review the evidence for genetic testing for thiopurine metabolism, which has become routine in multiple pediatric subspecialties. We discuss the pharmacogenetic research in proton pump inhibitors, for which clinical guidelines have recently been made available. With an increase in the prevalence of behavioral health disorders including attention deficit hyperactivity disorder (ADHD), we review the pharmacogenetic literature on selective serotonin reuptake inhibitors, selective norepinephrine reuptake inhibitors, and ADHD medications. We will conclude this section on the current pharmacogenetic data on ondansetron. We also provide our perspective on how to integrate the current research on pharmacogenetics into clinical care and what further research is needed. We discuss how institutions are managing pharmacogenetic test results and implementing them clinically, and how the electronic health record can be leveraged to ensure testing results are available and taken into consideration when prescribing medications.

Impact

  • While many reviews of pharmacogenetics literature are available, there are few focused on pediatrics.

  • Pediatricians across subspecialties will become more comfortable with pharmacogenetics terminology, know resources they can use to help inform their prescribing habits for drugs with known pharmacogenetic associations, and understand the limitations of testing and where further research is needed.

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Fig. 1: The relationship between prodrugs, active drugs, inactivated drug metabolites, and metabolizer status.
Fig. 2: A timeline of pharmacogenetic testing to demonstrate preemptive vs. reactive testing.

References

  1. Genetics Home Reference. What is pharmacogenomics?. https://ghr.nlm.nih.gov/primer/genomicresearch/pharmacogenomics (2020).

  2. PharmGKB. Pharmogenomics Knowledge Base. www.pharmgkb.org (2020).

  3. Pirmohamed, M. Pharmacogenetics and pharmacogenomics. Br. J. Clin. Pharmacol. 52, 345–347 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Caudle, K. E. et al. Standardizing terms for clinical pharmacogenetic test results: consensus terms from the Clinical Pharmacogenetics Implementation Consortium (CPIC). Genet. Med. 19, 215–223 (2017).

    PubMed  Google Scholar 

  5. Clinical Pharmacogenetics Implementation Consortium (CPIC®). https://cpicpgx.org/ (2020).

  6. Robarge, J. D., Li, L., Desta, Z., Nguyen, A. & Flockhart, D. A. The Star-Allele Nomenclature: retooling for translational genomics. Clin. Pharmacol. Ther. 82, 244–248 (2007).

    CAS  PubMed  Google Scholar 

  7. PharmVar. Pharmacogene Variation Consortium. www.pharmvar.org (2020).

  8. Center for Devices, Radiological Health. Table of Pharmacogenetic Associations (US Food and Drug Administration, 2020).

  9. Center for Drug Evaluation, Research. Table of Pharmacogenomic Biomarkers (US Food and Drug Administration, 2020).

  10. Thorn, C. F., Klein, T. E. & Altman, R. B. Codeine and morphine pathway. Pharmacogenet. Genomics 19, 556–558 (2009).

    CAS  PubMed  Google Scholar 

  11. Dayer, P., Desmeules, J., Leemann, T. & Striberni, R. Bioactivation of the narcotic drug codeine in human liver is mediated by the polymorphic monooxygenase catalyzing debrisoquine 4-hydroxylation (cytochrome P-450 dbl/bufI). Biochem. Biophys. Res. Commun. 152, 411–416 (1988).

    CAS  PubMed  Google Scholar 

  12. Mortimer, Ö. et al. Polymorphic formation of morphine from codeine in poor and extensive metabolizers of dextromethorphan: Relationship to the presence of immunoidentified cytochrome P-450IID1. Clin. Pharmacol. Ther. 47, 27–35 (1990).

    CAS  PubMed  Google Scholar 

  13. Yu, A., Kneller, B. M., Rettie, A. E. & Haining, R. L. Expression, purification, biochemical characterization, and comparative function of human cytochrome P450 2D6.1, 2D6.2, 2D6.10, and 2D6.17 allelic isoforms. J. Pharmacol. Exp. Ther. 303, 1291–1300 (2002).

    CAS  PubMed  Google Scholar 

  14. Shen, H. et al. Comparative metabolic capabilities and inhibitory profiles of CYP2D6.1, CYP2D6.10, and CYP2D6.17. Drug Metab. Dispos. 35, 1292–1300 (2007).

    CAS  PubMed  Google Scholar 

  15. Zhang, W.-Y., Tu, Y.-B., Haining, R. L. & Yu, A.-M. Expression and functional analysis of CYP2D6.24, CYP2D6.26, CYP2D6.27, and CYP2D7 isozymes. Drug Metab. Dispos. 37, 1–4 (2009).

    PubMed  Google Scholar 

  16. Gaedigk, A., Sangkuhl, K., Whirl-Carrillo, M., Klein, T. & Leeder, J. S. Prediction of CYP2D6 phenotype from genotype across world populations. Genet. Med. 19, 69–76 (2017).

    PubMed  Google Scholar 

  17. Yue, Q. Y., Svensson, J. O., Alm, C., Sjoqvist, F. & Sawe, J. Codeine O-demethylation co-segregates with polymorphic debrisoquine hydroxylation [Internet]. Br. J. Clin. Pharmacol. 28, 639–645 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Sindrup, S. H. et al. Codeine increases pain thresholds to copper vapor laser stimuli in extensive but not poor metabolizers of sparteine. Clin. Pharmacol. Ther. 48, 686–693 (1990).

    CAS  PubMed  Google Scholar 

  19. Chen, Z. R., Somogyi, A. A., Reynolds, G. & Bochner, F. Disposition and metabolism of codeine after single and chronic doses in one poor and seven extensive metabolisers. Br. J. Clin. Pharmacol. 31, 381–390 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Desmeules, J., Gascon, M. P., Dayer, P. & Magistris, M. Impact of environmental and genetic factors on codeine analgesia. Eur. J. Clin. Pharmacol. 41, 23–26 (1991).

    CAS  PubMed  Google Scholar 

  21. Caraco, Y., Sheller, J. & Wood, A. J. Pharmacogenetic determination of the effects of codeine and prediction of drug interactions. J. Pharmacol. Exp. Ther. 278, 1165–1174 (1996).

    CAS  PubMed  Google Scholar 

  22. Poulsen, L. et al. Codeine and morphine in extensive and poor metabolizers of sparteine: pharmacokinetics, analgesic effect and side effects. Eur. J. Clin. Pharmacol. 51, 289–295 (1996).

    CAS  PubMed  Google Scholar 

  23. Hedenmalm, K., Sundgren, M., Granberg, K., Spigset, O. & Dahlqvist, R. Urinary excretion of codeine, ethylmorphine, and their metabolites: relation to the CYP2D6 activity. Ther. Drug Monit. 19, 643–649 (1997).

    CAS  PubMed  Google Scholar 

  24. Mikus, G. et al. Effect of codeine on gastrointestinal motility in relation to CYP2D6 phenotype*. Clin. Pharmacol. Ther. 61, 459–466 (1997).

    CAS  PubMed  Google Scholar 

  25. Poulsen, L., Riishede, L., Brøsen, K., Clemensen, S. & Sindrup, S. H. Codeine in post-operative pain. Study of the influence of sparteine phenotype and serum concentrations of morphine and morphine-6-glucuronide. Eur. J. Clin. Pharm. 54, 451–454 (1998).

    CAS  Google Scholar 

  26. Lötsch, J. et al. Evidence for morphine-independent central nervous opioid effects after administration of codeine: contribution of other codeine metabolites. Clin. Pharmacol. Ther. 79, 35–48 (2006).

    PubMed  Google Scholar 

  27. Tseng, C. Y., Wang, S. L., Lai, M. D., Lai, M. L. & Huang, J. D. Formation of morphine from codeine in Chinese subjects of different CYP2D6 genotypes. Clin. Pharmacol. Ther. 60, 177–182 (1996).

    CAS  PubMed  Google Scholar 

  28. Williams, D. G., Patel, A. & Howard, R. F. Pharmacogenetics of codeine metabolism in an urban population of children and its implications for analgesic reliability. Br. J. Anaesth. 89, 839–845 (2002).

    CAS  PubMed  Google Scholar 

  29. Madadi, P. et al. Safety of codeine during breastfeeding: fatal morphine poisoning in the breastfed neonate of a mother prescribed codeine. Can. Fam. Physician 53, 33–35 (2007).

    PubMed  PubMed Central  Google Scholar 

  30. Madadi, P. et al. Pharmacogenetics of neonatal opioid toxicity following maternal use of codeine during breastfeeding: a case-control study. Clin. Pharmacol. Ther. 85, 31–35 (2009).

    CAS  PubMed  Google Scholar 

  31. ANI Pharmaceuticals, Inc. & BayPharma, Inc. Promethazine HCL and Codeine Phosphate Oral Solution - promethazine hydrochloride and codeine phosphate solution Drug Label (ANI Pharmaceuticals, Inc. & BayPharm, Inc. 2008).

  32. Huddart, R. et al. Standardized biogeographic grouping system for annotating populations in pharmacogenetic research. Clin. Pharmacol. Ther. 105, 1256–1262 (2019).

    PubMed  Google Scholar 

  33. Ciszkowski, C., Madadi, P., Phillips, M. S., Lauwers, A. E. & Koren, G. Codeine, ultrarapid-metabolism genotype, and postoperative death. N. Engl. J. Med. 361, 827–828 (2009).

    CAS  PubMed  Google Scholar 

  34. Voronov, P., Przybylo, H. J. & Jagannathan, N. Apnea in a child after oral codeine: a genetic variant - an ultra-rapid metabolizer. Paediatr. Anaesth. 17, 684–687 (2007).

    PubMed  Google Scholar 

  35. Kelly, L. E. et al. More codeine fatalities after tonsillectomy in North American children. Pediatrics 129, e1343–e1347 (2012).

    PubMed  Google Scholar 

  36. Food and Drug Administration. Safety Review Update of Codeine Use in Children; New Boxed Warning and Contraindication on Use After Tonsillectomy and/or Adenoidectomy (US Food and Drug Administration, 2013).

  37. Crews, K. R. et al. Clinical Pharmacogenetics Implementation Consortium guidelines for cytochrome P450 2D6 genotype and codeine therapy: 2014 update. Clin. Pharmacol. Ther. 95, 376–382 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Chua, K.-P., Shrime, M. G. & Conti, R. M. Effect of FDA investigation on opioid prescribing to children after tonsillectomy/adenoidectomy. Pediatrics 140, https://doi.org/10.1542/peds.2017-1765 (2017).

  39. Townsend, J. A., Sebastião, Y. V. & Cooper, J. N. Effect of FDA warning on codeine and alternate opioid prescribing after pediatric dental procedures in Ohio. Pediatr. Dent. 41, 439–445 (2019).

    PubMed  PubMed Central  Google Scholar 

  40. Center for Drug Evaluation, Research. FDA Drug Safety Communication: FDA Restricts Use of Prescription Codeine Pain and Cough Medicines and Tramadol Pain Medicines in Children; Recommends Against Use in Breastfeeding Women (US Food and Drug Administration, 2019).

  41. Gammal, R. S. et al. The case for pharmacogenetics-guided prescribing of codeine in children. Clin. Pharmacol. Ther. 105, 1300–1302 (2019).

    PubMed  Google Scholar 

  42. Gammal, R. S. et al. Pharmacogenetics for safe codeine use in sickle cell disease. Pediatrics 138, https://doi.org/10.1542/peds.2015-3479 (2016).

  43. Lassen, D., Damkier, P. & Brøsen, K. The pharmacogenetics of Tramadol. Clin. Pharmacokinet. 54, 825–836 (2015).

    CAS  PubMed  Google Scholar 

  44. Crews, K. R. et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2D6, OPRM1, and COMT genotype and select opioid therapy. Clin. Pharmacol. Ther. https://doi.org/10.1002/cpt.2149 (2021).

    Article  PubMed  Google Scholar 

  45. Ashworth, L. A. et al. Lymphoma risk in children and young adults with inflammatory bowel disease: analysis of a large single-center cohort. Inflamm. Bowel Dis. 18, 838–843 (2012).

    PubMed  Google Scholar 

  46. Relling, M. V. et al. Clinical Pharmacogenetics Implementation Consortium guideline for thiopurine dosing based on TPMT and NUDT 15 genotypes: 2018 update. Clin. Pharmacol. Ther. 105, 1095–1105 (2019).

    CAS  PubMed  Google Scholar 

  47. Evans, W. E. Pharmacogenetics of thiopurine S-methyltransferase and thiopurine therapy. Ther. Drug Monit. 26, 186–191 (2004).

    CAS  PubMed  Google Scholar 

  48. Weinshilboum, R. M. & Sladek, S. L. Mercaptopurine pharmacogenetics: monogenic inheritance of erythrocyte thiopurine methyltransferase activity. Am. J. Hum. Genet. 32, 651–662 (1980).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Van Loon, J. A. & Weinshilboum, R. M. Thiopurine methyltransferase biochemical genetics: human lymphocyte activity. Biochem. Genet. 20, 637–658 (1982).

    PubMed  Google Scholar 

  50. Van Loon, J. A. & Weinshilboum, R. M. Thiopurine methyltransferase isozymes in human renal tissue. Drug Metab. Dispos. 18, 632–638 (1990).

    PubMed  Google Scholar 

  51. Szumlanski, C. L., Honchel, R., Scott, M. C. & Weinshilboum, R. M. Human liver thiopurine methyltransferase pharmacogenetics: biochemical properties, liver-erythrocyte correlation and presence of isozymes. Pharmacogenetics 2, 148–159 (1992).

    CAS  PubMed  Google Scholar 

  52. Tai, H.-L., Krynetski, E. Y., Schuetz, E. G., Yanishevski, Y. & Evans, W. E. Enhanced proteolysis of thiopurine S-methyltransferase (TPMT) encoded by mutant alleles in humans (TPMT*3A, TPMT*2): mechanisms for the genetic polymorphism of TPMT activity. Proc. Natl Acad. Sci. USA 94, 6444–6449 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Tai, H. L. et al. Enhanced proteasomal degradation of mutant human thiopurine S-methyltransferase (TPMT) in mammalian cells: mechanism for TPMT protein deficiency inherited by TPMT*2, TPMT*3A, TPMT*3B or TPMT*3C. Pharmacogenetics 9, 641–650 (1999).

    CAS  PubMed  Google Scholar 

  54. Wang, L., Sullivan, W., Toft, D. & Weinshilboum, R. Thiopurine S-methyltransferase pharmacogenetics: chaperone protein association and allozyme degradation. Pharmacogenetics 13, 555–564 (2003).

    CAS  PubMed  Google Scholar 

  55. Relling, M. V. et al. Mercaptopurine therapy intolerance and heterozygosity at the thiopurine S-methyltransferase gene locus. J. Natl Cancer Inst. 91, 2001–2008 (1999).

    CAS  PubMed  Google Scholar 

  56. Relling, M. V., Pui, C.-H., Cheng, C. & Evans, W. E. Thiopurine methyltransferase in acute lymphoblastic leukemia. Blood 107, 843–844 (2006).

    CAS  PubMed  Google Scholar 

  57. Kaskas, B. A. et al. Safe treatment of thiopurine S-methyltransferase deficient Crohn’s disease patients with azathioprine. Gut 52, 140–142 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Lee, M.-N. et al. Successful azathioprine treatment with metabolite monitoring in a pediatric inflammatory bowel disease patient homozygous for TPMT*3C. Yonsei Med. J. 54, 1545–1549 (2013).

    PubMed  PubMed Central  Google Scholar 

  59. Benkov, K. et al. Role of thiopurine metabolite testing and thiopurine methyltransferase determination in pediatric IBD. J. Pediatr. Gastroenterol. Nutr. 56, 333–340 (2013).

    CAS  PubMed  Google Scholar 

  60. Moriyama, T. et al. NUDT15 polymorphisms alter thiopurine metabolism and hematopoietic toxicity. Nat. Genet. 48, 367–373 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Yang, J. J. et al. Inherited NUDT15 variant is a genetic determinant of mercaptopurine intolerance in children with acute lymphoblastic leukemia. J. Clin. Oncol. 33, 1235–1242 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Tanaka, Y. et al. Susceptibility to 6-MP toxicity conferred by aNUDT15variant in Japanese children with acute lymphoblastic leukaemia. Br. J. Haematol. 171, 109–115 (2015).

    CAS  PubMed  Google Scholar 

  63. Zgheib, N. K. et al. NUDT15 and TPMT genetic polymorphisms are related to 6-mercaptopurine intolerance in children treated for acute lymphoblastic leukemia at the Children’s Cancer Center of Lebanon. Pediatr. Blood Cancer 64, 146–150 (2017).

    CAS  PubMed  Google Scholar 

  64. Illueca, M., Alemayehu, B., Shoetan, N. & Yang, H. Proton pump inhibitor prescribing patterns in newborns and infants. J. Pediatr. Pharmacol. Ther. 19, 283–287 (2014).

    PubMed  PubMed Central  Google Scholar 

  65. Barron, J. J., Tan, H., Spalding, J., Bakst, A. W. & Singer, J. Proton pump inhibitor utilization patterns in infants. J. Pediatr. Gastroenterol. Nutr. 45, 421–427 (2007).

    CAS  PubMed  Google Scholar 

  66. Blank, M.-L. & Parkin, L. National study of off-label proton pump inhibitor use among New Zealand infants in the first year of life (2005-2012). J. Pediatr. Gastroenterol. Nutr. 65, 179–184 (2017).

    PubMed  Google Scholar 

  67. Rosen, R. et al. Pediatric Gastroesophageal Reflux Clinical Practice guidelines: Joint Recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition. J. Pediatr. Gastroenterol. Nutr. 66, 516–554 (2018).

    PubMed  PubMed Central  Google Scholar 

  68. Gibbons, T. E. & Gold, B. D. The use of proton pump inhibitors in children: a comprehensive review. Paediatr. Drugs 5, 25–40 (2003).

    PubMed  Google Scholar 

  69. Jones, N. L. et al. Joint ESPGHAN/NASPGHAN guidelines for the Management of Helicobacter pylori in Children and Adolescents (Update 2016). J. Pediatr. Gastroenterol. Nutr. 64, 991–1003 (2017).

    PubMed  Google Scholar 

  70. Dellon, E. S. et al. ACG clinical guideline: evidenced based approach to the diagnosis and management of esophageal eosinophilia and eosinophilic esophagitis (EoE). Am. J. Gastroenterol. 108, 679–692 (2013). quiz 693.

    PubMed  Google Scholar 

  71. Ummarino, D. et al. Impact of antisecretory treatment on respiratory symptoms of gastroesophageal reflux disease in children. Dis. Esophagus 25, 671–677 (2012).

    CAS  PubMed  Google Scholar 

  72. Wasilewska, J. et al. Respiratory response to proton pump inhibitor treatment in children with obstructive sleep apnea syndrome and gastroesophageal reflux disease. Sleep. Med. 13, 824–830 (2012).

    PubMed  Google Scholar 

  73. Ward, R. M. & Kearns, G. L. Proton pump inhibitors in pediatrics. Pediatr. Drugs 15, 119–131 (2013).

    Google Scholar 

  74. Abelo, A. et al. Stereoselective metabolism of omeprazole by human cytochrome P450 enZYMES. Drug Metab. Dispos. 28, 966–972 (2000).

    CAS  PubMed  Google Scholar 

  75. Center for Drug Evaluation, Research. Table of Substrates, Inhibitors and Inducers (US Food and Drug Administration, 2020).

  76. Gardiner, S. J. & Begg, E. J. Pharmacogenetics, drug-metabolizing enzymes, and clinical practice. Pharmacol. Rev. 58, 521–590 (2006).

    CAS  PubMed  Google Scholar 

  77. Shirai, N. et al. Effects of CYP2C19 genotypic differences in the metabolism of omeprazole and rabeprazole on intragastric pH. Aliment. Pharmacol. Ther. 15, 1929–1937 (2001).

    CAS  PubMed  Google Scholar 

  78. Lima, J. J. et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2C19 and proton pump inhibitor dosing. Clin. Pharmacol. Ther. https://doi.org/10.1002/cpt.2015 (2020).

    Article  PubMed  Google Scholar 

  79. Hicks, J. K. et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2D6 and CYP2C19 genotypes and dosing of selective serotonin reuptake inhibitors. Clin. Pharmacol. Ther. 98, 127–134 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Kearns, G. L. et al. Single-dose pharmacokinetics of oral and intravenous pantoprazole in children and adolescents. J. Clin. Pharm. 48, 1356–1365 (2008).

    CAS  Google Scholar 

  81. Ward, R. M. et al. Single-dose, multiple-dose, and population pharmacokinetics of pantoprazole in neonates and preterm infants with a clinical diagnosis of gastroesophageal reflux disease (GERD). Eur. J. Clin. Pharmacol. 66, 555–561 (2010).

    CAS  PubMed  Google Scholar 

  82. Gumus, E. et al. Evaluation of lansoprazole as a probe for assessing cytochrome P450 2C19 activity and genotype-phenotype correlation in childhood. Eur. J. Clin. Pharmacol. 68, 629–636 (2012).

    CAS  PubMed  Google Scholar 

  83. Kearns, G. L., Leeder, J. S. & Gaedigk, A. Impact of the CYP2C19*17 allele on the pharmacokinetics of omeprazole and pantoprazole in children: evidence for a differential effect. Drug Metab. Dispos. 38, 894–897 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Lima, J. J. et al. Association of CYP2C19 polymorphisms and lansoprazole-associated respiratory adverse effects in children. J. Pediatr. 163, 686–691 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Franciosi, J. P. et al. Association between CYP2C19*17 alleles and pH probe testing outcomes in children with symptomatic gastroesophageal reflux. J. Clin. Pharm. 58, 89–96 (2018).

    CAS  Google Scholar 

  86. Marier, J.-F. et al. Pharmacokinetics of omeprazole in healthy adults and in children with gastroesophageal reflux disease. Ther. Drug Monit. 26, 3–8 (2004).

    CAS  PubMed  Google Scholar 

  87. Tran, A. et al. Pharmacokinetic-pharmacodynamic study of oral lansoprazole in children. Clin. Pharmacol. Ther. 71, 359–367 (2002).

    CAS  PubMed  Google Scholar 

  88. Bernal, C. J. et al. CYP2C19 phenotype and risk of proton pump inhibitor-associated infections. Pediatrics 144, https://doi.org/10.1542/peds.2019-0857 (2019).

  89. Lochmann, D. & Richardson, T. Selective serotonin reuptake inhibitors. Handb. Exp. Pharmacol. 250, 135–144 (2019).

    CAS  PubMed  Google Scholar 

  90. Olfson, M., He, J.-P. & Merikangas, K. R. Psychotropic medication treatment of adolescents: results from the national comorbidity survey–adolescent supplement. J. Am. Acad. Child Adolesc. Psychiatry 52, 378–388 (2013).

    PubMed  PubMed Central  Google Scholar 

  91. Aka, I. et al. Clinical pharmacogenetics of cytochrome P450-associated drugs in children. J. Pers. Med. 7, https://doi.org/10.3390/jpm7040014 (2017).

  92. Rossow, K. M., Aka, I. T., Maxwell-Horn, A. C., Roden, D. M. & Van Driest, S. L. Pharmacogenetics to predict adverse events associated with antidepressants. Pediatrics 146, e20200957 (2020).

    PubMed  Google Scholar 

  93. Chang, M., Tybring, G., Dahl, M.-L. & Lindh, J. D. Impact of cytochrome P450 2C19 polymorphisms on citalopram/escitalopram exposure: a systematic review and meta-analysis. Clin. Pharmacokinet. 53, 801–811 (2014).

    CAS  PubMed  Google Scholar 

  94. Carlsson, B. et al. Enantioselective analysis of citalopram and metabolites in adolescents. Ther. Drug Monit. 23, 658–664 (2001).

    CAS  PubMed  Google Scholar 

  95. Bishop, J. R. et al. Escitalopram pharmacogenetics: CYP2C19 relationships with dosing and clinical outcomes in autism spectrum disorder. Pharmacogenet. Genomics 25, 548–554 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Rudberg, I., Hendset, M., Uthus, L. H., Molden, E. & Refsum, H. Heterozygous mutation in CYP2C19 significantly increases the concentration/dose ratio of racemic citalopram and escitalopram (S-citalopram). Ther. Drug Monit. 28, 102–105 (2006).

    CAS  PubMed  Google Scholar 

  97. Aldrich, S. L. et al. Influence of CYP2C19 Metabolizer status on escitalopram/citalopram tolerability and response in youth with anxiety and depressive disorders. Front. Pharmacol. 10, 99 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Poweleit, E. A. et al. Pharmacogenetics of sertraline tolerability and response in pediatric anxiety and depressive disorders. J. Child Adolesc. Psychopharmacol. 29, 348–361 (2019).

    CAS  PubMed  Google Scholar 

  99. AlOlaby, R. R. et al. Molecular biomarkers predictive of sertraline treatment response in young children with fragile X syndrome. Brain Dev. 39, 483–492 (2017).

    PubMed  PubMed Central  Google Scholar 

  100. Ramsey, L. B., Bishop, J. R. & Strawn, J. R. Pharmacogenetics of treating pediatric anxiety and depression. Pharmacogenomics 20, 867–870 (2019).

    CAS  PubMed  Google Scholar 

  101. Troy, T. F., Poweleit, E. A., Strawn, J. R., Martin, L. J. & Ramsey, L. B. The influence of pharmacodynamic genes on fluoxetine response in pediatric anxiety and depressive disorders. J. Child Adolesc. Psychopharmacol. 30, 276–277 (2020).

    PubMed  Google Scholar 

  102. Amitai, M. et al. Pharmacogenetics of citalopram-related side effects in children with depression and/or anxiety disorders. J. Neural Transm. 123, 1347–1354 (2016).

    CAS  PubMed  Google Scholar 

  103. Wolraich, M. L. et al. Subcommittee on children and adolescents with attention-deficit/hyperactive disorder. Clinical Practice Guideline for the Diagnosis, Evaluation, and Treatment and Treatment of Attention-Deficit/Hyperactivity Disorder in Children and Adolescents. Pediatrics 144, e20192528 (2019).

    PubMed  Google Scholar 

  104. Bruxel, E. M. et al. ADHD pharmacogenetics across the life cycle: new findings and perspectives. Am. J. Med. Genet. B 165B, 263–282 (2014).

    Google Scholar 

  105. Kambeitz, J., Romanos, M. & Ettinger, U. Meta-analysis of the association between dopamine transporter genotype and response to methylphenidate treatment in ADHD. Pharmacogenomics J. 14, 77–84 (2014).

    CAS  PubMed  Google Scholar 

  106. Joshua, F. D., Elizabeth, T. & Talia P. The Child Medication Fact Book for Psychiatric Practice (Carlat Publishing, 2018).

  107. Lachman, H. M. et al. Human catechol-O-methyltransferase pharmacogenetics: description of a functional polymorphism and its potential application to neuropsychiatric disorders. Pharmacogenetics 6, 243–250 (1996).

    CAS  PubMed  Google Scholar 

  108. Cheon, K.-A., Jun, J.-Y. & Cho, D.-Y. Association of the catechol-O-methyltransferase polymorphism with methylphenidate response in a classroom setting in children with attention-deficit hyperactivity disorder. Int. Clin. Psychopharmacol. 23, 291–298 (2008).

    PubMed  Google Scholar 

  109. Kereszturi, E. et al. Catechol-O-methyltransferase Val158Met polymorphism is associated with methylphenidate response in ADHD children. Am. J. Med. Genet. B 147B, 1431–1435 (2008).

    CAS  Google Scholar 

  110. Mills, S. et al. No evidence of association between catechol-O-methyltransferase (COMT) Val158Met genotype and performance on neuropsychological tasks in children with ADHD: a case-control study. BMC Psychiatry 4, 15 (2004).

    PubMed  PubMed Central  Google Scholar 

  111. Michelson, D. et al. CYP2D6 and clinical response to atomoxetine in children and adolescents with ADHD. J. Am. Acad. Child Adolesc. Psychiatry 46, 242–251 (2007).

    PubMed  Google Scholar 

  112. Brown, J. T. et al. Clinical Pharmacogenetics Implementation Consortium guideline for cytochrome P450 (CYP)2D6 genotype and atomoxetine therapy. Clin. Pharmacol. Ther. 106, 94–102 (2019).

    PubMed  Google Scholar 

  113. Trzepacz, P. T. et al. CYP2D6 metabolizer status and atomoxetine dosing in children and adolescents with ADHD. Eur. Neuropsychopharmacol. 18, 79–86 (2008).

    CAS  PubMed  Google Scholar 

  114. Eli Lily and Company. Atomoxetine food and drug administration drug label. https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/021411s029s030lbl.pdf (2009).

  115. Huddart, R., Altman, R. B. & Klein, T. E. PharmGKB summary: ondansetron and tropisetron pathways, pharmacokinetics and pharmacodynamics. Pharmacogenet. Genomics 29, 91–97 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Dixon, C. M. et al. Multiple forms of cytochrome P450 are involved in the metabolism of ondansetron in humans. Drug Metab. Dispos. 23, 1225–1230 (1995).

    CAS  PubMed  Google Scholar 

  117. Kaiser, R. et al. Patient-tailored antiemetic treatment with 5-hydroxytryptamine type 3 receptor antagonists according to cytochrome P-450 2D6 genotypes. J. Clin. Oncol. 20, 2805–2811 (2002).

    CAS  PubMed  Google Scholar 

  118. Candiotti, K. A. et al. The impact of pharmacogenomics on postoperative nausea and vomiting: do CYP2D6 allele copy number and polymorphisms affect the success or failure of ondansetron prophylaxis? Anesthesiology 102, 543–549 (2005).

    CAS  PubMed  Google Scholar 

  119. Edwards, A. & Ramsey L. The Influence of CYP2D6 Metabolizer Status on the Control of Emesis by Ondansetron in Pediatric Patients Undergoing Hematopoietic Stem Cell Transplantation. University of Cincinnati Master’s Thesis (2020).

  120. Bell, G. C. et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2D6 genotype and use of ondansetron and tropisetron. Clin. Pharmacol. Ther. 102, 213–218 (2017).

    CAS  PubMed  Google Scholar 

  121. Endo, T. et al. Neurochemistry and neuropharmacology of emesis - the role of serotonin. Toxicology 153, 189–201 (2000).

    CAS  PubMed  Google Scholar 

  122. Yamada, Y. et al. Receptor occupancy theory-based analysis of antiemetic effects and standard doses of 5-HT3 receptor antagonists in cancer patients. Cancer Chemother. Pharmacol. 54, 185–190 (2004).

    CAS  PubMed  Google Scholar 

  123. Ayuhara, H. et al. Receptor occupancy theory-based analysis of interindividual differences in antiemetic effects of 5-HT3 receptor antagonists. Int. J. Clin. Oncol. 14, 518–524 (2009).

    CAS  PubMed  Google Scholar 

  124. Tremblay, P.-B. et al. Variations in the 5-hydroxytryptamine type 3B receptor gene as predictors of the efficacy of antiemetic treatment in cancer patients. J. Clin. Oncol. 21, 2147–2155 (2003).

    CAS  PubMed  Google Scholar 

  125. Lehmann, A. S. et al. Pharmacogenetic predictors of nausea and vomiting of pregnancy severity and response to antiemetic therapy: a pilot study. BMC Pregnancy Childbirth 13, 132 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Weitzel, K. W., Cavallari, L. H. & Lesko, L. J. Preemptive panel-based pharmacogenetic testing: the time is now. Pharm. Res. 34, 1551–1555 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Krebs, K. & Milani, L. Translating pharmacogenomics into clinical decisions: do not let the perfect be the enemy of the good. Hum. Genomics 13, 39 (2019).

    PubMed  PubMed Central  Google Scholar 

  128. Roden, D. M. et al. Pharmacogenomics. Lancet 394, 521–532 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Van Driest, S. L. et al. Clinically actionable genotypes among 10,000 patients with preemptive pharmacogenomic testing. Clin. Pharm. Ther. 95, 423–431 (2014).

    Google Scholar 

  130. Relling, M. V. & Evans, W. E. Pharmacogenomics in the clinic. Nature 526, 343–350 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Dunnenberger, H. M. et al. Preemptive clinical pharmacogenetics implementation: current programs in five US medical centers. Annu. Rev. Pharmacol. Toxicol. 55, 89–106 (2015).

    CAS  PubMed  Google Scholar 

  132. Keeling, N. J. et al. Preemptive pharmacogenetic testing: exploring the knowledge and perspectives of US payers. Genet. Med. 21, 1224–1232 (2019).

    PubMed  Google Scholar 

  133. Stanek, E. J. et al. Adoption of pharmacogenomic testing by US physicians: results of a nationwide survey. Clin. Pharmacol. Ther. 91, 450–458 (2012).

    CAS  PubMed  Google Scholar 

  134. Owusu Obeng, A. et al. Physician-reported benefits and barriers to clinical implementation of genomic medicine: a Multi-Site IGNITE-Network Survey. J. Pers. Med. 8, https://doi.org/10.3390/jpm8030024 (2018).

  135. Roden, D. M. et al. Development of a large-scale de-identified DNA biobank to enable personalized medicine. Clin. Pharmacol. Ther. 84, 362–369 (2008).

    CAS  PubMed  Google Scholar 

  136. Hoffman, J. M. et al. PG4KDS: a model for the clinical implementation of pre-emptive pharmacogenetics. Am. J. Med. Genet. C 166C, 45–55 (2014).

    Google Scholar 

  137. van der Wouden, C. H. et al. Implementing pharmacogenomics in Europe: design and implementation strategy of the Ubiquitous Pharmacogenomics Consortium. Clin. Pharmacol. Ther. 101, 341–358 (2017).

    PubMed  Google Scholar 

  138. Pulley, J. M. et al. Operational implementation of prospective genotyping for personalized medicine: the design of the Vanderbilt PREDICT project. Clin. Pharmacol. Ther. 92, 87–95 (2012).

    CAS  PubMed  Google Scholar 

  139. Sukasem, C. & Chantratita, W. A success story in pharmacogenomics: genetic ID card for SJS/TEN. Pharmacogenomics 17, 455–458 (2016).

    CAS  PubMed  Google Scholar 

  140. Wagner, J. B. et al. Impact of SLCO1B1 genotype on pediatric simvastatin acid pharmacokinetics. J. Clin. Pharmacol. 58, 823–833 (2018).

    CAS  PubMed  Google Scholar 

  141. Liu, M. et al. A tutorial for pharmacogenomics implementation through end-to-end clinical decision support based on ten years of experience from PREDICT. Clin. Pharmacol. Ther. https://doi.org/10.1002/cpt.2079 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  142. Ramsey, L. B. et al. Implementation of pharmacogenetics at Cincinnati Children’s Hospital Medical Center: lessons learned over 14 years of personalizing medicine. Clin. Pharmacol. Ther. 105, 49–52 (2019).

    PubMed  Google Scholar 

  143. Bousman, C. A. & Dunlop, B. W. Genotype, phenotype, and medication recommendation agreement among commercial pharmacogenetic-based decision support tools. Pharmacogenomics J. 18, 613–622 (2018).

    CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Brendan (Tex) Armstreet for assistance with designing Fig. 1, and Drs. Catherine Forster and Todd Florin for critical feedback on this manuscript. Figures were created with Biorender.com. S.C.T.G. was supported by the National Institute of Child Health and Development Cincinnati Pediatric Clinical Pharmacology Postdoctoral Training Program [5T32HD069054–09] and K.M.R. was supported by the National Institute of Child Health and Development & National Institute of General Medical Sciences Vanderbilt Pediatric Clinical Pharmacology Postdoctoral Training Program [5T32GM007569–43].

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Authors and Affiliations

  1. Division of Hospital Medicine, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

    Sonya C. Tang Girdwood

  2. Division of Clinical Pharmacology, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

    Sonya C. Tang Girdwood & Laura B. Ramsey

  3. Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA

    Sonya C. Tang Girdwood & Laura B. Ramsey

  4. Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, USA

    Katelyn M. Rossow & Sara L. Van Driest

  5. Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA

    Sara L. Van Driest

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Each author provided substantial contribution to the conception and design of this manuscript, drafted significant portions of the manuscripts, revised the manuscript critically for important intellectual content, and approved the final version.

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Tang Girdwood, S.C., Rossow, K.M., Van Driest, S.L. et al. Perspectives from the Society for Pediatric Research: pharmacogenetics for pediatricians. Pediatr Res 91, 529–538 (2022). https://doi.org/10.1038/s41390-021-01499-2

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