Clinical Pharmacokinetics

, Volume 45, Issue 11, pp 1077–1097 | Cite as

Guidelines on Paediatric Dosing on the Basis of Developmental Physiology and Pharmacokinetic Considerations

  • Imke H. Bartelink
  • Carin M. A. Rademaker
  • Alfred F. A. M. Schobben
  • John N. van den Anker
Review Article

Abstract

The approach to paediatric drug dosing needs to be based on the physiological characteristics of the child and the pharmacokinetic parameters of the drug. This review summarises the current knowledge on developmental changes in absorption, distribution, metabolism and excretion and combines this knowledge with in vivo and in vitro pharmacokinetic data that are currently available. In addition, dosage adjustments based on practical problems, such as child-friendly formulations and feeding regimens, disease state, genetic make-up and environmental influences are presented.

Modification of a dosage based on absorption, depends on the route of absorption, the physico chemical properties of the drug and the age of the child. For oral drug absorption, a distinction should be made between the very young and children over a few weeks old. In the latter case, it is likely that practical considerations, like appropriate formulations, have much greater relevance to oral drug absorption.

The volume of distribution (Vd) may be altered in children. Hydrophilic drugs with a high Vd in adults should be normalised to bodyweight in young children (age <2 years), whereas hydrophilic drugs with a low Vd in adults should be normalised to body surface area (BSA) in these children. For drugs that are metabolised by the liver, the effect of the Vd becomes apparent in children <2 months of age. In general, only the first dose should be based on the Vd subsequent doses should be determined by the clearance. Pharmacokinetic studies on renal and liver function clarify that a distinction should be made between maturation and growth of the organs. After the maturation process has finished, the main influences on the clearance of drugs are growth and changes in blood flow of the liver and kidney. Drugs that are primarily metabolised by the liver should be administered with extreme care until the age of 2 months. Modification of dosing should be based on response and on therapeutic drug monitoring. At the age of 2–6 months, a general guideline based on bodyweight may be used. After 6 months of age, BSA is a good marker as a basis for drug dosing. However, even at this age, drugs that are primarily metabolised by cytochrome P450 2D6 and uridine diphosphate glucuronosyltransferase should be normalised to bodyweight.

In the first 2 years of life, the renal excretion rate should be determined by markers of renal function, such as serum creatinine and p-aminohippuric acid clearance. A dosage guideline for drugs that are significantly excreted by the kidney should be based on the determination of renal function in first 2 years of life. After maturation, the dose should be normalised to BSA.

These guidelines are intended to be used in clinical practice and to form a basis for more research. The integration of these guidelines, and combining them with pharmacodynamic effects, should be considered and could form a basis for further study.

References

  1. 1.
    Rodman JH. Pharmacokinetic variability in the adolescent: implications of body size and organ function for dosage regimen design. J Adolesc Health 1994; 15(8): 654–62PubMedCrossRefGoogle Scholar
  2. 2.
    Crawford JD, Terry ME, Rourke GM. Simplification of drug dosage calculation by application of the surface area principle. Pediatrics 1950; 5(5): 783–90PubMedGoogle Scholar
  3. 3.
    Meine Jansen CF, Toet MC, Rademaker CM, et al. Treatment of symptomatic congenital cytomegalovirus infection with valganciclovir. J Perinat Med 2005; 33(4): 364–6Google Scholar
  4. 4.
    Yaffe SJ, Aranda JV. Neonatal and pediatric pharmacology therapeutic principles in practice. 3rd ed. Philadelphia (PA): Lippincott Williams & Wilkins, 2004Google Scholar
  5. 5.
    Holford HG. A size standard for pharmacokinetics. Clin Pharmacokinet 1996; 30(5): 329–32PubMedCrossRefGoogle Scholar
  6. 6.
    Kearns GL, Abdel-Rahman SM, Alander SW, et al. Developmental pharmacology-drug disposition, action, and therapy in infants and children. N Engl J Med 2003; 349: 1157–67PubMedCrossRefGoogle Scholar
  7. 7.
    Moore P. Children are not small adults. Lancet 1998; 352(9128): 630PubMedCrossRefGoogle Scholar
  8. 8.
    Ritschel WA, Kearns GL. Handbook of basis pharmacokinetics including clinical applications. 6th ed. Washington, DC: American Pharmaceutical Association, 2004: 227–240Google Scholar
  9. 9.
    Rennie JM, Roberten NRC. Textbook of neonatology. 3rd ed. Edinburgh: Churchill Livingstone, 1999Google Scholar
  10. 10.
    McLeod HL, Relling MV, Crom WR, et al. Disposition of antineoplastic agents in the very young child: pharmacokinetics in children. Br J Cancer Suppl 1992; 18: S23–9PubMedGoogle Scholar
  11. 11.
    Strolin Benedetti M, Baltes EL. Drug metabolism and disposition in children. Fundam Clin Pharmacol 2003; 17: 281–99CrossRefGoogle Scholar
  12. 12.
    Kearns GL. Impact of developmental pharmacology on pediatric study desing; overcoming the challenges. J Allergy Clin Immunol 2000; 106: S128–39PubMedCrossRefGoogle Scholar
  13. 13.
    Hunseler C, Roth B, Pothmann R, et al. Intramuscular injections in children [in German]. Schmerz 2005 Apr; 19(2): 140–3PubMedCrossRefGoogle Scholar
  14. 14.
    Jatzen JP, Diehl P. Rectal administration of drugs: fundamentals and applications in anesthesia [in German]. Anaesthesist 1991; 40(5): 251–61Google Scholar
  15. 15.
    American Academy of Pediatrics Committee on Drugs. Alternative routes of drug administration: advantages and disadvantages. Pediatrics 1997; 100: 143–52CrossRefGoogle Scholar
  16. 16.
    Anderson BJ, van Lingen RA, Hansen TG, et al. Acetaminophen developmental pharmacokinetics in premature neonates and infants: a pooled population analysis. Anesthesiology 2002; 96(6): 1336–45PubMedCrossRefGoogle Scholar
  17. 17.
    Kearns GL, Robinson PK, Wilson JT, et al. Pharmacokinetics and drug disposition cisapride disposition in neonates and infants: in vivo reflection of cytochrome P450 3A4 ontogeny. Clin Pharmacol Ther 2003; 4: 312–25CrossRefGoogle Scholar
  18. 18.
    Kearns GL, Bradley JS, Jacobs RF, et al. Single dose pharmacokinetics of pleconaril in neonates. Pediatr Infect Dis J 2000; 19(9): 833–9PubMedCrossRefGoogle Scholar
  19. 19.
    de Wildt SN, Kearns GL, Hop WC, et al. Pharmacokinetics and metabolism of oral midazolam in preterm infants. Br J Clin Pharmacol 2002 Apr; 53(4): 390–2PubMedCrossRefGoogle Scholar
  20. 20.
    Boucher FD, Modlin JF, Weiler S, et al. Phase I evaluation of zidovudine administered to infants exposed at birth to the human immunodeficiency virus. J Pediatr 1993; 122: 1137–44Google Scholar
  21. 21.
    Capparelli EV, Mirochnick M, Dankner WM, et al. Pharmacokinetics and tolerance of zidovudine in preterm infants. J Pediatr 2003; 142: 47–52PubMedCrossRefGoogle Scholar
  22. 22.
    Albani M, Wernicke I. Oral phenytoin in infancy: dose requirement, absorption, and elimination. Pediatr Pharmacol (New York) 1983; 3(3–4): 229–36Google Scholar
  23. 23.
    de Repentigny L, Ratelle J, Leclerc JM, et al. Repeated-dose pharmacokinetics of an oral solution of itraconazole in infants and children. Antimicrob Agents Chemother 1998; 42(2): 404–8PubMedGoogle Scholar
  24. 24.
    Abdel-Rahman SM, Johnson FK, Connor JD, et al. Developmental pharmacokinetics and pharmacodynamics of nizatidine. J Pediatr Gastroenterol Nutr 2004; 38(4): 442–51PubMedCrossRefGoogle Scholar
  25. 25.
    Kokki H, Karvinen M, Suhonen P. Pharmacokinetics of intravenous and rectal ketoprofen in young children. Clin Pharmacokinet 2003; 42(4): 373–9PubMedCrossRefGoogle Scholar
  26. 26.
    Ishizaki T, Sasaki T, Suganuma T. Pharmacokinetics of ketoprofen following single oral, intramuscular and rectal doses and after repeated oral administration. Eur J Clin Pharmacol 1980; 18(5): 407–14PubMedCrossRefGoogle Scholar
  27. 27.
    van Lingen RA, Deinum JT, Quak JME, et al. Pharmacokinetics and metabolism of rectally administered paracetamol in preterm neonates. Arch Dis Child Fetal Neonatal Ed 1999; 80: F59–63PubMedCrossRefGoogle Scholar
  28. 28.
    Zwaveling J, Bubbers S, van Meurs AH, et al. Pharmacokinetics of rectal tramadol in postoperative paediatric patients. Br J Anaesth 2004; 93(2): 224–7PubMedCrossRefGoogle Scholar
  29. 29.
    Rudolph AM, Kamei RK, Overby K J. Rudolph’s fundamentals of pediatrics. 2nd ed. Stanford: Appleton & Lange, 1998: 400Google Scholar
  30. 30.
    Ginsberg G, Hattis D, Miller M, et al. Pediatrie pharmacokinetic data: implications for environmental risk assessment for children. Pediatrics 2004; 113(4): 973–83PubMedGoogle Scholar
  31. 31.
    Kimura T, Sunakawa K, Matsuura N, et al. Population pharmacokinetics of arbekacin, vancomycin, and panipenem in neonates. Antimicrob Agents Chemother 2004; 48(4): 1159–67PubMedCrossRefGoogle Scholar
  32. 32.
    Bartels H. Drug therapy in childhood: what has been done and what has to be done? Pediatr Pharmacol (New York) 1983; 3: 131–43Google Scholar
  33. 33.
    Kearns GL, Jungbluthy GL, Abdel-Rahman SM, et al. Impact of ontogeny on linezolid disposition in neonates and infants. Clin Pharmacol Ther 2003; 74(5): 413–22PubMedCrossRefGoogle Scholar
  34. 34.
    Hayani KC, Hatzopoulos FK, Frank AL, et al. Pharmacokinetics of once-daily dosing of gentamicin in neonates. J Pediatr 1997; 131: 76–80PubMedCrossRefGoogle Scholar
  35. 35.
    Watterberg KL, Kelly HW, Angelus P, et al. The need for a loading dose of gentamicin in neonates. Ther Drug Monit 1989; 11(1): 16–20PubMedCrossRefGoogle Scholar
  36. 36.
    Allegaert K, Anderson BJ, Verbesselt R, et al. Tramadol disposition in the very young: an attempt to assess in vivo cytochrome P-450 activity. Br J Anaesth 2005; 95(2): 231–9PubMedCrossRefGoogle Scholar
  37. 37.
    Anderson GD. Children versus adults: pharmacokinetic and adverse-effect differences. Epilepsia 2002; 43: 53–9PubMedCrossRefGoogle Scholar
  38. 38.
    Capparelli EV, Lane JR, Romanowski GL, et al. The influences of renal function and maturation on vancomycin elimination in newborns and infants. J Clin Pharmacol 2001; 41: 927–34PubMedCrossRefGoogle Scholar
  39. 39.
    Alcorn J, McNamara PJ. Ontogeny of hepatic and renal systemic clearance pathways in infants part 1. Clin Pharmacokinet 2002; 41(12): 959–98PubMedCrossRefGoogle Scholar
  40. 40.
    Rating D, Jager-Roman E, Nau H, et al. Enzyme induction in neonates after fetal exposure to antiepileptic drugs. Pediatr Pharmacol (New York) 1983; 3(3–4): 209–18Google Scholar
  41. 41.
    Morselli PL. Antiepileptic drugs. Milan: 1976: 1–45Google Scholar
  42. 42.
    Pineiro-Carrero VM, Pineiro EO. Liver. Pediatrics 2004; 113 (4 Suppl.): 1097–106PubMedGoogle Scholar
  43. 43.
    Wildt SN, Kearns GL, Leeder JS, et al. Glucuronidation in humans: pharmacogenitic and developmental aspects. Clin Pharmacokinet 1999; 36(6): 439–43PubMedCrossRefGoogle Scholar
  44. 44.
    Wildt SN, Kearns GL, Leeder JS, et al. Cytochrome P450 3A: ontogeny and drug disposition. Clin Pharmacokinet 1999; 37(6): 485–505PubMedCrossRefGoogle Scholar
  45. 45.
    Bouwmeester NJ, Anderson BJ, Tibboel D, et al. Developmental pharmacokinetics of morphine and its metabolites in neonates, infants and young children. Br J Anaesth 2004 Feb; 92(2): 208–17PubMedCrossRefGoogle Scholar
  46. 46.
    Murry DJ, Crom WR, Reddick WE, et al. Liver volume as a determinant of drug clearance in children and adolescents. Drug Metab Dispos 1995; 23(10): 1110–6PubMedGoogle Scholar
  47. 47.
    Kanamori M, Takahaski H, Echizen H. Developmental changes in the liver weight- and body weight-normalized clearance of theophylline, phenytoine and cyclosporine in children. Int J Clin Pharmacol Ther 2002; 40(11): 485–92PubMedGoogle Scholar
  48. 48.
    Blanco JG, Harrison PL, Evans WE, et al. human cytochrome P450 maximal activities in pediatric versus adult liver. Drug Metab Dispos 2000; 28(4): 379–82PubMedGoogle Scholar
  49. 49.
    Björkman S. Prediction of cytochrome P450-mediated hepatic drug clearance in neonates, infants and children: how accurate are available scaling methods? Clin Pharmacokinet 2006; 45(11): 1–11PubMedCrossRefGoogle Scholar
  50. 50.
    Ginsberg G, Hattis D, Miller M, et al. Evaluation of child/adult pharmacokinetic differences from a database derived from the therapeutic drug literature. Toxicol Sci 2002; 66: 185–200PubMedCrossRefGoogle Scholar
  51. 51.
    Alcorn J, McNamara PJ. Ontogeny of hepatic and renal systemic clearance pathways in infants part 2. Clin Pharmacokinet 2002; 41(13): 1077–94PubMedCrossRefGoogle Scholar
  52. 52.
    Murat I, Billard V, Vernois J, et al. Pharmacokinetics of propofol after a single dose in children aged 1–3 years with minor burns: comparison of three data analysis approaches. Anesthesiology 1996 Mar; 84(3): 526–32PubMedCrossRefGoogle Scholar
  53. 53.
    Kataria BK, Ved SA, Nicodemus HF, et al. The pharmacokinetics of propofol in children using three different data analysis approaches. Anesthesiology 1994 Jan; 80(1): 104–22PubMedCrossRefGoogle Scholar
  54. 54.
    Valtonen M, Lisalo E, Kanto J, et al. Propofol as an induction agent in children: pain on injection and pharmacokinetics. Acta Anaesthesiol Scand 1989; 33: 152–5PubMedCrossRefGoogle Scholar
  55. 55.
    Knibbe CAJ, Zuideveld KP, Aarts LPHJ, et al. Allometric relationships between the pharmacokinetics of propofol in rats, children and adults. Br J Clin Pharmacol 2005; 59(6): 705–11PubMedCrossRefGoogle Scholar
  56. 56.
    Evans WE, Relling MV, de Graaf S, et al. Hepatic drug clearance in children: studies with indocyanine green as a model substrate. J Pharmaceut Sci 1989 Jun; 78(6): 452–6CrossRefGoogle Scholar
  57. 57.
    Cooney GF, Habucky K, Hoppu K. Cyclosporin pharmacokinetics in paediatric transplant recipients. Clin Pharmacokinet 1997; 32(6): 481–95PubMedCrossRefGoogle Scholar
  58. 58.
    Kearns GL, Andersson T, James LP, et al. Omeprazole disposition in infants and children; role of age and CYP2C19 genotype. J Clin Pharmacol 2003 Aug; 43(8): 840–8PubMedCrossRefGoogle Scholar
  59. 59.
    Crom WR, Relling MV, Christensen ML, et al. Age-related differences in hepatic drug clearance in children: studies with lorazepam and antipyrine. Clin Pharmacol Ther 1991; 50(2): 132–40PubMedCrossRefGoogle Scholar
  60. 60.
    Hunt A, Joel S, Dick G, et al. Population pharmacokinetics of oral morphine and its glucuronides in children receiving morphine as immediate-release liquid or sustained-release tablets for cancer pain. J Pediatr 1999 Jul; 135(1): 47–55PubMedCrossRefGoogle Scholar
  61. 61.
    Bakshi SS, Britto P, Capparelli E, et al. Evaluation of pharmacokinetics, safety, tolerance, and activity of combination of zalcitabine and zidovudine in stable, zidovudine-treated pediatric patients with human immunodeficiency virus infection. AIDS Clinical Trials Group Protocol 190 Team. J Infect Dis 1997 May; 175(5): 1039–50PubMedCrossRefGoogle Scholar
  62. 62.
    Payne KA, Roelofse JA, Shipton EA. Pharmacokinetics of oral tramadol drops for postoperative pain relief in children aged 4 to 7 years: a pilot study. Anesth Prog 2002; 49(4): 109–12PubMedGoogle Scholar
  63. 63.
    Murthy BVS, Pandya KS, Booker PD, et al. Pharmacokinetics of tramadol in children after i.V. or caudal epidural administration. Br J Anaesth 2000; 84(3): 346–9PubMedCrossRefGoogle Scholar
  64. 64.
    Van Der Marel CD, Anderson BJ, Van Lingen RA, et al. Paracetamol and metabolite pharmacokinetics in infants. Eur J Clin Pharmacol 2003; 59: 243–51PubMedCrossRefGoogle Scholar
  65. 65.
    Yared A, Ichikawa I. Glomerular circulation and function in pediatric nephrology. 3rd ed. Baltimore: Williams and Wilkins, 1994: 39–55Google Scholar
  66. 66.
    Brande van den JL, Gelderen van HH, Monnens LAH. Pediatrics [in Dutch]. Utrecht: Bunge, 1990Google Scholar
  67. 67.
    Bird NJ, Henderson BL, Lui D, et al. Indexing glomerular filtration rate to suit children. J Nucl Med 2003; 44: 1037–4PubMedGoogle Scholar
  68. 68.
    Sawyer M, Ratain MJ. Body surface area as a determinant of pharmacokinetics and drug dosing. InvestNew Drugs 2001; 19(2): 171–7PubMedCrossRefGoogle Scholar
  69. 69.
    Hayton WL. Maturation and growth of renal faction: dosing renally cleared drugs in children. AAPS PharmSci 2002; 2(3): e3Google Scholar
  70. 70.
    Peters AM, Henderson BL, Lui D. Indexed glomerular filtration rate as a function of age and body size. Clin Sci 2000; 98: 439–44PubMedCrossRefGoogle Scholar
  71. 71.
    Siegel SR, Oh W. Renal function as a marker of human fetal maturation. Acta Paediatr Scand 1976; 65: 481–5PubMedCrossRefGoogle Scholar
  72. 72.
    Gallini F, Maggio L, Romagnoli C, et al. Progression of renal function in preterm neonates with gestational age ≤32 weeks. Pediatr Nephrol 2000; 14: 119–24CrossRefGoogle Scholar
  73. 73.
    Rennie JM, Roberten NRC. Textbook of neonatology. 3rd ed. Edinburgh: Churchill Livingstone, 1999: 417–433Google Scholar
  74. 74.
    Filler G, Lepage N. Should the Schwartz formula for estimation of GFR be replaced by cystatin C formula? Pediatr Nephrol 2003 Oct; 18(10): 981–5PubMedCrossRefGoogle Scholar
  75. 75.
    Brion LP, Fleischman AR, Schwartz GJ. Gentamicin interval in newborn infants as determined by renal function and postconceptional age. Pediatr Nephrol 1991; 5: 675–8PubMedCrossRefGoogle Scholar
  76. 76.
    Schwartz GJ, Haycock GB, Edelmann CM, et al. Simple estimate of glomerular filtration rate in children derived from body length and plasma creatinine. Pediatrics 1976; 58: 259–63PubMedGoogle Scholar
  77. 77.
    Hogg RJ, Furth S, Lemley KV, et al. National Kidney Foundation’s kidney disease outcomes quality initiative clinical practice guidelines for chronic kidney disease in children and adolescents: evaluation, classification, and stratification. Pediatrics 2003; 111(6): 1416–21PubMedCrossRefGoogle Scholar
  78. 78.
    Counahan R, Chantier C, Ghazali S, et al. Estimation of glomerular filtration rate from plasma creatinine concentration in children. Arch Dis Child 1976; 51: 875–8PubMedCrossRefGoogle Scholar
  79. 79.
    Morris MC, Allanby CW, Tolesland P, et al. Evaluation of a height/plasma creatinine formula in the measurement of glomerular filtration rate. Arch Dis Child 1982; 57: 611–5PubMedCrossRefGoogle Scholar
  80. 80.
    Leger F, Bouissou F, Coulais Y, et al. Estimation of glomerular filtration rate in children. Pediatr Nephrol 2002; 17: 903–7PubMedCrossRefGoogle Scholar
  81. 81.
    Hellerstein S, Alon U, Warady BA. Creatinine for estimation of glomerular filtration rate. Pediatr Nephrol 1992; 6(6): 507–11PubMedCrossRefGoogle Scholar
  82. 82.
    Pierrat A, Gravier E, Saunders C, et al. Predicting GFR in children and adults: a comparison of the Cockcroft-Gault, Schwartz and Modification of Diet in Renal Disease formulas. Kidney Int 2003; 64: 1425–36PubMedCrossRefGoogle Scholar
  83. 83.
    Saul JP, Schaffer MS, Karpawich PP, et al. Single-dose pharmacokinetics of sotalol in a pediatric population with supraventricular and/or ventricular tachyarrhythmia. J Clin Pharmacol 2001; 41(1): 35–43PubMedCrossRefGoogle Scholar
  84. 84.
    Rossum LK, Mathot RAA, Cransberg K, et al. Estimation of the glomerular filtration rate in children: which algorithm should be used? Pediatr Nephrol 2005; 20: 1769–75PubMedCrossRefGoogle Scholar
  85. 85.
    van den Anker JN, de Groot R, Broerse HM, et al. Assessment of glomerular filtration rate in preterm infants by serum creatinine: comparison with inulin clearance. Pediatrics 1995 Dec; 96(6): 1156–8PubMedGoogle Scholar
  86. 86.
    Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976; 16: 31–41PubMedCrossRefGoogle Scholar
  87. 87.
    Reed MD, Kliegman RM, Yamashita TS, et al. Clinical pharmacology of imipenem and cilastatin in premature infants during the first week of life. Antimicrob Agents Chemother 1990; 34(6): 1172–7PubMedCrossRefGoogle Scholar
  88. 88.
    Jacobs RF, Kearns GL, Brown AL, et al. Renal clearance of imipenem in children. Eur J Clin Microbiol 1984; 3(5): 471–4PubMedCrossRefGoogle Scholar
  89. 89.
    Soyka LF. Pediatric clinical pharmacology of digoxin. Pediatr Clin North Am 1981 Feb; 28(1): 203–16PubMedGoogle Scholar
  90. 90.
    De Hoog M, Mouton JW, van den Anker JN. New dosing strategies for antibacterial agents in the neonate. Semin Fetal Neonatal Med 2005; 10: 185–94PubMedCrossRefGoogle Scholar
  91. 91.
    Thomson AH, Kerr S, Wright S. Population pharmacokinetics of caffeine in neonates and young infants. Ther Drug Monit 1996 Jun; 18(3): 245–53PubMedCrossRefGoogle Scholar
  92. 92.
    Paul D, Standifer KM, Inturrisi CE, et al. Pharmacological characterization of morphine-6 beta-glucuronide, a very potent morphine metabolite. Pharmacol Exp Ther 1989; 251(2): 447–83Google Scholar
  93. 93.
    Fanaroff AA, Martin RJ, editors. Neonatal-perinatal medicine. 7th ed. New York: Elsevier, 2001Google Scholar
  94. 94.
    Rigby-Jones AEB, Nolan JA, Priston MJ, et al. Pharmacokinetics of propofol infusions in critically ill neonates, infants, and children in an intensive care unit. Anesthesiology 2002; 97(6): 1393–400PubMedCrossRefGoogle Scholar
  95. 95.
    Rodman JH, Relling MV, Stewart CF, et al. Clinical pharmacokinetics and pharmacodynamics of anticancer drugs in children. Semin Oncol 1993; 20(1): 18–29PubMedGoogle Scholar
  96. 96.
    van den Anker JN, Hop WC, de Groot R, et al. Effects of prenatal exposure to betamethasone and indomethacin on the glomerular filtration rate in the preterm infant. Pediatr Res 1994 Nov; 36(5): 578–81PubMedCrossRefGoogle Scholar
  97. 97.
    Zwaveling J, Bredius RGM, Cremers SCLM, et al. Intravenous busulfan in children prior to stem cell transplantation: study of pharmacokinetics in association with early clinical outcome and toxicity. Bone Marrow Transplant 2005 Jan; 35(1): 17–23PubMedCrossRefGoogle Scholar
  98. 98.
    Kleinknecht D, Ganeval D, Droz D. Acute renal failure after high doses of gentamicin and cephalothin. Lancet 1973; I: 1129CrossRefGoogle Scholar
  99. 99.
    Soldin OP, Soldin SJ. Review: therapeutic drug monitoring in pediatrics. Ther Drug Monit 2002; 24: 1–8PubMedCrossRefGoogle Scholar
  100. 100.
    Johnson TN. Modelling approaches to dose estimation in children. Br J Clin Pharmacol 2005; 59(6): 663–9PubMedCrossRefGoogle Scholar
  101. 101.
    Baber NS. Tripartite meeting. Paediatric regulatory guidelines: do they help in optimizing dose selection for children? Br J Clin Pharmacol 2005; 69(6): 660–2CrossRefGoogle Scholar
  102. 102.
    Laer S, Elshoff JP, Meibohm B, et al. Development of a safe and effective pediatric dosing regimen for sotalol based on population pharmacokinetics and pharmacodynamics in children with supraventricular tachycardia. J Am Coll Cardiol 2005; 46(7): 1322–30PubMedCrossRefGoogle Scholar
  103. 103.
    Bjorkman S. Prediction of drug disposition in infants and children by means of physiologically based pharmacokinetic (PBPK) modelling: theophylline and midazolam as model drugs. Br J Clin Pharmacol 2004; 59(6): 691–704CrossRefGoogle Scholar
  104. 104.
    Ginsberg G, Hattis D, Russ A, et al. Physiologically based pharmacokinetic (PBPK) modeling of caffeine and theophylline in neonated and adults: implications for assessing children/s risks from environmental agents. J Toxicol Environ Health A 2004; 67: 297–329PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2006

Authors and Affiliations

  • Imke H. Bartelink
    • 1
  • Carin M. A. Rademaker
    • 2
  • Alfred F. A. M. Schobben
    • 1
  • John N. van den Anker
    • 3
    • 4
    • 5
  1. 1.Department of PharmacyUniversity Medical Center UtrechtUtrechtThe Netherlands
  2. 2.Department of PharmacyWilhelmina Children’s Hospital University Medical CenterUtrechtThe Netherlands
  3. 3.Department of Pediatrics, Erasmus MC-SophiaSophia Children’s HospitalRotterdamThe Netherlands
  4. 4.Division of Pediatric Clinical PharmacologyChildren’s National Medical CenterWashington, DCUSA
  5. 5.Departments of Pediatrics, Pharmacology and PhysiologyGeorge Washington University School of Medicine and Health SciencesWashington, DCUSA

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