Developmental Physiology and Pharmacotherapy in Pediatric Surgical Newborns

  • John N. van den Anker
  • Dick Tibboel


Human development consists of a continuum of physiologic events that includes somatic growth, neurobehavioral maturation and eventual reproduction, and is often divided into infancy, childhood, adolescence and early adulthood. Across this period of time organ size and function change as does body composition, protein expression, and cellular function. Some tissues may be more sensitive to effects early in life whereas later in life function may decline. This holds true in particular when organ development has resulted in major congenital anomalies. As these developmental changes in function and form occur, their implications with respect to the clinical pharmacology of drugs and their appropriate place in pediatric therapy must be considered.


Newborn physiology Pharmacology Newborn surgery 


  1. 1.
    Bartelink IH, Rademaker CM, Schobben AF, van den Anker JN. Guidelines on paediatric dosing on the basis of developmental physiology and pharmacokinetic considerations. Clin Pharmacokinet. 2006;45:1077–97.CrossRefGoogle Scholar
  2. 2.
    Johnson TN, Rostami-Hodjegan A, Tucker GT. Prediction of the clearance of eleven drugs and associated variability in neonates, infants and children. Clin Pharmacokinet. 2006;45:931–56.CrossRefGoogle Scholar
  3. 3.
    Kearns GL, Abdel-Rahman SM, Alander SW, Blowey DL, Leeder JS, Kauffman RE. Developmental pharmacology—drug disposition, action, and therapy in infants and children. N Engl J Med. 2003;349:1157–67.CrossRefGoogle Scholar
  4. 4.
    Rakhmanina NY, Van den Anker JN. Pharmacological research in pediatrics: from neonates to adolescents. Adv Drug Deliv Rev. 2006;58:4–14.CrossRefGoogle Scholar
  5. 5.
    Edginton AN, Schmitt W, Voith B, Willmann S. A mechanistic approach for the scaling of clearance in children. Clin Pharmacokinet. 2006;45:683–704.CrossRefGoogle Scholar
  6. 6.
    Anderson BJ, Holford NH. Mechanism-based concepts of size and maturity in pharmacokinetics. Annu Rev Pharmacol Toxicol. 2008;48:303–32.CrossRefGoogle Scholar
  7. 7.
    Blake MJ, Abdel-Rahman SM, Pearce RE, Leeder JS, Kearns GL. Effect of diet on the development of drug metabolism by cytochrome P-450 enzymes in healthy infants. Pediatr Res. 2006;60(6):717–23.CrossRefGoogle Scholar
  8. 8.
    Van den Anker JN, Hop W, de Groot R, van der Heijden AJ, Broerse HM, Lindemans J, et al. Effects of prenatal exposure to betamethasone and indomethacin on the glomerular filtration rate in the preterm infant. Pediatr Res. 1994;36:578–81.CrossRefGoogle Scholar
  9. 9.
    Allegaert K, van Schaik RH, Vermeersch S, Verbesselt R, Cossey V, Vanhole C, et al. Postmenstrual age and CYP2D6 polymorphisms determine tramadol O-demethylation in critically ill neonates and infants. Pediatr Res. 2008;63:674–9.CrossRefGoogle Scholar
  10. 10.
    Leeder JS. Developmental and pediatric pharmacogenomics. Pharmacogenomics. 2003;4:331–41.CrossRefGoogle Scholar
  11. 11.
    Krekels EH, van den Anker JN, Baiardi P, Cella M, Cheng KY, Gibb DM, et al. Pharmacogenetics and paediatric drug development: issues and consequences to labelling and dosing recommendations. Expert Opin Pharmacother. 2007;8:1787–99.CrossRefGoogle Scholar
  12. 12.
    Leeder JS, Kearns GL, Spielberg SP, van den Anker JN. Understanding the relative roles of pharmacogenetics and ontogeny in pediatric drug development and regulatory science. J Clin Pharmacol. 2010;50(12):1377-87.CrossRefGoogle Scholar
  13. 13.
    Kelly EJ, Newell SJ. Gastric ontogeny: clinical implications. Arch Dis Child. 1994;71:F136–41.CrossRefGoogle Scholar
  14. 14.
    Sankaran K, Hayton S, Duff E, Waygood B. Time-wise sequential analysis of gastric aspirate for occult blood and pH in sick preterm infants. Clin Invest Med. 1984;7:115–8.Google Scholar
  15. 15.
    Strolin Benedetti M, Baltes EL. Drug metabolism and disposition in children. Fundam Clin Pharmacol. 2003;17:281–99.CrossRefGoogle Scholar
  16. 16.
    Kearns GL. Impact of developmental pharmacology on pediatric study design: overcoming the challenges. J Allergy Clin Immunol. 2000;106:S128–39.CrossRefGoogle Scholar
  17. 17.
    Anderson BJ, van Lingen RA, Hansen TG, Lin YC, Holford NH. Acetaminophen developmental pharmacokinetics in premature neonates and infants: a pooled population analysis. Anesthesiology. 2002;96(6):1336–45.CrossRefGoogle Scholar
  18. 18.
    Kearns GL, Robinson PK, Wilson JT, Wilson-Costello D, Knight GR, Ward RM, et al. Cisapride disposition in neonates and infants: in vivo reflection of cytochrome P450 3A4 ontogeny. Clin Pharmacol Ther. 2003;4:312–25.CrossRefGoogle Scholar
  19. 19.
    Radde IC, McKercher HG. Transport through membranes and development of membrane transport. In: MacLeod SM, Radde IC, editors. Textbook of pediatric clinical pharmacology. Littleton, MA: PSG Publishing Company; 1985. p. 1–16.Google Scholar
  20. 20.
    Ginsberg G, Hattis D, Miller M, Sonawane B. Pediatric pharmacokinetic data: implications for environmental risk assessment for children. Pediatrics. 2004;113(4):973–83.Google Scholar
  21. 21.
    Turner JW. Death of a child from topical diphenhydramine. Am J Forensic Med Pathol. 2009;30:380–1.CrossRefGoogle Scholar
  22. 22.
    Armstrong RW, Eichner ER, Klein DE, Barthel WF, Bennett JV, Jonsson V, et al. Pentachlorophenol poisoning in a nursery for newborn infants. II. Epidemiologic and toxicologic studies. J Pediatr. 1969;75:317–25.CrossRefGoogle Scholar
  23. 23.
    Feinblatt BI, Aceto T, Beckhorn G, Bruck E. Percutaneous absorption of hydrocortisone in children. Am J Dis Child. 1966;112:218–24.Google Scholar
  24. 24.
    Choonara IA. Giving drugs per rectum for systemic effect. Arch Dis Child. 1987;62:771–2.CrossRefGoogle Scholar
  25. 25.
    Friis-Hansen B. Water distribution in the foetus and newborn infant. Acta Paediatr Scand. 1983;305:7–11.CrossRefGoogle Scholar
  26. 26.
    De Hoog M, Mouton JW, van den Anker JN. New dosing strategies for antibacterial agents in the neonate. Semin Fetal Neonatal Med. 2005;10:185–94.CrossRefGoogle Scholar
  27. 27.
    Kearns GL, Jungbluth GL, Abdel-Rahman SM, Hopkins NK, Welshman IR, Grzebyk RP, et al. Impact of ontogeny on linezolid disposition in neonates and infants. Clin Pharmacol Ther. 2003;74(5):413–22.CrossRefGoogle Scholar
  28. 28.
    Daood M, Tsai C, Ahdab-Barmada M, Watchko JF. ABC transporter (P-gp/ABCB1, MRP1/ABCC1, BCRP/ABCG2) expression in the developing human CNS. Neuropediatrics. 2008;39:211–8.CrossRefGoogle Scholar
  29. 29.
    Johnson TN, Thomson M. Intestinal metabolism and transport of drugs in children: the effects of age and disease. J Pediatr Gastroenterol Nutr. 2008;47:3–10.CrossRefGoogle Scholar
  30. 30.
    Miethke A, Balistreri WF. Morphogenesis of the liver and biliary system. In: Kliegman RM, Stanton BF, Schor NF III JWSG, Behram RE, editors. Nelson textbook of pediatrics. Philadelphia: Elsevier; 2011.Google Scholar
  31. 31.
    Hines RN, McCarver DG. The ontogeny of human drug-metabolizing enzymes: phase I oxidative enzymes. J Pharmacol Exp Ther. 2002;300:355–60.CrossRefGoogle Scholar
  32. 32.
    McCarver DG, Hines RN. The ontogeny of human drug metabolizing enzymes: phase II conjugation enzymes and regulatory mechanisms. J Pharmacol Exp Ther. 2002;300:361–6.CrossRefGoogle Scholar
  33. 33.
    De Wildt SN, Kearns GL, Leeder JS, van den Anker JN. Glucuronidation in humans: Pharmacogenetic and developmental aspects. Clin Pharmacokinet. 1999;36:439–52.CrossRefGoogle Scholar
  34. 34.
    Alcorn J, McNamara PJ. Ontogeny of hepatic and renal systemic clearance pathways in infants: Part I. Clin Pharmacokinet. 2002;41:959–98.CrossRefGoogle Scholar
  35. 35.
    Hines RN. The ontogeny of drug metabolism enzymes and implications for adverse drug events. Pharmacol Ther. 2008;118:250–67.CrossRefGoogle Scholar
  36. 36.
    Balistreri W, Zimmer L, Suchy FJ, Bove KE. Bile salt sulfotransferase: alterations during maturation and non-inducibility during substrate ingestion. J Lipid Res. 1984;25:228–35.Google Scholar
  37. 37.
    Bard SE, Tompkins SF, Brien JF. Ontogeny of the activity of alcohol dehydrogenase and aldehyde dehydrogenase in the liver and placenta of the guinea pig. Biochem Pharmacol. 1989;38:2535–41.CrossRefGoogle Scholar
  38. 38.
    Blake MJ, Gaedigk A, Pearce RE, Bomgaars LR, Christensen ML, Stowe C, et al. Ontogeny of dextromethorphan O- and N-demethylation in the first year of life. Clin Pharmacol Ther. 2007;81(4):510–6.CrossRefGoogle Scholar
  39. 39.
    Blake MJ, Castro L, Leeder JS, Kearns GL. Ontogeny of drug metabolizing enzymes in the neonate. Semin Fetal Neonatal Med. 2005;10(2):123–8.CrossRefGoogle Scholar
  40. 40.
    De Wildt SN, Kearns GL, Hop WC, Murry DJ, Abdel-Rahman SM, van den Anker JN. Pharmacokinetics and metabolism of intravenous midazolam in preterm infants. Clin Pharmacol Ther. 2001;70(6):525–31.CrossRefGoogle Scholar
  41. 41.
    Kinirons MT, O’Shea D, Kim RB, Groopman JD, Thummel KE, Wood AJ, et al. Failure of erythromycin breath test to correlate with midazolam clearance as a probe of cytochrome P4503A. Clin Pharmacol Ther. 1999;66:224–31.CrossRefGoogle Scholar
  42. 42.
    Payne K, Mattheyse FJ, Liedenberg D, Dawes T. The pharmacokinetics of midazolam in paediatric patients. Eur J Clin Pharmacol. 1989;37:267–72.CrossRefGoogle Scholar
  43. 43.
    Bajpai M, Roskos LK, Shen DD, Levy RH. Roles of cytochrome P4502C9 and cytochrome P4502C19 in the stereoselective metabolism of phenytoin to its major metabolite. Drug Metab Dispos. 1996;24:1401–3.Google Scholar
  44. 44.
    Loughnan PM, Greenwald A, Purton WW, Aranda JV, Watters G, Neims AH. Pharmacokinetic observations of phenytoin disposition in the newborn and young infant. Arch Dis Child. 1977;52:302–9.CrossRefGoogle Scholar
  45. 45.
    Aranda JV, Collinge JM, Zinman R, Watters G. Maturation of caffeine elimination in infancy. Arch Dis Child. 1979;54:946–9.CrossRefGoogle Scholar
  46. 46.
    Zanger UM, Fischer J, Raimundo S, Stuven T, Evert BO, Schwab M, Eichelbaum M. Comprehensive analysis of the genetic factors determining expression and function of hepatic CYP2D6. Pharmacogenetics. 2001;11:573–85.CrossRefGoogle Scholar
  47. 47.
    Stevens JC, Hines RN, Gu C, Koukouritaki SB, Manro JR, Tandler PJ, et al. Developmental expression of the major human hepatic CYP3A enzymes. J Pharmacol Exp Ther. 2003;307(2):573–82.CrossRefGoogle Scholar
  48. 48.
    Min DI, Ellingrod VL, Marsh S, McLeod H. CYP3A5 polymorphism and the ethnic differences in cyclosporine pharmacokinetics in healthy subjects. Ther Drug Monit. 2004;26:524–8.CrossRefGoogle Scholar
  49. 49.
    Evans WE, Relling MV, Petros WP, Meyer WH, Mirro J Jr, Crom WR. Dextromethorphan and caffeine as probes for simultaneous determination of debrisoquin-oxidation and N-acetylation phenotypes in children. Clin Pharmacol Ther. 1989;45(5):568–73.CrossRefGoogle Scholar
  50. 50.
    Erenberg A, Leff RD, Haack DG, Mosdell KW, Hicks GM, Wynne BA. Caffeine citrate for the treatment of apnea of prematurity: a double-blind, placebo-controlled study. Pharmacotherapy. 2000;20(6):644–52.CrossRefGoogle Scholar
  51. 51.
    Lambert GH, Schoeller DA, Kotake AN, Flores C, Hay D. The effect of age, gender, and sexual maturation on the caffeine breath test. Dev Pharmacol Ther. 1986;9(6):375–88.CrossRefGoogle Scholar
  52. 52.
    Zanger UM, Raimundo S, Eichelbaum M. Cytochrome P450 2D6: overview and update on pharmacology, genetics and biochemistry. Naunyn Schmiedebergs Arch Pharmacol. 2004;369:23–37.CrossRefGoogle Scholar
  53. 53.
    Gaedigk A, Simon D, Pearce RE, Bradford LD, Kennedy MJ, Leeder JS. The CYP2D6 activity score: Translating genotype information into a quantitative measure of phenotype. Clin Pharmacol Ther. 2008;83:234–42.CrossRefGoogle Scholar
  54. 54.
    Treluyer JM, Jacqz-Aigrain E, Alvarez F, Cresteil T. Expression of CYP2D6 in developing human liver. Eur J Biochem. 1991;202(2):583–8.CrossRefGoogle Scholar
  55. 55.
    Johnson TN, Tucker GT, Rostami-Hodjegan A. Development of CYP2D6 and CYP3A4 in the first year of life. Clin Pharmacol Ther. 2008;83:670–1.CrossRefGoogle Scholar
  56. 56.
    Allegaert K, Rochette A, Veyckemans F. Developmental pharmacology of tramadol during infancy: ontogeny, pharmacogenetics and elimination clearance. Paediatr Anaesth. 2011;21(3):266–73.CrossRefGoogle Scholar
  57. 57.
    Lee CR, Goldstein JA, Pieper JA. Cytochrome P450 2C9 polymorphisms: a comprehensive review of the in vitro and human data. Pharmacogenetics. 2002;12(3):251–63.CrossRefGoogle Scholar
  58. 58.
    Koukouritaki SB, Manro JR, Marsh SA, Stevens JC, Rettie AE, McCarver DG, et al. Developmental expression of human hepatic CYP2C9 and CYP2C19. J Pharmacol Exp Ther. 2004;308(3):965–74.CrossRefGoogle Scholar
  59. 59.
    Suzuki Y, Mimaki T, Cox S, Koepke J, Hayes J, Walson PD. Phenytoin age-dose-concentration relationship in children. Ther Drug Moni. 1994;16(2):145–50.CrossRefGoogle Scholar
  60. 60.
    Kearns GL, Winter HS. Proton pump inhibitors in pediatrics: relevant pharmacokinetics and pharmacodynamics. J Pediatr Gastroenterol Nutr. 2003;37(Suppl I):S52–9.CrossRefGoogle Scholar
  61. 61.
    Kearns GL, Anderson T, James LP, Gaedigk A, Kraynak RA, Abdel-Rahman SM, et al. Omeprazole disposition in children following single dose administration. J Clin Pharmacol. 2003;43(8):840–8.CrossRefGoogle Scholar
  62. 62.
    Jung F, Richardson TH, Raucy JL, Johnson EF. Diazepam metabolism by cDNA-expressed human 2C P450s: identification of P4502C18 and P4502C19 as low K(M) diazepam N-demethylases. Drug Metab Dispos. 1997;25(2):133–9.Google Scholar
  63. 63.
    Brandolese R, Scordo MG, Spina E, Gusella M, Padrini R. Severe phenytoin intoxication in a subject homozygous for CYP2C9*3. Clin Pharmacol Ther. 2001;70(4):391–4.Google Scholar
  64. 64.
    Jimenez-Lopez JM, Cederbaum AI. CYP2E1-dependent oxidative stress and toxicity: role in ethanol-induced liver injury. Expert Opin Drug Metab Toxicol. 2005;1(4):671–85.CrossRefGoogle Scholar
  65. 65.
    Johnsrud EK, Koukouritaki SB, Divakaran K, Brunengraber LL, Hines RN, McCarver DG. Human hepatic CYP2E1 expression during development. J Pharmacol Exp Ther. 2003;307(1):402–7.CrossRefGoogle Scholar
  66. 66.
    Choonara IA, McKay P, Hain R, Rane A. Morphine metabolism in children. Br J Clin Pharmacol. 1989;28:599–604.CrossRefGoogle Scholar
  67. 67.
    Rhodin MM, Anderson BJ, Peters AM, Coulthard MG, Wilkins B, Cole M, et al. Human renal function maturation: a quantitative description using weight and postmenstrual age. Pediatr Nephrol. 2009;24:67–76.CrossRefGoogle Scholar
  68. 68.
    Chen N, Aleksa K, Woodland C, Rieder M, Koren GL. Ontogeny of drug elimination by the human kidney. Pediatr Nephrol. 2006;21:160–8.CrossRefGoogle Scholar
  69. 69.
    Van den Anker JN, Schoemaker R, Hop W, van der Heijden BJ, Weber A, Sauer PJ, et al. Ceftazidime pharmacokinetics in preterm infants: effects of renal function and gestational age. Clin Pharmacol Ther. 1995;58:650–9.CrossRefGoogle Scholar
  70. 70.
    Filler G, Lepage N. Should the Schwartz formula for estimation of GFR be replaced by cystatin C formula? Pediatr Nephrol. 2003;18(10):981–5.CrossRefGoogle Scholar
  71. 71.
    Capparelli EV, Lane JR, Romanowski GL, McFeely EJ, Murray W, Sousa P, et al. The influences of renal function and maturation on vancomycin elimination in newborns and infants. J Clin Pharmacol. 2001;41:927–34.CrossRefGoogle Scholar
  72. 72.
    Van den Anker JN, de Groot R, Broerse HM, Sauer PJ, van der Heijden BJ, Neijens HJ, et al. Assessment of glomerular filtration rate in preterm infants by serum creatinine: comparison with inulin clearance. Pediatrics. 1995;96(6):1156–8.Google Scholar
  73. 73.
    Hayton WL. Maturation and growth of renal function: dosing renally cleared drugs in children. AAPS PharmSci. 2002;2(3):e3.Google Scholar
  74. 74.
    James LP, Marotti T, Stowe C, Farrar HC, Taylor B, Kearns GL. Pharmacokinetics and pharmacodynamics of famotidine in infants. J Clin Pharmacol. 1998;38:1089–95.Google Scholar
  75. 75.
    De Hoog M, Mouton JW, Schoemaker RC, Verduin CM, van den Anker JN. Extended-interval dosing of tobramycin in neonates: implications for therapeutic drug monitoring. Clin Pharmacol Ther. 2002;71:349–58.CrossRefGoogle Scholar
  76. 76.
    Van den Anker JN, Van der Heijden AJ, Hop WCJ, Schoemaker RC, Broerse HM, Neijens HJ, et al. The effect of asphyxia on the pharmacokinetics of ceftazidime in the term newborn. Pediatr Res. 1995;38:808–11.CrossRefGoogle Scholar
  77. 77.
    Van den Anker JN, Hop WCJ, Schoemaker RC, Van der Heijden AJ, Neijens HJ, De Groot R. Ceftazidime pharmacokinetics in preterm infants: effects of postnatal age and postnatal exposure to indomethacin. Br J Clin Pharmacol. 1995;40:439–43.PubMedPubMedCentralGoogle Scholar
  78. 78.
    Van Overmeire B, Touw D, Schepens PJC, Kearns GL, van den Anker JN. Ibuprofen pharmacokinetics in preterm infants with patent ductus arteriosus. Clin Pharmacol Ther. 2001;70:336–43.CrossRefGoogle Scholar
  79. 79.
    Roka A, Melinda KT, Vasarhelyi B, Machay T, Azzopardi D, Szabo M. Elevated morphine concentrations in neonates treated with morphine and prolonged hypothermia for hypoxic ischemic encephalopathy. Pediatrics. 2008;121(4):e844–9.CrossRefGoogle Scholar
  80. 80.
    Schwab M, Eichelbaum M, Fromm MF. Genetic polymorphisms of the human MDR1 drug transporter. Annu Rev Pharmacol Toxicol. 2003;43:285–307.CrossRefGoogle Scholar
  81. 81.
    Nies AT, Schwab M, Keppler D. Interplay of conjugating enzymes with OATP uptake transporters and ABCC/MRP efflux pumps in the elimination of drugs. Expert Opin Drug Metab Toxicol. 2008;4:545–68.CrossRefGoogle Scholar
  82. 82.
    Niemi M, Pasanen MK, Neuvonen PJ. Organic anion transporting polypeptide 1B1: a genetically polymorphic transporter of major importance for hepatic drug uptake. Pharmacol Rev. 2011;63(1):157–81.CrossRefGoogle Scholar
  83. 83.
    Russo R, Capasso M, Paolucci P, Iolascon A. TEDDY European Network of Excellence. Pediatric pharmacogenetic and pharmacogenomic studies: the current state and future perspectives. Eur J Clin Pharmacol. 67(Suppl 1):17–27.CrossRefGoogle Scholar
  84. 84.
    Willmann S, Edgington AN, Coboeken K, Ahr G, Lippert J. Risk to the breast-fed neonate from codeine treatment to the mother: a quantitative mechanistic modelling study. Clin Pharmacol Ther. 2009;86:634–43.CrossRefGoogle Scholar
  85. 85.
    Henschel O, Gipson KE, Bordey A. GABA receptors, anesthetics and anticonvulsants in brain development. CNS Neurol Disord Drug Targets. 2008;7:211–24.CrossRefGoogle Scholar
  86. 86.
    Kretz FJ, Reimann B. Ontogeny of receptors relevant to anesthesiology. Curr Opin Anaesthesiol. 2003;16:281–4.CrossRefGoogle Scholar
  87. 87.
    Holford N. Dosing in children. Clin Pharmacol Ther. 2010;87:367–70.CrossRefGoogle Scholar

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Authors and Affiliations

  1. 1.Erasmus Medical Center, Sophia Children’s HospitalRotterdamThe Netherlands
  2. 2.Department of Intensive CareErasmus Medical Center, Sophia Children’s HospitalRotterdamThe Netherlands

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