Advertisement

Clinical Pharmacokinetics

, Volume 45, Issue 7, pp 683–704 | Cite as

A Mechanistic Approach for the Scaling of Clearance in Children

  • Andrea N. EdgintonEmail author
  • Walter Schmitt
  • Barbara Voith
  • Stefan Willmann
Original Research Article

Abstract

Background and objective

Clearance is an important pharmacokinetic concept for scaling dosage, understanding the risks of drug-drug interactions and environmental risk assessment in children. Accurate clearance scaling to children requires prior knowledge of adult clearance mechanisms and the age-dependence of physiological and enzymatic development. The objective of this research was to develop and evaluate ontogeny models that would provide an assessment of the age-dependence of clearance.

Methods

Using in vitro data and/or in vivo clearance values for children for eight compounds that are eliminated primarily by one process, models for the ontogeny of renal clearance, cytochrome P450 (CYP) 3A4, CYP2E1, CYP1A2, uridine diphosphate glucuronosyltransferase (UGT) 2B7, UGT1A6, sulfonation and biliary clearance were developed. Resulting ontogeny models were evaluated using six compounds that demonstrated elimination via multiple pathways. The proportion of total clearance attributed to each clearance pathway in adults was delineated. Each pathway was individually scaled to the desired age, inclusive of protein-binding prediction, and summed to generate a total plasma clearance for the child under investigation. The paediatric age range included in the study was premature neonates to sub-adults.

Results

There was excellent correlation between observed and predicted clearances for the model development (R2 = 0.979) and test sets (Q2 = 0.927). Clearance in premature neonates could also be well predicted (development R2 = 0.951; test Q2 = 0.899).

Conclusion

Paediatric clinical trial development could greatly benefit from clearance scaling, particularly in guiding dosing regimens. Furthermore, since the proportion of clearance via different elimination pathways is age-dependent, information could be gained on the developmental extent of drug-drug interactions.

Keywords

Glomerular Filtration Rate Ropivacaine Alfentanil Total Clearance Unbind Fraction 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgements

The authors acknowledge valuable discussions with the colleagues from the Clinical Pharmacokinetics Department of Bayer HealthCare AG, particularly Dr Gertrud Ahr and Dr Heino Stass.

No sources of funding were used to assist in the preparation of this study. The authors have no conflicts of interest that are directly relevant to the content of this study.

References

  1. 1.
    Choonara I. Unlicensed and off-label drug use in children: implications for safety. Expert Opin Drug Saf 2004; 3(2): 81–3PubMedCrossRefGoogle Scholar
  2. 2.
    Choonara I, Conroy S. Unlicensed and off-label drug use in children: implications for safety. Drug Saf 2002; 25(1): 1–5PubMedCrossRefGoogle Scholar
  3. 3.
    Conroy S, Choonara I, Impicciatore P, et al. Survey of unlicensed and off label drug use in paediatric wards in European countries. European Network for Drug Investigation in Children. BMJ 2000; 320(7227): 79–82Google Scholar
  4. 4.
    Turner S, Nunn AJ, Fielding K, et al. Adverse drug reactions to unlicensed and off-label drugs on paediatric wards: a prospective study. Acta Paediatr 1999; 88(9): 965–8PubMedCrossRefGoogle Scholar
  5. 5.
    Schirm E, Tobi H, de Jong-van den Berg LT. Risk factors for unlicensed and off-label drug use in children outside the hospital. Pediatrics 2003; 111(2): 291–5PubMedCrossRefGoogle Scholar
  6. 6.
    McNamara PJ, Alcorn J. Protein binding predictions in infants. AAPS PharmSci 2002; 4(1): 1–8CrossRefGoogle Scholar
  7. 7.
    International Commission on Radiological Protection (ICRP). Basic anatomical and physiological data for use in radiological protection: reference values. ICRP Publication 89. Amsterdam: Elsevier Science, 2002Google Scholar
  8. 8.
    Lopez Barrio AM, De Palma Gaston MA, Munoz Conde J. Evaluation of the portal blood flow in healthy children by doppler duplex echography [in Spanish]. An Esp Pediatr 1996; 44(1): 45–9PubMedGoogle Scholar
  9. 9.
    Kagimoto S, Fujisuka S, Kinoshita K, et al. Study to establish normal values for portal vein blood flow in children using a duplex ultrasound system. Acta Paediatr Jpn 1991; 33(6): 693–6PubMedCrossRefGoogle Scholar
  10. 10.
    Winso O, Biber B, Gustavsson B, et al. Portal blood flow in man during graded positive end-expiratory pressure ventilation. Intensive Care Med 1985; 12(2): 80–8Google Scholar
  11. 11.
    Greenway CV, Stark RD. Hepatic vascular bed. Physiol Rev 1971; 51(1): 23–5PubMedGoogle Scholar
  12. 12.
    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
  13. 13.
    Darrow DC, Cary MK. The serum albumin and globulin of newborn, premature and normal infants. J Pediatr 1933; 3: 573–9CrossRefGoogle Scholar
  14. 14.
    Bertz RJ, Granneman GR. Use of in vitro and in vivo data to estimate the likelihood of metabolic pharmacokinetic interactions. Clin Pharmacokinet 1997; 32(3): 210–58PubMedCrossRefGoogle Scholar
  15. 15.
    Hardman JG, Limbird LE, editors. Goodman and Gilman’s: the pharmacological basis of therapeutics. 10th ed. New York: McGraw Hill, 2001Google Scholar
  16. 16.
    Lin C, Korduba C, Affrime M, et al. Pharmacokinetics and metabolism of 14C-isepamicin in humans following intravenous administration. Antimicrob Agents Chemother 1995; 39(10): 2201–3PubMedCrossRefGoogle Scholar
  17. 17.
    Halstenson CE, Kelloway JS, Affrime MB, et al. Isepamicin disposition in subjects with various degrees of renal function. Antimicrob Agents Chemother 1991; 35(11): 2382–7PubMedCrossRefGoogle Scholar
  18. 18.
    Chauvin M, Bonnet F, Montembault C, et al. The influence of hepatic plasma flow on alfentanil plasma concentration plateaus achieved with an infusion model in humans: measurement of alfentanil hepatic extraction coefficient. Anesth Analg 1986; 65(10): 999–1003PubMedCrossRefGoogle Scholar
  19. 19.
    Kharasch ED, Russell M, Mautz D, et al. The role of cytochrome P450 3A4 in alfentanil clearance: implications for interindividual variability in disposition and perioperative drug interactions. Anesthesiology 1997; 87(1): 36–50PubMedCrossRefGoogle Scholar
  20. 20.
    Roure P, Jean N, Leclerc AC, et al. Pharmacokinetics of alfentanil in children undergoing surgery. Br J Anaesth 1987; 59(11): 1437–40PubMedCrossRefGoogle Scholar
  21. 21.
    Macfie AG, Magides AD, Reilly CS. Disposition of alfentanil in burns patients. Br J Anaesth 1992; 69(5): 447–50PubMedCrossRefGoogle Scholar
  22. 22.
    Smith MT, Eadie MJ, Brophy O. The pharmacokinetics of midazolam in man. Eur J Clin Pharmacol 1981; 19(4): 271–8PubMedCrossRefGoogle Scholar
  23. 23.
    Sen S, Ytrebo LM, Rose C, et al. Albumin dialysis: a new therapeutic strategy for intoxication from protein-bound drugs. Intensive Care Med 2004; 30(3): 496–501PubMedCrossRefGoogle Scholar
  24. 24.
    Dorne JL, Walton K, Renwick AG. Uncertainty factors for chemical risk assessment: human variability in the pharmacokinetics of CYP1A2 probe substrates. Food Chem Toxicol 2001; 39(7): 681–96PubMedCrossRefGoogle Scholar
  25. 25.
    Blanchard J, Sawers SJ. Comparative pharmacokinetics of caffeine in young and elderly men. J Pharmacokinet Biopharm 1983; 11(2): 109–26PubMedGoogle Scholar
  26. 26.
    Valko K, Nunhuck S, Bevan C, et al. Fast gradient HPLC method to determine compounds binding to human serum albumin: relationships with octanol/water and immobilized artificial membrane lipophilicity. J Pharm Sci 2003; 92(11): 2236–48PubMedCrossRefGoogle Scholar
  27. 27.
    Arlander E, Ekstrom G, Alm C, et al. Metabolism of ropivacaine in humans is mediated by CYP1A2 and to a minor extent by CYP3A4: an interaction study with fluvoxamine and ketoconazole as in vivo inhibitors. Clin Pharmacol Ther 1998; 64(5): 484–91PubMedCrossRefGoogle Scholar
  28. 28.
    Ekstrom G, Gunnarsson U. Ropivacaine, a new amide-type local anesthetic agent, is metabolized by cytochromes P450 1A and 3A in human liver microsomes. Drug Metab Dispos 1996; 24(9): 955–9PubMedGoogle Scholar
  29. 29.
    Mazoit JX, Dalens BJ. Pharmacokinetics of local anaesthetics in infants and children. Clin Pharmacokinet 2004; 43(1): 17–32PubMedCrossRefGoogle Scholar
  30. 30.
    Kart T, Christrup LL, Rasmussen M. Recommended use of morphine in neonates, infants and children based on a literature review. Part 1: pharmacokinetics. Paediatr Anaesth 1997; 7(1): 5–11Google Scholar
  31. 31.
    Kiang TK, Ensom MH, Chang TK. UDP-glucuronosyltransferases and clinical drug-drug interactions. Pharmacol Ther 2005; 106(1): 97–132PubMedCrossRefGoogle Scholar
  32. 32.
    de Wildt SN, Kearns GL, Leeder JS, et al. Glucuronidation in humans: pharmacogenetic and developmental aspects. Clin Pharmacokinet 1999; 36(6): 439–52PubMedCrossRefGoogle Scholar
  33. 33.
    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
  34. 34.
    Oda Y, Mizutani K, Hase I, et al. Fentanyl inhibits metabolism of midazolam: competitive inhibition of CYP3A4 in vitro. Br J Anaesth 1999; 82(6): 900–3PubMedCrossRefGoogle Scholar
  35. 35.
    Mather LE. Clinical pharmacokinetics of fentanyl and its newer derivatives. Clin Pharmacokinet 1983; 8(5): 422–46PubMedCrossRefGoogle Scholar
  36. 36.
    Forrest JA, Clements JA, Prescott LF. Clinical pharmacokinetics of paracetamol. Clin Pharmacokinet 1982; 7(2): 93–107PubMedCrossRefGoogle Scholar
  37. 37.
    Bailey DN, Briggs JR. The binding of selected therapeutic drugs to human serum [alpha]-1 acid glycoprotein and to human serum albumin in vitro. Ther Drug Monit 2004; 26(1): 40–3PubMedCrossRefGoogle Scholar
  38. 38.
    Granfors MT, Backman JT, Neuvonen M, et al. Ciprofloxacin greatly increases concentrations and hypotensive effect of tizanidine by inhibiting its cytochrome P450 lA2-mediated presystemic metabolism. Clin Pharmacol Ther 2004; 76(6): 598–606PubMedCrossRefGoogle Scholar
  39. 39.
    Davis RL, Koup JR, Williams-Warren J, et al. Pharmacokinetics of ciprofloxacin in cystic fibrosis. Antimicrob Agents Chemother 1987; 31(6): 915–9PubMedCrossRefGoogle Scholar
  40. 40.
    Shah A, Lettieri J, Heller A, et al. Pharmacokinetics of IV ciprofloxacin in subjects with normal renal function and with various degrees of renal impairment. Internal Report No. R6098. West Haven (CN). Institute of Clinical Pharmacology International, Bayer HealthCare - Pharma. 1993Google Scholar
  41. 41.
    Sorgel F, Naber KG, Jaehde U, et al. Gastrointestinal secretion of ciprofloxacin: evaluation of the charcoal model for investigations in healthy volunteers. Am J Med 1989; 87(5A): S62–5CrossRefGoogle Scholar
  42. 42.
    Davis RL, Markham A, Balfour JA. Ciprofloxacin: an updated review of its pharmacology, therapeutic efficacy and tolerability. Drugs 1996; 51(6): 1019–74PubMedCrossRefGoogle Scholar
  43. 43.
    Hand CW, Sear JW, Uppington J, et al. Buprenorphine disposition in patients with renal impairment: single and continuous dosing, with special reference to metabolites. Br J Anaesth 1990; 64(3): 276–82PubMedCrossRefGoogle Scholar
  44. 44.
    Kobayshi K, Yamamoto T, Chiba K, et al. Human buprenorphine N-dealkylation is catalyzed by cytochrome P450 3A4. Drug Metab Dispos 1998; 26(8): 818–21Google Scholar
  45. 45.
    Mihaly GW, Moore G, Thomas J, et al. The pharmacokinetics and metabolism of the anilide local anaesthetics in neonates. Eur J Clin Pharmacol 1978; 13(2): 143–52PubMedCrossRefGoogle Scholar
  46. 46.
    Orlando R, Piccoli P, De MS, et al. Cytochrome P450 1A2 is a major determinant of lidocaine metabolism in vivo: effects of liver function. Clin Pharmacol Ther 2004; 75(1): 80–8PubMedCrossRefGoogle Scholar
  47. 47.
    Pons G, Blais J, Rey E, et al. Maturation of caffeine N-demethy-lation in infancy: a study using the 13CO2 breath test. Pediatr Res 1988; 23(6): 632–6PubMedCrossRefGoogle Scholar
  48. 48.
    Hansen TG, Ilett KF, Reid C, et al. Caudal ropivacaine in infants: population pharmacokinetics and plasma concentrations. Anesthesiology 2001; 94(4): 579–84PubMedCrossRefGoogle Scholar
  49. 49.
    McCann ME, Sethna NF, Mazoit JX, et al. The pharmacokinetics of epidural ropivacaine in infants and young children. Anesth Analg 2001; 93(4): 893–7PubMedCrossRefGoogle Scholar
  50. 50.
    Lonnqvist PA, Westrin P, Larsson BA, et al. Ropivacaine pharmacokinetics after caudal block in 1-8 year old children. Br J Anaesth 2000; 85(4): 506–11PubMedCrossRefGoogle Scholar
  51. 51.
    Van Obbergh LJ, Roelants FA, Veyckemans F, et al. In children, the addition of epinephrine modifies the pharmacokinetics of ropivacaine injected caudally. Can J Anaesth 2003; 50(6): 593–8PubMedCrossRefGoogle Scholar
  52. 52.
    Habre W, Bergesio R, Johnson C, et al. Pharmacokinetics of ropivacaine following caudal analgesia in children. Paediatr Anaesth 2000; 10(2): 143–7PubMedCrossRefGoogle Scholar
  53. 53.
    Ecoffey C, Desparmet J, Berdeaux A, et al. Pharmacokinetics of lignocaine in children following caudal anaethesia. Br J Anaesth 1984; 56(12): 1399–402PubMedCrossRefGoogle Scholar
  54. 54.
    Hook JB, Baillie MD. Perinatal renal pharmacology. Annu Rev Pharmacol Toxicol 1979; 19: 491–509PubMedCrossRefGoogle Scholar
  55. 55.
    Rubin M, Bruck E, Rapoport M. Maturation of renal function in childhood: clearance studies. J Clin Invest 1949; 28: 1144–62CrossRefGoogle Scholar
  56. 56.
    Hayton WL. Maturation and growth of renal function: dosing renally cleared drugs. AAPS PharmSci 2002; 2(1): 1–7CrossRefGoogle Scholar
  57. 57.
    Leake RD, Trygstad CW, Oh W. Inulin clearance in the new-born infant: relationship to gestational and postnatal age. Pediatr Res 1976; 10(8): 759–62PubMedGoogle Scholar
  58. 58.
    Leake RD, Trygstad CW. Glomerular filtration rate during the period of adaptation to extrauterine life. Pediatr Res 1977; 92(5): 705–12Google Scholar
  59. 59.
    Sato Y. Pharmacokinetics of antibiotics in neonates. Acta Paediatr Jpn 1997; 39(1): 124–31PubMedCrossRefGoogle Scholar
  60. 60.
    Parkinson A, Mudra DR, Johnson C, et al. The effects of gender, age, ethnicity, and liver cirrhosis on cytochrome P450 enzyme activity in human liver microsomes and induciblity in cultured human hepatocytes. Toxicol Appl Pharmacol 2004; 199(3): 193–209PubMedCrossRefGoogle Scholar
  61. 61.
    Bebia Z, Buch SC, Wilson JW, et al. Bioequivalence revisited: influence of age and sex on CYP enzymes. Clin Pharmacol Ther 2004; 76(6): 618–27PubMedCrossRefGoogle Scholar
  62. 62.
    de Wildt SN, Kearns GL, Leeder JS, et al. Cytochrome P450 3A: ontogeny and drug disposition. Clin Pharmacokinet 1999; 37(6): 485–505PubMedCrossRefGoogle Scholar
  63. 63.
    Hines RN, McCarver DG. The ontogeny of human drug-metabolizing enzymes: phase I oxidative enzymes. J Pharmacol Exp Ther 2002; 300(2): 355–60PubMedCrossRefGoogle Scholar
  64. 64.
    Tateishi T, Nakura H, Asoh M, et al. A comparison of hepatic cytochrome P450 protein expression between infancy and postinfancy. Life Sci 1997; 61(26): 2567–74PubMedCrossRefGoogle Scholar
  65. 65.
    Treluyer JM, Bowers G, Cazali N, et al. Oxidative metabolism of amprenavir in the human liver: effect of the CYP3A maturation. Drug Metab Dispos 2003; 31(3): 275–81PubMedCrossRefGoogle Scholar
  66. 66.
    Alcorn J, McNamara PJ. Ontogeny of hepatic and renal systemic clearance pathways in infants: part I. Clin Pharmacokinet 2002; 41(12): 959–98PubMedCrossRefGoogle Scholar
  67. 67.
    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
  68. 68.
    Dorne JL, Walton K, Renwick AG. Human variability in CYP3A4 metabolism and CYP3A4-related uncertainty factors for risk assessment. Food Chem Toxicol 2003; 41(2): 201–24PubMedCrossRefGoogle Scholar
  69. 69.
    Sonnier M, Cresteil T. Delayed ontogenesis of CYP1A2 in the human liver. Eur J Biochem 1998; 251(3): 893–8PubMedCrossRefGoogle Scholar
  70. 70.
    Johnsrud EK, Koukouritaki SB, Divakaran K, et al. Human hepatic CYP2E1 expression during development. J Pharmacol Exp Ther 2003; 307(1): 402–7PubMedCrossRefGoogle Scholar
  71. 71.
    Rollins DE, von Bahr C, Glaumann H, et al. Acetaminophen: potentially toxic metabolite formed by human fetal and adult liver microsomes and isolated fetal liver cells. Science 1979; 205(4413): 1414–6PubMedCrossRefGoogle Scholar
  72. 72.
    Vieira I, Sonnier M, Cresteil T. Developmental expression of CYP2E1 in the human liver: hypermethylation control of gene expression during the neonatal period. Eur J Biochem 1996; 238(2): 476–83PubMedCrossRefGoogle Scholar
  73. 73.
    McCarver DG, Hines RN. The ontogeny of human drug-metabolizing enzymes: phase II conjugation enzymes and regulatory mechanisms. J Pharmacol Exp Ther 2002; 300(2): 361–3PubMedCrossRefGoogle Scholar
  74. 74.
    Pacifici GM, Sawe J, Kager L, et al. Morphine glucuronidation in human fetal and adult liver. Eur J Clin Pharmacol 1982; 22(6): 553–8PubMedCrossRefGoogle Scholar
  75. 75.
    Strassburg CP, Strassburg A, Kneip S, et al. Developmental aspects of human hepatic drug glucuronidation in young children and adults. Gut 2002; 50(2): 259–65PubMedCrossRefGoogle Scholar
  76. 76.
    Alam SN, Roberts RJ, Fischer LJ. Age-related differences in salicylamide and acetaminophen conjugation in man. J Pediatr 1977; 90(1): 130–5PubMedCrossRefGoogle Scholar
  77. 77.
    Pacifici GM, Kubrich M, Giuliani L, et al. Sulphation and glucuronidation of ritodrine in human foetal and adult tissues. Eur J Clin Pharmacol 1993; 44(3): 259–64PubMedCrossRefGoogle Scholar
  78. 78.
    Levy G, Khanna NN, Soda DM, et al. Pharmacokinetics of acetaminophen in the human neonate: formation of acetaminophen glucuronide and sulfate in relation to plasma bilirubin concentration and D-glucaric acid excretion. Pediatrics 1975; 55(6): 818–25PubMedGoogle Scholar
  79. 79.
    Brashear WT, Kuhnert BR, Wei R. Maternal and neonatal urinary excretion of sulfate and glucuronide ritodrine conjugates. Clin Pharmacol Ther 1988; 44(6): 634–41PubMedCrossRefGoogle Scholar
  80. 80.
    Van Lingen RA, Deinum JT, Quak JM, et al. Pharmacokinetics and metabolism of rectally administered paracetamol in preterm neonates. Arch Dis Child Fetal Neonatal Ed 1999; 80(1): F59–63PubMedCrossRefGoogle Scholar
  81. 81.
    Van der Marel CD, Anderson BJ, Van Lingen RA, et al. Paracetamol and metabolite pharmacokinetics in infants. Eur J Clin Pharmacol 2003; 59(3): 243–51PubMedCrossRefGoogle Scholar
  82. 82.
    Miller RP, Roberts RJ, Fischer LJ. Acetaminophen elimination kinetics in neonates, children, and adults. Clin Pharmacol Ther 1976; 19(3): 284–94PubMedGoogle Scholar
  83. 83.
    Kauffman FC. Sulfonation in pharmacology and toxicology. Drug Metab Rev 2004; 36(3–4): 823–43PubMedCrossRefGoogle Scholar
  84. 84.
    Richard K, Hume R, Kaptein E, et al. Sulfation of thyroid hormone and dopamine during human development: ontogeny of phenol sulfotransferases and arylsulfatase in liver, lung, and brain. J Clin Endocrinol Metab 2001; 86(6): 2734–42PubMedCrossRefGoogle Scholar
  85. 85.
    Dorne JL, Walton K, Renwick AG. Human variability for metabolic pathways with limited data (CYP2A6, CYP2C9, CYP2E1, ADH, esterases, glycine and sulphate conjugation). Food Chem Toxicol 2004; 42(3): 397–421PubMedCrossRefGoogle Scholar
  86. 86.
    Cagen SZ, Gibson JE. Characteristics of hepatic excretory function during development. J Pharmacol Exp Ther 1979; 210(1): 15–21PubMedGoogle Scholar
  87. 87.
    Balistreri WF. Immaturity of hepatic excretory function and the ontogeny of bile acid metabolism. J Pediatr Gastroenterol Nutr 1983; 2(S1): S207–14PubMedCrossRefGoogle Scholar
  88. 88.
    West GB, Brown JH, Enquist BJ. The fourth dimension of life: fractal geometry and allometric scaling of organisms. Science 1999; 284(5420): 1677–9PubMedCrossRefGoogle Scholar
  89. 89.
    Sheiner LB, Beal SL. Some suggestions for measuring predictive performance. J Pharmacokinet Biopharm 1981; 9(4): 503–12PubMedGoogle Scholar
  90. 90.
    Kirkpatrick CMJ, Duffull SB, Begg EJ. Pharmacokinetics of gentamicin in 957 patients with varying renal function dosed once daily. Br J Clin Pharmacol 1999; 47: 637–43PubMedCrossRefGoogle Scholar
  91. 91.
    Vervelde ML, Rademaker CM, Krediet TG, et al. Population pharmacokinetics of gentamicin in preterm neonates: evaluation of a once-daily dosage regimen. Ther Drug Monit 1999; 21(5): 514–9PubMedCrossRefGoogle Scholar
  92. 92.
    Assael BM, Cavanna G, Jusko WJ, et al. Multiexponential elimination of gentamicin: a kinetic study during development. Dev Pharmacol Ther 1980; 1(2–3): 171–81PubMedGoogle Scholar
  93. 93.
    Pons G, d’Athis P, Rey E, et al. Gentamicin monitoring in neonates. Ther Drug Monit 1988; 10(4): 421–7PubMedCrossRefGoogle Scholar
  94. 94.
    Rocha MJ, Almeida AM, Afonso E, et al. The kinetic profile of gentamicin in premature neonates. J Pharm Pharmacol 2000; 52(9): 1091–7PubMedCrossRefGoogle Scholar
  95. 95.
    Ho KK, Bryson SM, Thiessen JJ, et al. The effects of age and chemotherapy on gentamicin pharmacokinetics and dosing in pediatric oncology patients. Pharmacotherapy 1995; 15(6): 754–64PubMedGoogle Scholar
  96. 96.
    Gonzalez-Martin G, Bravo I, Vargas H, et al. Pharmacokinetics of gentamicin in children with nephrotic syndrome. Int J Clin Pharmacol Ther Toxicol 1986; 24(10): 555PubMedGoogle Scholar
  97. 97.
    Scaglione F, Vigano A, Colucci R, et al. Pharmacokinetics of isepamicin in paediatric patients. J Chemother 1995; 7(S2): 63–9PubMedGoogle Scholar
  98. 98.
    Nomeir AA, Radwanski E, Cutler D, et al. Single-dose pharmacokinetics of isepamicin in young and geriatric volunteers. J Clin Pharmacol 1997; 37(11): 1021–30PubMedGoogle Scholar
  99. 99.
    Radwanski E, Batra V, Cayen M, et al. Pharmacokinetics of isepamicin following a single administration by intravenous infusion or intramuscular injections. Antimicrob Agents Chemother 1997; 41(8): 1794–6PubMedGoogle Scholar
  100. 100.
    Davis PJ, Killian A, Stiller RL, et al. Pharmacokinetics of alfentanil in newborn premature infants and older children. Dev Pharmacol Ther 1989; 13(1): 21–7PubMedGoogle Scholar
  101. 101.
    Marlow N, Weindling AM, Van Peer A, et al. Alfentanil pharmacokinetics in preterm infants. Arch Dis Child 1990; 65(4): 349–51PubMedCrossRefGoogle Scholar
  102. 102.
    Kharasch ED, Russell M, Garton K, et al. Assessment of cyto-chrome P450 3A4 activity during the menstrual cycle using alfentanil as a noninvasive probe. Anesthesiology 1997; 87(1): 26–35PubMedCrossRefGoogle Scholar
  103. 103.
    Killian A, Davis PJ, Stiller RL, et al. Influence of gestational age on pharmacokinetics of alfentanil in neonates. Dev Pharmacol Ther 1990; 15(2): 82–5PubMedGoogle Scholar
  104. 104.
    Wiest DB, Ohning BL, Garner SS. The disposition of alfentanil in neonates with respiratory distress. Pharmacotherapy 1991; 11(4): 308–11PubMedGoogle Scholar
  105. 105.
    Goresky GV, Koren G, Sabourin MA, et al. The pharmacokinetics of alfentanil in children. Anesthesiology 1987; 67(5): 654–9PubMedCrossRefGoogle Scholar
  106. 106.
    den Hollander JM, Hennis PJ, Burm AG, et al. Alfentanil in infants and children with congenital heart defects. J Cardiothorac Anesth 1998; 2(1): 12–7CrossRefGoogle Scholar
  107. 107.
    Meistelman C, Saint-Maurice C, Lepaul M, et al. A comparison of alfentanil pharmacokinetics in children and adults. Anesthesiology 1987; 66(1): 13–6PubMedCrossRefGoogle Scholar
  108. 108.
    de Wildt SN, Kearns GL, Hop CJ, et al. Pharmacokinetics and metabolism of intravenous midazolam in preterm infants. Clin Pharmacol Ther 2001; 70(6): 525–31PubMedCrossRefGoogle Scholar
  109. 109.
    Jacqz-Aigrain E, Wood C, Robieux I. Pharmacokinetics of midazolam in critically ill neonates. Eur J Clin Pharmacol 1990; 39(3): 191–2PubMedCrossRefGoogle Scholar
  110. 110.
    Yu KS, Cho JY, Jang IJ, et al. Effect of the CYP3A5 genotype on the pharmacokinetics of intravenous midazolam during inhibited and induced metabolic states. Clin Pharmacol Ther 2004; 76(2): 104–12PubMedCrossRefGoogle Scholar
  111. 111.
    Mulla H, McCormack P, Lawson G, et al. Pharmacokinetics of midazolam in neonates undergoing extracorporeal membrane oxygenation. Anesthesiology 2003; 99(2): 275–82PubMedCrossRefGoogle Scholar
  112. 112.
    Reed MD, Rodarte A, Blumer JL, et al. The single-dose pharmacokinetics of midazolam and its primary metabolites in pediatric patients after oral and intravenous administration. J Clin Pharmacol 2001; 41(12): 1359–69PubMedCrossRefGoogle Scholar
  113. 113.
    Mathews HM, Carson IW, Lyons SM, et al. A pharmacokinetic study of midazolam in paediatric patients undergoing cardiac surgery. Br J Anaesth 1988; 61(3): 302–7PubMedCrossRefGoogle Scholar
  114. 114.
    Payne K, Mattheyse FJ, Liebenberg D, et al. The pharmacokinetics of midazolam in paediatric patients. Eur J Pharmacol 1989; 37(3): 267–72CrossRefGoogle Scholar
  115. 115.
    Jokinen MJ, Olkkola KT, Ahonen J, et al. Effect of ciprofloxacin on the pharmacokinetics of ropivacaine. Eur J Clin Pharmacol 2003; 58(10): 653–7PubMedGoogle Scholar
  116. 116.
    Emanuelsson BM, Persson J, Aim C, et al. Systemic absorption and block after epidural injection of ropivacaine in healthy volunteers. Anesthesiology 1997; 87(6): 1309–17PubMedCrossRefGoogle Scholar
  117. 117.
    Jokinen MJ, Olkkola KT, Ahonen J, et al. Effect of rifampin and tobacco smoking on the pharmacokinetics of ropivacaine. Clin Pharmacol Ther 2001; 70(4): 344–50PubMedGoogle Scholar
  118. 118.
    Pere P, Salonen M, Jokinen M, et al. Pharmacokinetics of ropivacaine in uremic and nonuremic patients after axillary brachial plexus block. Anesth Analg 2003; 96(2): 563–9PubMedGoogle Scholar
  119. 119.
    Aranda JV, Cook CE, Gorman W, et al. Pharmacokinetic profile of caffeine in the premature newborn infant with apnea. J Pediatr 1979; 94(4): 663–8PubMedCrossRefGoogle Scholar
  120. 120.
    Parsons WD, Neims AH. Effect of smoking on caffeine clearance. Clin Pharmacol Ther 1978; 24(1): 40–5PubMedGoogle Scholar
  121. 121.
    Gorodischer R, Karplus M. Pharmacokinetic aspects of caffeine in premature infants with apnoea. Eur J Clin Pharmacol 1982; 22(1): 47–52PubMedCrossRefGoogle Scholar
  122. 122.
    Lee TC, Charles B, Steer P, et al. Population pharmacokinetics of intravenous caffeine in neonates with apnea of prematurity. Clin Pharmacol Ther 1997; 61(6): 628–40PubMedCrossRefGoogle Scholar
  123. 123.
    Lee HS, Khoo YM, Chirino-Barcelo Y, et al. Caffeine in apnoeic Asian neonates: a sparse data analysis. Br J Clin Pharmacol 2002; 54(1): 31–7PubMedCrossRefGoogle Scholar
  124. 124.
    Pons G, Carrier O, Richard MO, et al. Developmental changes in caffeine elimination in infancy. Dev Pharmacol Ther 1988; 11(5): 258–64PubMedGoogle Scholar
  125. 125.
    Baillie SP, Bateman DN, Coates PE, et al. Age and the pharmacokinetics of morphine. Age Aging 1989; 18(4): 258–62CrossRefGoogle Scholar
  126. 126.
    Skarke C, Schmidt H, Geisslinger G, et al. Pharmacokinetics of morphine are not altered in subjects with Gilbert’s syndrome. Br J Clin Pharmacol 2003; 56(2): 228–31PubMedCrossRefGoogle Scholar
  127. 127.
    Mikkelsen S, Feilberg VL, Chistensen CB, et al. Morphine pharmacokinetics in premature and mature newborn infants. Acta Paediatr 1994; 83(10): 1025–8PubMedCrossRefGoogle Scholar
  128. 128.
    Saarenmaa E, Neuvonen PJ, Rosenberg P, et al. Morphine clearance and effects in newborn infants in relation to gestational age. Clin Pharmacol Ther 2000; 68(2): 160–6PubMedCrossRefGoogle Scholar
  129. 129.
    Lynn AM, Nespeca MK, Bratton SL, et al. Intravenous morphine in postoperative infants: intermittent bolus dosing versus targeted continuous infusions. Pain 2000; 88(1): 89–95PubMedCrossRefGoogle Scholar
  130. 130.
    Lynn A, Nespeca M, Bratton SL, et al. Clearance of morphine in postoperative infants during intravenous infusion: the influence of age and surgery. Anesth Analg 1998; 86(5): 958–63PubMedGoogle Scholar
  131. 131.
    Hain RD, Hardcastle A, Pinkerton CR, et al. Morphine and morphine-6-glucuronide in the plasma and cerebrospinal fluid of children. Br J Clin Pharmacol 1999; 48(1): 37–42PubMedCrossRefGoogle Scholar
  132. 132.
    McDermott CA, Kowalczyk AL, Schnitzler E, et al. Pharmacokinetics of lorazepam in critically ill neonates with seizures. J Pediatr 1992; 120(3): 479–83PubMedCrossRefGoogle Scholar
  133. 133.
    Crom WR, Webster SL, Bobo L, et al. Simultaneous administration of multiple model substrates to assess hepatic drug clearance. Clin Pharmacol Ther 1987; 41(6): 645–50PubMedCrossRefGoogle Scholar
  134. 134.
    Relling MV, Mulhern RK, Dodge RK, et al. Lorazepam pharmacodynamics and pharmacokinetics in children. J Pediatr 1989; 114 (4 Pt 1): 641–6PubMedCrossRefGoogle Scholar
  135. 135.
    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
  136. 136.
    Kearns GL, Crom WR, Karlson KH, et al. Hepatic drug clearance in patients with mild cystic fibrosis. Clin Pharmacol Ther 1996; 59(5): 529–40PubMedCrossRefGoogle Scholar
  137. 137.
    Streisand JB, Varvel JR, Stanski DR, et al. Absorption and bioavailability of oral transmucosal fentanyl citrate. Anesthesiology 1991; 75(2): 223–9PubMedCrossRefGoogle Scholar
  138. 138.
    Saarenmaa E, Neuvonen PJ, Fellman V. Gestational age and birth weight effects on plasma clearance of fentanyl in newborn infants. J Pediatr 2000; 136(6): 767–70PubMedGoogle Scholar
  139. 139.
    Ibrahim AE, Feldman J, Karim A, et al. Simultaneous assessment of drug interactions with low- and high-extraction opioids: application to parecoxib effects on the pharmacokinetics and pharmacodynamics of fentanyl and alfentanil. Anesthesiology 2003; 98(4): 853–61PubMedCrossRefGoogle Scholar
  140. 140.
    Koehntop DE, Rodman JH, Brundage DM, et al. Pharmacokinetics of fentanyl in neonates. Anesth Analg 1986; 65(3): 227–32PubMedCrossRefGoogle Scholar
  141. 141.
    Gauntlett IS, Fisher DM, Hertzka RE, et al. Pharmacokinetics of fentanyl in neonatal humans and lambs: effects of age. Anesthesiology 1988; 69(5): 683–7PubMedCrossRefGoogle Scholar
  142. 142.
    Katz R, Kelly HW. Pharmacokinetics of continuous infusions of fentanyl in critically ill children. Crit Care Med 1993; 21(7): 995–1000PubMedCrossRefGoogle Scholar
  143. 143.
    Singleton MA, Rosen JI, Fisher DM. Pharmacokinetics of fentanyl for infants and adults [abstract]. Anesthesiology 1984; 61(7): A440CrossRefGoogle Scholar
  144. 144.
    Dsida RM, Wheeler M, Birmingham PK, et al. Premedication of pediatric tonsillectomy patients with oral transmucosal fentanyl citrate. Anesth Analg 1998; 86(1): 66–70PubMedGoogle Scholar
  145. 145.
    Ginsberg B, Howell S, Glass PS, et al. Pharmacokinetic model-driven infusion of fentanyl in children. Anesthesiology 1996; 85(6): 1268–75PubMedCrossRefGoogle Scholar
  146. 146.
    Mitenko PA, Ogilvie RI. Pharmacokinetics on intravenous theophylline. Clin Pharmacol Ther 1973; 14(4): 509–13PubMedGoogle Scholar
  147. 147.
    Islam SI, Ali AS, Sheikh AA, et al. Pharmacokinetics of theophylline in preterm neonates during the first month of life. Saudi Med J 2004; 25(4): 459–65PubMedGoogle Scholar
  148. 148.
    Stringer KA, Mallet J, Clarke M, et al. The effect of three different oral doses of verapamil on the disposition of theophylline. Eur J Clin Pharmacol 1992; 43(1): 35–8PubMedCrossRefGoogle Scholar
  149. 149.
    Aranda JV, Turmen T, Sasyniuk BI. Pharmacokinetics of diuretics and methyl xanthines in the neonate. Eur J Pharmacol 1980; 18: 55–63CrossRefGoogle Scholar
  150. 150.
    Prince RA, Casabar E, Adair CG, et al. Effect of quinolone antimicrobials on theophylline pharmacokinetics. J Clin Pharmacol 1989; 29(7): 650–4PubMedGoogle Scholar
  151. 151.
    Simons FE, Simons KJ. Pharmacokinetics of theophylline in infancy. J Clin Pharmacol 1978; 18: 472–6PubMedGoogle Scholar
  152. 152.
    Loughnan PM, Sitar DS, Ogilvie RI, et al. Pharmacokinetic analysis of the disposition of intravenous theophylline in young children. J Pediatr 1976; 88: 874–9PubMedCrossRefGoogle Scholar
  153. 153.
    Vichyanond P, Aranyanark N, Visitsuntorn N, et al. Theophylline pharmacokinetics in Thai children. Asian Pac J Allergy Immunol 1994; 12(2): 137–43PubMedGoogle Scholar
  154. 154.
    Ginchansky E, Weinberger M. Relationship of theophylline clearance to oral dosage in children with chronic asthma. J Pediatr 1977; 91: 655–60PubMedCrossRefGoogle Scholar
  155. 155.
    Arnold JD, Hill GN, Sansom LN. A comparison of the pharmacokinetics of theophylline in asthmatic children in the acute episode and in remission. Eur J Pharmacol 1981; 20: 443–7CrossRefGoogle Scholar
  156. 156.
    Ellis EF, Koysooko R, Levy G. Pharmacokinetics of theophylline in children with asthma. Pediatrics 1976; 58(4): 542–7PubMedGoogle Scholar
  157. 157.
    Agbaba D, Pokrajac M, Varagic VM, et al. Dependence of the renal excretion of theophylline on its plasma concentrations and urine flow rate in asthmatic children. J Pharmacol 1990; 42: 827–30CrossRefGoogle Scholar
  158. 158.
    Bannwarth B, Netter P, Lapicque F, et al. Plasma and cerebrospinal fluid concentrations of paracetamol after a single intravenous dose of propacetamol. Br J Clin Pharmacol 1992; 34(1): 79–81PubMedCrossRefGoogle Scholar
  159. 159.
    Allegaert K, Anderson BJ, Naulaers G, et al. Intravenous paracetamol (propacetamol) pharmacokinetics in term and preterm neonates. Eur J Clin Pharmacol 2004; 60(3): 191–7PubMedCrossRefGoogle Scholar
  160. 160.
    Depre M, van Hecken HA, Verbesselt R, et al. Tolerance and pharmacokinetics of propacetamol, a paracetamol formulation for intravenous use. Fundam Clin Pharmacol 1992; 6(6): 259–62PubMedCrossRefGoogle Scholar
  161. 161.
    Allegaert K, Van der Marel CD, Debeer A, et al. Pharmacokinetics of single dose intravenous propacetamol in neonates: effect of gestational age. Arch Dis Child Fetal Neonatal Ed 2004; 89(1): F25–8PubMedCrossRefGoogle Scholar
  162. 162.
    Flouvat B, Leneveu A, Fitoussi S, et al. Bioequivalence study comparing a new paracetamol solution for injection and propacetamol after single intravenous infusion in healthy subjects. Int J Clin Pharmacol Ther 2004; 42(1): 50–7PubMedGoogle Scholar
  163. 163.
    Autret E, Dutertre JP, Breteau M, et al. Pharmacokinetics of paracetamol in the neonate and infant after administration of propacetamol chlorhydrate. Dev Pharmacol Ther 1993; 20(3–4): 129–34PubMedGoogle Scholar
  164. 164.
    Granry JC, Rod B, Boccard E, et al. Pharmacokinetics and antipyretic effects of an injectable prodrug of paracetamol (proparacetamol) in children. Paediatr Anaesth 1992; 2: 291–5CrossRefGoogle Scholar
  165. 165.
    Payen S, Serreau R, Munck A, et al. Population pharmacokinetics of ciprofloxacin in pediatric and adolescent patients with acute infections. Antimicrob Agents Chemother 2003; 47(10): 3170–8PubMedCrossRefGoogle Scholar
  166. 166.
    Plaisance KI, Drusano GL, Forrest A, et al. Effect of dose size on bioavailability of ciprofloxacin. Antimicrob Agents Chemother 1987; 31(6): 956–8PubMedCrossRefGoogle Scholar
  167. 167.
    Hoffken G, Lode H, Prinzing C, et al. Pharmacokinetics of ciprofloxacin after oral and parenteral administration. Antimicrob Agents Chemother 1985; 27(3): 375–9PubMedCrossRefGoogle Scholar
  168. 168.
    Rajagopalan P, Gastonguay MR. Population pharmacokinetics of ciprofloxacin in pediatric patients. Pediatrics 2003; 43: 698–710Google Scholar
  169. 169.
    Rey E, Radvanyi-Bouvet MF, Bodiou C, et al. Intravenous lidocaine in the treatment of convulsions in the neonatal period: monitoring plasma levels. Ther Drug Monit 1990; 12: 316–20PubMedCrossRefGoogle Scholar
  170. 170.
    Finholt DA, Stirt JA, Difazio CA, et al. Lindocaine pharmacokinetics in children during general anesthesia. Anesth Analg 1986; 65(3): 279–82PubMedCrossRefGoogle Scholar
  171. 171.
    Burrows FA, Lerman J, Ledez KM, et al. Pharmacokinetics of lidocaine in children. Can J Anaesth 1991; 38(2): 196–200PubMedCrossRefGoogle Scholar
  172. 172.
    Kuhlman JJ, Lalani S, Magluilo J. Human pharmacokinetics of intravenous, sublingual, and buccal buprenorphine. J Anal Toxicol 2005; 20(6): 369–78Google Scholar
  173. 173.
    Barrett DA, Simpson J, Rutter N, et al. The pharmacokinetics and physiological effects of buprenorphine infusion in premature neonates. Br J Clin Pharmacol 1993; 36(3): 215–9PubMedCrossRefGoogle Scholar
  174. 174.
    Amani A, Joseph T, Balasaraswathi K. Buprenorphine pharmacokinetic parameters during coronary artery bypass graft surgery. Indian J Physiol Pharmacol 1997; 41(4): 361–8PubMedGoogle Scholar
  175. 175.
    Olkkola KT, Maunuksela EL, Korpela R. Pharmacokinetics of intravenous buprenorphine in children. Br J Clin Pharmacol 1989; 28(2): 202–4PubMedCrossRefGoogle Scholar
  176. 176.
    Ginsberg G, Hattis D, Sonawane B. Incorporating pharmacokinetic differences between children and adults in assessing children’s risks to environmental toxicants. Toxicol Appl Pharmacol 2004; 198(2): 164–83PubMedCrossRefGoogle Scholar
  177. 177.
    Alcorn J, McNamara PJ. Ontogeny of hepatic and renal systemic clearance pathways in infants: part II. Clin Pharmacokinet 2002; 41(13): 1077–1PubMedCrossRefGoogle Scholar
  178. 178.
    Alcorn J, McNamara PJ. Pharmacokinetics in the newborn. Adv Drug Deliv Rev 2003; 55(5): 667–86PubMedCrossRefGoogle Scholar
  179. 179.
    Ginsberg G, Hattis D, Russ A, et al. Physiologically based pharmacokinetic (PBPK) modeling of caffeine and theophyl-line in neonates and adults: implications for assessing children’s risks from environmental agents. J Toxicol Environ Health A 2004; 67(4): 297–329PubMedCrossRefGoogle Scholar
  180. 180.
    Best Pharmaceuticals for Children Act, 2002 Jan 4, (Public Law No. 107–109) [online]. Available from URL: http://www.fda.gov/opacom/laws/pharmkids/contents.html [Accessed 2006 Jun 16]
  181. 181.
    Proposal for regulation of the European Parliament and of the council on medicinal products for paediatric use and amending Council Regulation (EEC) No. 1768/92, Directive 2001/83/EC and Regulation (EC) No 726/2004 [online]. Available from URL: http://pharmacos.eudra.org/F2/Paediatrics/docs/_2004_09/EN.pdf
  182. 182.
    Renwick AG, Dorne JL, Walton K. An analysis of the need for an additional uncertainty factor for infants and children. Regul Toxicol Pharmacol 2000; 31(3): 286–2PubMedCrossRefGoogle Scholar
  183. 183.
    Ginsberg G, Hattis D, Miller RM, et al. Pediatric pharmacokinetic data: implications for environmental risk assessment for children. Pediatrics 2004; 113(4): 973–83PubMedGoogle Scholar
  184. 184.
    Johnson TN. Modelling approaches to dose estimation in children. Br J Clin Pharmacol 2005; 59(6): 663–9PubMedCrossRefGoogle Scholar
  185. 185.
    Edginton AN, Schmitt W, Willmann S. Development and evaluation of a generic physiology-based pharmacokinetic (PBPK) model for children. Clin Pharmacokinet 2006. In press.Google Scholar

Copyright information

© Adis Data Information BV 2006

Authors and Affiliations

  • Andrea N. Edginton
    • 1
    Email author
  • Walter Schmitt
    • 1
  • Barbara Voith
    • 2
  • Stefan Willmann
    • 1
  1. 1.Competence Center Systems BiologyBayer Technology Services GmbHLeverkusenGermany
  2. 2.Department for Clinical PharmacokineticsBayer HealthCare AGWuppertalGermany

Personalised recommendations