Advertisement

The Relationship Between Pharmacogenomics and Pharmacokinetics and Its Impact on Drug Choice and Dosing Regimens in Pediatrics

  • Venkata K. Yellepeddi
  • Jessica K. Roberts
  • Leslie Escobar
  • Casey Sayre
  • Catherine M. Sherwin
Chapter

Abstract

The concept of precision or personalized medicine in pediatrics is still in its infancy, and due to ethical and logistical constraints, it is difficult to conduct clinical studies in pediatric to obtain meaningful correlations between ontogeny and drug disposition. However, as a result of initiatives by the Food and Drug Administration (FDA) aimed toward incentivizing companies for conducting pediatric trials, knowledge on pediatric pharmacogenomics is slowly increasing. The information on pediatric pharmacogenomics is utilized to implement pharmacogenomic testing in pediatrics to allow clinicians to make an informed decision on selection and dosing of drugs in pediatrics. The ontogeny of drug-metabolizing enzymes (DMEs), transporters, and target proteins is the most crucial factor in pediatric pharmacogenomics. Based on in vitro and in vivo studies on the ontogeny of DMEs, various pharmacogenomic tests in pediatrics were evaluated concerning the pharmacokinetics of drugs utilized in pediatric pharmacotherapy. Needing to obtain clinically relevant advantages of incorporating pharmacogenomics in pediatric drug therapy, clinicians must be informed on pharmacogenomic terms by appropriate educational programs. Furthermore, a comprehensive database that can bank all pediatric pharmacogenomic information that can seamlessly collaborate with other international databases must be established.

Keywords

Pharmacogenomics Pediatrics Pharmacokinetics CYP enzymes Transporters Pediatric trials Codeine Pediatric formulations Tacrolimus Thiopurine methyltransferase (TPMT

References

  1. Abaji R, Krajinovic M (2016) Current perspective on pediatric pharmacogenomics. Expert Opin Drug Metab Toxicol 12:363–365CrossRefGoogle Scholar
  2. Agunod M, Yamaguchi N, Lopez R et al (1969) Correlative study of hydrochloric acid, pepsin, and intrinsic factor secretion in newborns and infants. Am J Dig Dis 14:400–414CrossRefGoogle Scholar
  3. Anderson BJ, van Lingen RA, Hansen TG et al (2002) Acetaminophen developmental pharmacokinetics in premature neonates and infants: a pooled population analysis. Anesthesiology 96:1336–1345CrossRefGoogle Scholar
  4. Anderson GD, Lynn AM (2009) Optimizing pediatric dosing: a developmental pharmacologic approach. Pharmacotherapy 29:680–690CrossRefGoogle Scholar
  5. Berman W Jr, Whitman V, Marks KH, Friedman Z, Maisels MJ, Musselman J (1978) Inadvertent overadministration of digoxin to low-birth-weight infants. J Pediatr 92(6):1024–1025CrossRefGoogle Scholar
  6. Birdwell KA, Decker B, Barbarino JM et al (2015) Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for CYP3A5 genotype and tacrolimus dosing. Clin Pharmacol Ther 98:19–24CrossRefGoogle Scholar
  7. Biss TT, Avery PJ, Brandao LR et al (2012) VKORC1 and CYP2C9 genotype and patient characteristics explain a large proportion of the variability in warfarin dose requirement among children. Blood 119:868–873CrossRefGoogle Scholar
  8. Blumer JL (1999) Off-label uses of drugs in children. Pediatrics 104:598–602PubMedGoogle Scholar
  9. Brown AL, Lupo PJ, Okcu MF et al (2015) SOD2 genetic variant associated with treatment-related ototoxicity in cisplatin-treated pediatric medulloblastoma. Cancer Med 4:1679–1686CrossRefGoogle Scholar
  10. Brown RD, Campoli-Richards DM (1989) Antimicrobial therapy in neonates, infants and children. Clin Pharmacokinet 17:105–115CrossRefGoogle Scholar
  11. Bruggemann RJ, Alffenaar JW, Blijlevens NM et al (2009) Clinical relevance of the pharmacokinetic interactions of azole antifungal drugs with other coadministered agents. Clin Infect Dis 48:1441–1458CrossRefGoogle Scholar
  12. Center for Drug Evaluation and Research (CDER), Food and Drug Administration (1994) Guidance for industry: the content and format for pediatric use supplementsGoogle Scholar
  13. Constance JE, Campbell SC, Somani AA et al (2017) Pharmacokinetics, pharmacodynamics and pharmacogenetics associated with nonsteroidal anti-inflammatory drugs and opioids in pediatric cancer patients. Expert Opin Drug Metab Toxicol 13:715–724CrossRefGoogle Scholar
  14. Crews KR, Gaedigk A, Dunnenberger HM et al (2014) Clinical Pharmacogenetics Implementation Consortium guidelines for cytochrome P450 2D6 genotype and codeine therapy: 2014 update. Clin Pharmacol Ther 95:376–382CrossRefGoogle Scholar
  15. Crom WR (1994) Pharmacokinetics in the child. Environ Health Perspect 102:111–117CrossRefGoogle Scholar
  16. Cuzzolin L, Atzei A, Fanos V (2006) Off-label and unlicensed prescribing for newborns and children in different settings: a review of the literature and a consideration about drug safety. Expert Opin Drug Saf 5:703–718CrossRefGoogle Scholar
  17. Debotton N, Dahan A (2014) A mechanistic approach to understanding oral drug absorption in pediatrics: an overview of fundamentals. Drug Discov Today 19:1322–1336CrossRefGoogle Scholar
  18. Drew L (2016) Pharmacogenetics: the right drug for you. Nature 537(7619):S60–S62.  https://doi.org/10.1038/537S60aCrossRefPubMedGoogle Scholar
  19. de Wildt SN, Kearns GL, Leeder JS et al (1999) Glucuronidation in humans. Pharmacogenetic and developmental aspects. Clin Pharmacokinet 36:439–452CrossRefGoogle Scholar
  20. Elens L, Capron A, van Schaik RH et al (2013) Impact of CYP3A4*22 allele on tacrolimus pharmacokinetics in early period after renal transplantation: toward updated genotype-based dosage guidelines. Ther Drug Monit 35:608–616PubMedGoogle Scholar
  21. Engels MJ, Ciarkowski SL, Rood J et al (2016) Standardization of compounded oral liquids for pediatric patients in Michigan. Am J Health Syst Pharm 73:981–990CrossRefGoogle Scholar
  22. Evans WE, Relling MV, Petros WP et al (1989) Dextromethorphan and caffeine as probes for simultaneous determination of debrisoquin-oxidation and N-acetylation phenotypes in children. Clin Pharmacol Ther 45:568–573CrossRefGoogle Scholar
  23. Food and Drug Administration (2018) Table of pharmacogenomic biomarkers in drug labeling (2018). https://www.fda.gov/Drugs/ScienceResearch/ucm572698.htm
  24. Frattarelli DA, Galinkin JL, Green TP et al (2014) Off-label use of drugs in children. Pediatrics 133:563–567CrossRefGoogle Scholar
  25. Fukudo M, Yano I, Masuda S et al (2006) Population pharmacokinetic and pharmacogenomic analysis of tacrolimus in pediatric living-donor liver transplant recipients. Clin Pharmacol Ther 80:331–345CrossRefGoogle Scholar
  26. Food and Drug Administration Modernization Act of 1997. (1997). https://www.govtrack.us/congress/bills/105/s830/text. Accessed 1 May 2018
  27. Ganiere-Monteil C, Medard Y, Lejus C et al (2004) Phenotype and genotype for thiopurine methyltransferase activity in the French Caucasian population: impact of age. Eur J Clin Pharmacol 60:89–96CrossRefGoogle Scholar
  28. Giubergia V, Gravina L, Castanos C et al (2013) Influence of beta(2)-adrenergic receptor polymorphisms on asthma exacerbation in children with severe asthma regularly receiving salmeterol. Ann Allergy Asthma Immunol 110:156–160CrossRefGoogle Scholar
  29. Gershanik J, Boecler B, Ensley H et al (1982) The gasping syndrome and benzyl alcohol poisoning. New Engl J Med 307:1384–1388CrossRefGoogle Scholar
  30. Gore R, Chugh PK, Tripathi CD et al (2017) Pediatric off-label and unlicensed drug use and its implications. Curr Clin Pharmacol 12:18–25CrossRefGoogle Scholar
  31. Harries JT, Fraser AJ (1968) The acidity of the gastric contents of premature babies during the first fourteen days of life. Biol Neonat Neo-natal Stud 12(3):186–193CrossRefGoogle Scholar
  32. Hume R, Burchell A, Allan BB et al (1996) The ontogeny of key endoplasmic reticulum proteins in human embryonic and fetal red blood cells. Blood 87:762–770PubMedGoogle Scholar
  33. Hume R, Coughtrie MW, Burchell B (1995) Differential localisation of UDP-glucuronosyltransferase in kidney during human embryonic and fetal development. Arch Toxicol 69:242–247CrossRefGoogle Scholar
  34. Johnson TN, Thomson M (2008) Intestinal metabolism and transport of drugs in children: the effects of age and disease. J Pediatr Gastroenterol Nutr 47:3–10CrossRefGoogle Scholar
  35. Kadam RS, Van Den Anker JN (2016) Pediatric clinical pharmacology of voriconazole: role of pharmacokinetic/pharmacodynamic modeling in pharmacotherapy. Clin Pharmacokinet 55:1031–1043CrossRefGoogle Scholar
  36. Kalra A, Goindi S (2014) Issues impacting therapeutic outcomes in pediatric patients: an overview. Curr Pediatr Rev 10:184–193PubMedGoogle Scholar
  37. Kato Y, Ichida F, Saito K et al (2011) Effect of the VKORC1 genotype on warfarin dose requirements in Japanese pediatric patients. Drug Metab Pharmacokinet 26:295–299CrossRefGoogle Scholar
  38. Kearin M, Kelly JG, O’Malley K (1980) Digoxin “receptors” in neonates: an explanation of less sensitivity to digoxin than in adults. Clin Pharmacol Ther 28(3):346–349CrossRefGoogle Scholar
  39. Kearns GL, Abdel-Rahman SM, Alander SW et al (2003) Developmental pharmacology--drug disposition, action, and therapy in infants and children. N Engl J Med 349:1157–1167CrossRefGoogle Scholar
  40. Kearns GL (2015) Selecting the proper pediatric dose: it is more than size that matters. Clin Pharmacol Ther 98(3):238–240.  https://doi.org/10.1002/cpt.168CrossRefPubMedPubMedCentralGoogle Scholar
  41. Kirchheiner J, Stormer E, Meisel C et al (2003) Influence of CYP2C9 genetic polymorphisms on pharmacokinetics of celecoxib and its metabolites. Pharmacogenetics 13:473–480CrossRefGoogle Scholar
  42. Kirschner BS (1998) Safety of azathioprine and 6-mercaptopurine in pediatric patients with inflammatory bowel disease. Gastroenterology 115:813–821CrossRefGoogle Scholar
  43. Korbel L, George M, Kitzmiller J (2014) Clinically relevant pharmacogenomic testing in pediatric practice. Clin Pediatr (Phila) 53:831–838CrossRefGoogle Scholar
  44. Lam MS (2011) Extemporaneous compounding of oral liquid dosage formulations and alternative drug delivery methods for anticancer drugs. Pharmacotherapy 31(2):164–192.  https://doi.org/10.1592/phco.31.2.164CrossRefPubMedGoogle Scholar
  45. Lavertu A, McInnes G, Daneshjou R et al (2018) Pharmacogenomics and big genomic data: from lab to clinic and back again. Hum Mol Genet 27:R72–R78CrossRefGoogle Scholar
  46. Lanvers-Kaminsky C, Sprowl JA, Malath I et al (2015) Human OCT2 variant c.808G>T confers protection effect against cisplatin-induced ototoxicity. Pharmacogenomics 16:323–332CrossRefGoogle Scholar
  47. Leeder JS, Kearns GL (1997) Pharmacogenetics in pediatrics. Implications for practice. Pediatr Clin North Am 44:55–77CrossRefGoogle Scholar
  48. Lennard L, Lilleyman JS, Van Loon J et al (1990) Genetic variation in response to 6-mercaptopurine for childhood acute lymphoblastic leukaemia. Lancet 336:225–229CrossRefGoogle Scholar
  49. Lennard L, Van Loon JA, Lilleyman JS et al (1987) Thiopurine pharmacogenetics in leukemia: correlation of erythrocyte thiopurine methyltransferase activity and 6-thioguanine nucleotide concentrations. Clin Pharmacol Ther 41:18–25CrossRefGoogle Scholar
  50. Lipworth BJ, Basu K, Donald HP et al (2013) Tailored second-line therapy in asthmatic children with the Arg(16) genotype. Clin Sci (Lond) 124:521–528.  https://doi.org/10.1042/CS20120528CrossRefGoogle Scholar
  51. Liu SG, Gao C, Zhang RD, Zhao XX et al (2017) Polymorphisms in methotrexate transporters and their relationship to plasma methotrexate levels, toxicity of high-dose methotrexate, and outcome of pediatric acute lymphoblastic leukemia. Oncotarget 8:37761–37772PubMedPubMedCentralGoogle Scholar
  52. Maitland-van der Zee AH, Raaijmakers JA (2012) Variation at GLCCI1 and FCER2: one step closer to personalized asthma treatment. Pharmacogenomics 13:243–245CrossRefGoogle Scholar
  53. McLeod HL, Krynetski EY, Wilimas JA et al (1995) Higher activity of polymorphic thiopurine S-methyltransferase in erythrocytes from neonates compared to adults. Pharmacogenetics 5:281–286CrossRefGoogle Scholar
  54. Mlakar V, Huezo-Diaz Curtis P, Satyanarayana Uppugunduri CR, Krajinovic M, Ansari M (2016) Pharmacogenomics in pediatric oncology: review of gene-drug associations for clinical use. Int J Mol Sci 17(9).  https://doi.org/10.3390/ijms17091502
  55. Moreau C, Bajolle F, Siguret V et al (2012) Vitamin K antagonists in children with heart disease: height and VKORC1 genotype are the main determinants of the warfarin dose requirement. Blood 119:861–867CrossRefGoogle Scholar
  56. Moriyama T, Nishii R, Lin TN et al (2017a) The effects of inherited NUDT15 polymorphisms on thiopurine active metabolites in Japanese children with acute lymphoblastic leukemia. Pharmacogenet Genomics 27:236–239CrossRefGoogle Scholar
  57. Moriyama T, Yang YL, Nishii R et al (2017b) Novel variants in NUDT15 and thiopurine intolerance in children with acute lymphoblastic leukemia from diverse ancestry. Blood 130:1209–1212CrossRefGoogle Scholar
  58. Mukattash TL, Nuseir KQ, Jarab AS et al (2014) Sources of information used when prescribing for children, a survey of hospital based pediatricians. Curr Clin Pharmacol 9:395–398CrossRefGoogle Scholar
  59. Murto K, Lamontagne C, McFaul C et al (2015) Celecoxib pharmacogenetics and pediatric adenotonsillectomy: a double-blinded randomized controlled study. Can J Anaesth 62:785–797CrossRefGoogle Scholar
  60. Neville KA, Becker ML, Goldman JL et al (2011) Developmental pharmacogenomics. Paediatr Anaesth 21:255–265CrossRefGoogle Scholar
  61. Nowak-Gottl U, Dietrich K, Schaffranek D et al (2010) In pediatric patients, age has more impact on dosing of vitamin K antagonists than VKORC1 or CYP2C9 genotypes. Blood 116:6101–6105CrossRefGoogle Scholar
  62. Palmaro A, Bissuel R, Renaud N et al (2015) Off-label prescribing in pediatric outpatients. Pediatrics 135:49–58CrossRefGoogle Scholar
  63. Palmer CN, Lipworth BJ, Lee S et al (2006) Arginine-16 beta2 adrenoceptor genotype predisposes to exacerbations in young asthmatics taking regular salmeterol. Thorax 61:940–944CrossRefGoogle Scholar
  64. Preventing errors relating to commonly used anticoagulants (2008). Sentinel Event Alert (41):1–4Google Scholar
  65. Pussegoda K, Ross CJ, Visscher H, CPNDS Consortium et al (2013) Replication of TPMT and ABCC3 genetic variants highly associated with cisplatin-induced hearing loss in children. Clin Pharmacol Ther 94:243–251CrossRefGoogle Scholar
  66. Quiñones L, Roco A, Cayun JP et al (2017) Clinical applications of pharmacogenomics. Rev Med Chil 145:483–500CrossRefGoogle Scholar
  67. Ramos-Martin V, O’Connor O, Hope W (2015) Clinical pharmacology of antifungal agents in pediatrics: children are not small adults. Curr Opin Pharmacol 24:128–134CrossRefGoogle Scholar
  68. Relling MV, Gardner EE, Sandborn WJ et al (2011) Clinical Pharmacogenetics Implementation Consortium guidelines for thiopurine methyltransferase genotype and thiopurine dosing. Clin Pharmacol Ther 89:387–391CrossRefGoogle Scholar
  69. Roberts JK, Stockmann C, Constance JE et al (2014) Pharmacokinetics and pharmacodynamics of antibacterials, antifungals, and antivirals used most frequently in neonates and infants. Clin Pharmacokinet 53:581–610CrossRefGoogle Scholar
  70. Rood JM, Engels MJ, Ciarkowski SL et al (2014) Variability in compounding of oral liquids for pediatric patients: a patient safety concern. J Am Pharm Assoc: JAPhA 54:383–389CrossRefGoogle Scholar
  71. Ross CJ, Katzov-Eckert H, Dube MP, CPNDS Consortium et al (2009) Genetic variants in TPMT and COMT are associated with hearing loss in children receiving cisplatin chemotherapy. Nat Genet 41:1345–1349CrossRefGoogle Scholar
  72. Sachs AN, Avant D, Lee CS et al (2012) Pediatric information in drug product labeling. Jama 307:1914–1915CrossRefGoogle Scholar
  73. Schmiegelow K, Nielsen SN, Frandsen TL et al (2014) Mercaptopurine/methotrexate maintenance therapy of childhood acute lymphoblastic leukemia: clinical facts and fiction. J Pediatr Hematol Oncol 36:503–517CrossRefGoogle Scholar
  74. Sharma S, Ellis EC, Gramignoli R et al (2013) Hepatobiliary disposition of 17-OHPC and taurocholate in fetal human hepatocytes: a comparison with adult human hepatocytes. Drug Metab Dispos 41:296–304CrossRefGoogle Scholar
  75. Shaw K, Amstutz U, Hildebrand C et al (2014) VKORC1 and CYP2C9 genotypes are predictors of warfarin-related outcomes in children. Pediatr Blood Cancer 61:1055–1062CrossRefGoogle Scholar
  76. Stevens JC, Marsh SA, Zaya MJ et al (2008) Developmental changes in human liver CYP2D6 expression. Drug Metab Dispos 36:1587–1593CrossRefGoogle Scholar
  77. Stockmann C, Fassl B, Gaedigk R et al (2013) Fluticasone propionate pharmacogenetics: CYP3A4*22 polymorphism and pediatric asthma control. J Pediatr 162:1222–1227, 1227 e1221–1222CrossRefGoogle Scholar
  78. Stockmann C, Reilly CA, Fassl B et al (2015) Effect of CYP3A5*3 on asthma control among children treated with inhaled beclomethasone. J Allergy Clin Immunol 136:505–507CrossRefGoogle Scholar
  79. Table of Pharmacogenomic Biomarkers in Drug Labeling (2018) Center for Drug Evaluation and Research https://www.fda.gov/Drugs/ScienceResearch/ucm572698.htm
  80. Teusink A, Vinks A, Zhang K et al (2016) Genotype-directed dosing leads to optimized voriconazole levels in pediatric patients receiving hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 22:482–486CrossRefGoogle Scholar
  81. Turner S, Francis B, Vijverberg S et al (2016) Pharmacogenomics in childhood asthma C childhood asthma exacerbations and the Arg16 beta2-receptor polymorphism: a meta-analysis stratified by treatment. J Allergy Clin Immunol 138:107–113CrossRefGoogle Scholar
  82. Vear SI, Ayers GD, Van Driest SL et al (2014) The impact of age and CYP2C9 and VKORC1 variants on stable warfarin dose in the paediatric population. Br J Haematol 165:832–835CrossRefGoogle Scholar
  83. Walsh TJ, Karlsson MO, Driscoll T et al (2004) Pharmacokinetics and safety of intravenous voriconazole in children after single- or multiple-dose administration. Antimicrob Agents Chemother 48:2166–2172CrossRefGoogle Scholar
  84. Wright FA, Bebawy M, O’Brien TA (2015) An analysis of the therapeutic benefits of genotyping in pediatric hematopoietic stem cell transplantation. Future Oncol 11:833–851CrossRefGoogle Scholar
  85. Wehry AM, Ramsey L, Dulemba SE et al (2018) Pharmacogenomic testing in child and adolescent psychiatry: an evidence-based review. Curr Probl Pediatr Adolesc Health Care 48:40–49CrossRefGoogle Scholar
  86. Xie HG (2010) Personalized immunosuppressive therapy in pediatric heart transplantation: Progress, pitfalls and promises. Pharmacol Ther 126:146–158CrossRefGoogle Scholar
  87. Xu H, Robinson GW, Huang J et al (2015) Common variants in ACYP2 influence susceptibility to cisplatin-induced hearing loss. Nat Genet 47:263–266CrossRefGoogle Scholar
  88. Zhao W, Elie V, Roussey G et al (2009) Population pharmacokinetics and pharmacogenetics of tacrolimus in de novo pediatric kidney transplant recipients. Clin Pharmacol Ther 86:609–618CrossRefGoogle Scholar
  89. Zhao W, Fakhoury M, Baudouin V et al (2013) Population pharmacokinetics and pharmacogenetics of once daily prolonged-release formulation of tacrolimus in pediatric and adolescent kidney transplant recipients. Eur J Clin Pharmacol 69:189–195CrossRefGoogle Scholar
  90. Zuurhout MJ, Vijverberg SJ, Raaijmakers JA et al (2013) Arg16 ADRB2 genotype increases the risk of asthma exacerbation in children with a reported use of long-acting beta2-agonists: results of the PACMAN cohort. Pharmacogenomics 14:1965–1971CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  • Venkata K. Yellepeddi
    • 1
    • 2
  • Jessica K. Roberts
    • 1
  • Leslie Escobar
    • 3
  • Casey Sayre
    • 4
  • Catherine M. Sherwin
    • 1
    • 2
    • 5
  1. 1.Division of Clinical Pharmacology, Department of PediatricsUniversity of UtahSalt Lake CityUSA
  2. 2.Department of Pharmaceutics & Pharmaceutical ChemistryCollege of Pharmacy, University of UtahSalt Lake CityUSA
  3. 3.Department of Pediatrics and Infant Surgery, Faculty of MedicineUniversity of ChileSantiagoChile
  4. 4.College of Pharmacy, Roseman University of Health SciencesSouth JordanUSA
  5. 5.Department of PharmacotherapyCollege of Pharmacy, University of UtahSalt Lake CityUSA

Personalised recommendations