Pharmaceutical Research

, Volume 31, Issue 10, pp 2643–2654 | Cite as

Simultaneous Pharmacokinetic Modeling of Gentamicin, Tobramycin and Vancomycin Clearance from Neonates to Adults: Towards a Semi-physiological Function for Maturation in Glomerular Filtration

  • Roosmarijn F. W. De Cock
  • Karel Allegaert
  • Janneke M. Brussee
  • Catherine M. T. Sherwin
  • Hussain Mulla
  • Matthijs de Hoog
  • Johannes N. van den Anker
  • Meindert Danhof
  • Catherijne A. J. Knibbe
Research Paper



Since glomerular filtration rate (GFR) is responsible for the elimination of a large number of water-soluble drugs, the aim of this study was to develop a semi-physiological function for GFR maturation from neonates to adults.


In the pharmacokinetic analysis (NONMEM VI) based on data of gentamicin, tobramycin and vancomycin collected in 1,760 patients (age 1 day–18 years, bodyweight 415 g–85 kg), a distinction was made between drug-specific and system-specific information. Since the maturational model for clearance is considered to contain system-specific information on the developmental changes in GFR, one GFR maturational function was derived for all three drugs.


Simultaneous analysis of these three drugs showed that maturation of GFR mediated clearance from preterm neonates to adults was best described by a bodyweight-dependent exponent (BDE) function with an exponent varying from 1.4 in neonates to 1.0 in adults (ClGFR = Cldrug*(BW/4 kg)BDE with BDE = 2.23*BW−0.065). Population clearance values (Cldrug) for gentamicin, tobramycin and vancomycin were 0.21, 0.28 and 0.39 L/h for a full term neonate of 4 kg, respectively.


Based on an integrated analysis of gentamicin, tobramycin and vancomycin, a semi-physiological function for GFR mediated clearance was derived that can potentially be used to establish evidence based dosing regimens of renally excreted drugs in children.


antibiotics developmental changes glomerular filtration pediatric age range 



Bodyweight-dependent exponent




Glomerular filtration rate


Normalized prediction distribution error method






Postnatal age



This study was performed within the framework of Top Institute Pharma project number D2-104. The clinical research of K. Allegaert is supported by the Fund for Scientific Research, Flanders (Belgium) (clinical fellowship 1800214N) and has been supported by an IWT-SBO project (130033). The clinical research of J. van den Anker is supported by NIH grants (R01HD060543, K24DA027992, R01HD048689, U54HD071601) and FP7 grants TINN (223614), TINN2 (260908), NEUROSIS (223060), and GRIP (261060). The authors also would like to thank LAP&P Consultants for their technical support with NONMEM.


  1. 1.
    De Cock RF, Piana C, Krekels EH, Danhof M, Allegaert K, Knibbe CA. The role of population PK-PD modelling in paediatric clinical research. Eur J Clin Pharmacol. 2011;67 Suppl 1:5–16.PubMedCrossRefPubMedCentralGoogle Scholar
  2. 2.
    Bellanti F, Della Pasqua O. Modelling and simulation as research tools in paediatric drug development. Eur J Clin Pharmacol. 2011;67 Suppl 1:75–86.PubMedCrossRefPubMedCentralGoogle Scholar
  3. 3.
    Cella M, Knibbe C, Danhof M, Della Pasqua O. What is the right dose for children? Br J Clin Pharmacol. 2010;70(4):597–603.PubMedCrossRefPubMedCentralGoogle Scholar
  4. 4.
    Knibbe CA, Danhof M. Individualized dosing regimens in children based on population PKPD modelling: are we ready for it? Int J Pharm. 2011;415(1–2):9–14.PubMedCrossRefGoogle Scholar
  5. 5.
    Knibbe CA, Krekels EH, Danhof M. Advances in paediatric pharmacokinetics. Expert Opin Drug Metab Toxicol. 2011;7(1):1–8.PubMedCrossRefGoogle Scholar
  6. 6.
    Krekels EHJ, Neely M, Panoilia E, Tibboel D, Capparelli E, Danhof M, et al. From pediatric covariate model to semiphysiological function for maturation: part I–extrapolation of a covariate model from morphine to zidovudine. CPT: Pharmacometrics & Systems Pharmacology. 2012;1:e9. doi: 10.1038/psp.2012.11. Published online 3 October 2012.Google Scholar
  7. 7.
    Krekels EHJ, Johnson TN, den Hoedt SM, Rostami-Hodjegan A, Danhof M, Tibboel D, et al. From pediatric covariate model to semiphysiological function for maturation: part II—sensitivity to physiological and physicochemical properties. CPT: Pharmacometrics & Systems Pharmacology. 2012;1:e10. doi: 10.1038/psp.2012.12. Published online 10 October 2012.Google Scholar
  8. 8.
    Alcorn J, McNamara PJ. Ontogeny of hepatic and renal systemic clearance pathways in infants: part I. Clin Pharmacokinet. 2002;41(12):959–98.PubMedCrossRefGoogle Scholar
  9. 9.
    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(12):1157–67.PubMedCrossRefGoogle Scholar
  10. 10.
    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(11):1077–97.PubMedCrossRefGoogle Scholar
  11. 11.
    Chen N, Aleksa K, Woodland C, Rieder M, Koren G. Ontogeny of drug elimination by the human kidney. Pediatr Nephrol. 2006;21(2):160–8.PubMedCrossRefGoogle Scholar
  12. 12.
    Landers S, Berry PL, Kearns GL, Kaplan SL, Rudolph AJ. Gentamicin disposition and effect on development of renal function in the very low birth weight infant. Dev Pharmacol Ther. 1984;7(5):285–302.PubMedGoogle Scholar
  13. 13.
    Koren G, James A, Perlman M. A simple method for the estimation of glomerular filtration rate by gentamicin pharmacokinetics during routine drug monitoring in the newborn. Clin Pharmacol Ther. 1985;38(6):680–5.PubMedCrossRefGoogle Scholar
  14. 14.
    Zarowitz BJ, Robert S, Peterson EL. Prediction of glomerular filtration rate using aminoglycoside clearance in critically ill medical patients. Ann Pharmacother. 1992;26(10):1205–10.PubMedGoogle Scholar
  15. 15.
    Sherwin CM, McCaffrey F, Broadbent RS, Reith DM, Medlicott NJ. Discrepancies between predicted and observed rates of intravenous gentamicin delivery for neonates. J Pharm Pharmacol. 2009;61(4):465–71.PubMedCrossRefGoogle Scholar
  16. 16.
    Lopez SA, Mulla H, Durward A, Tibby SM. Extended-interval gentamicin: population pharmacokinetics in pediatric critical illness. Pediatr Crit Care Med. 2010;11(2):267–74.PubMedCrossRefGoogle Scholar
  17. 17.
    de Hoog M, Schoemaker RC, Mouton JW, van den Anker JN. Tobramycin population pharmacokinetics in neonates. Clin Pharmacol Ther. 1997;62(4):392–9.PubMedCrossRefGoogle Scholar
  18. 18.
    Anderson BJ, Allegaert K, Van den Anker JN, Cossey V, Holford NH. Vancomycin pharmacokinetics in preterm neonates and the prediction of adult clearance. Br J Clin Pharmacol. 2007;63(1):75–84.PubMedCrossRefPubMedCentralGoogle Scholar
  19. 19.
    Administration FaD. Guidance for industry - E11 clinical investigation of medicinal products in the pediatric population 2000. Available from
  20. 20.
    Uemura O, Honda M, Matsuyama T, Ishikura K, Hataya H, Yata N, et al. Age, gender, and body length effects on reference serum creatinine levels determined by an enzymatic method in Japanese children: a multicenter study. Clin Exp Nephrol. 2011;15(5):694–9.PubMedCrossRefGoogle Scholar
  21. 21.
    Boer DP, de Rijke YB, Hop WC, Cransberg K, Dorresteijn EM. Reference values for serum creatinine in children younger than 1 year of age. Pediatr Nephrol. 2010;25(10):2107–13.PubMedCrossRefPubMedCentralGoogle Scholar
  22. 22.
    Allegaert K, Kuppens M, Mekahli D, Levtchenko E, Vanstapel F, Vanhole C, et al. Creatinine reference values in ELBW infants: impact of quantification by Jaffe or enzymatic method. J Matern Fetal Neonatal Med. 2012;25(9):1678–81.PubMedCrossRefGoogle Scholar
  23. 23.
    Farmacotherapeutisch kompas. Referentiewaarden klinische chemie. Available from: referentiewaarden klinische chemie.
  24. 24.
    Rudd PT, Hughes EA, Placzek MM, Hodes DT. Reference ranges for plasma creatinine during the first month of life. Arch Dis Child. 1983;58(3):212–5.PubMedCrossRefPubMedCentralGoogle Scholar
  25. 25.
    Krekels EH, van Hasselt JG, Tibboel D, Danhof M, Knibbe CA. Systematic evaluation of the descriptive and predictive performance of paediatric morphine population models. Pharm Res. 2011;28(4):797–811.PubMedCrossRefPubMedCentralGoogle Scholar
  26. 26.
    Montgomery DC, Peck EA. Introduction to linear regression analysis. New York: Wiley; 1982. p. 301–2.Google Scholar
  27. 27.
    Karlsson MO, Savic RM. Diagnosing model diagnostics. Clin Pharmacol Ther. 2007;82(1):17–20.PubMedCrossRefGoogle Scholar
  28. 28.
    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(9):927–34.PubMedCrossRefGoogle Scholar
  29. 29.
    De Cock RF, Allegaert K, Schreuder MF, Sherwin CM, de Hoog M, van den Anker JN, et al. Maturation of the glomerular filtration rate in neonates, as reflected by amikacin clearance. Clin Pharmacokinet. 2012;51(2):105–17.PubMedCrossRefGoogle Scholar
  30. 30.
    Knibbe CA, Krekels EH, van den Anker JN, DeJongh J, Santen GW, van Dijk M, et al. Morphine glucuronidation in preterm neonates, infants and children younger than 3 years. Clin Pharmacokinet. 2009;48(6):371–85.PubMedCrossRefGoogle Scholar
  31. 31.
    Wang C, Peeters MY, Allegaert K, van Blusse Oud-Alblas HJ, Krekels EH, Tibboel D, et al. A bodyweight-dependent allometric exponent for scaling clearance across the human life-span. Pharm Res. 2012;29(6):1570–81.PubMedCrossRefPubMedCentralGoogle Scholar
  32. 32.
    Bartelink IH, Boelens JJ, Bredius RG, Egberts AC, Wang C, Bierings MB, et al. Body weight-dependent pharmacokinetics of busulfan in paediatric haematopoietic stem cell transplantation patients: towards individualized dosing. Clin Pharmacokinet. 2012;51(5):331–45.PubMedCrossRefGoogle Scholar
  33. 33.
    Ince I, de Wildt SN, Wang C, Peeters MY, Burggraaf J, Jacqz-Aigrain E, et al. A novel maturation function for clearance of the cytochrome P450 3A substrate midazolam from preterm neonates to adults. Clin Pharmacokinet. 2013;52(7):555–65.PubMedCrossRefGoogle Scholar
  34. 34.
    Brendel K, Dartois C, Comets E, Lemenuel-Diot A, Laveille C, Tranchand B, et al. Are population pharmacokinetic and/or pharmacodynamic models adequately evaluated? A survey of the literature from 2002 to 2004. Clin Pharmacokinet. 2007;46(3):221–34.PubMedCrossRefPubMedCentralGoogle Scholar
  35. 35.
    Comets E, Brendel K, Mentre F. Computing normalised prediction distribution errors to evaluate nonlinear mixed-effect models: the npde add-on package for R. Comput Methods Programs Biomed. 2008;90(2):154–66.PubMedCrossRefGoogle Scholar
  36. 36.
    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(1):67–76.PubMedCrossRefGoogle Scholar
  37. 37.
    Cuzzolin L, Fanos V, Pinna B, di Marzio M, Perin M, Tramontozzi P, et al. Postnatal renal function in preterm newborns: a role of diseases, drugs and therapeutic interventions. Pediatr Nephrol. 2006;21(7):931–8.PubMedCrossRefGoogle Scholar
  38. 38.
    De Cock RF, Allegaert K, Sherwin CM, Nielsen EI, de Hoog M, van den Anker JN, et al. A neonatal amikacin covariate model can be used to predict ontogeny of other drugs eliminated through glomerular filtration in neonates. Pharm Res. 2014;31(3):754–67.Google Scholar
  39. 39.
    Zhao W, Biran V, Jacqz-Aigrain E. Amikacin maturation model as a marker of renal maturation to predict glomerular filtration rate and vancomycin clearance in neonates. Clin Pharmacokinet. 2013;52(12):1127–34.PubMedCrossRefGoogle Scholar
  40. 40.
    van den Anker JN, de Groot R, Broerse HM, Sauer PJ, van der Heijden BJ, Hop WC, et al. Assessment of glomerular filtration rate in preterm infants by serum creatinine: comparison with inulin clearance. Pediatrics. 1995;96(6):1156–8.PubMedGoogle Scholar
  41. 41.
    Zhao W, Kaguelidou F, Biran V, Zhang D, Allegaert K, Capparelli EV, et al. External evaluation of population pharmacokinetic models of vancomycin in neonates: the transferability of published models to different clinical settings. Br J Clin Pharmacol. 2012. doi: 10.1111/j.1365-2125.2012.04406.x.Google Scholar
  42. 42.
    Delanghe JR. How to estimate GFR in children. Nephrol Dial Transplant. 2009;24(3):714–6.PubMedCrossRefGoogle Scholar
  43. 43.
    Prigent A. Monitoring renal function and limitations of renal function tests. Semin Nucl Med. 2008;38(1):32–46.PubMedCrossRefGoogle Scholar
  44. 44.
    Perrone RD, Madias NE, Levey AS. Serum creatinine as an index of renal function: new insights into old concepts. Clin Chem. 1992;38(10):1933–53.PubMedGoogle Scholar
  45. 45.
    Kuppens M, George I, Lewi L, Levtchenko E, Allegaert K. Creatinaemia at birth is equal to maternal creatinaemia at delivery: does this paradigm still hold? J Matern Fetal Neonatal Med. 2012;25(7):978–80.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Roosmarijn F. W. De Cock
    • 1
  • Karel Allegaert
    • 2
  • Janneke M. Brussee
    • 1
  • Catherine M. T. Sherwin
    • 3
  • Hussain Mulla
    • 4
  • Matthijs de Hoog
    • 5
  • Johannes N. van den Anker
    • 5
    • 6
  • Meindert Danhof
    • 1
  • Catherijne A. J. Knibbe
    • 1
    • 7
  1. 1.Division of Pharmacology, LACDRLeiden UniversityLeidenThe Netherlands
  2. 2.Neonatal Intensive Care UnitUniversity Hospital LeuvenLeuvenBelgium
  3. 3.Division of Clinical Pharmacology & Clinical Trials Office Department of PediatricsUniversity of Utah School of MedicineSalt Lake CityUSA
  4. 4.Department of PharmacyUniversity Hospitals of LeicesterLeicesterUK
  5. 5.Department of Pediatric Intensive CareErasmus MC - Sophia Children’s HospitalRotterdamThe Netherlands
  6. 6.Division of Pediatric Clinical PharmacologyChildren’s National Medical CenterWashingtonUSA
  7. 7.Department of Clinical PharmacySt. Antonius HospitalNieuwegeinThe Netherlands

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