Clinical Drug Investigation

, Volume 33, Issue 7, pp 523–534 | Cite as

Developmental Changes in Morphine Clearance Across the Entire Paediatric Age Range are Best Described by a Bodyweight-Dependent Exponent Model

  • Chenguang Wang
  • Senthilkumar Sadhavisvam
  • Elke H. J. Krekels
  • Albert Dahan
  • Dick Tibboel
  • Meindert Danhof
  • Alexander A. Vinks
  • Catherijne A. J. KnibbeEmail author
Original Research Article


Background and Objective

Morphine clearance has been successfully scaled from preterm neonates to 3-year-old children on the basis of a bodyweight-based exponential (BDE) function and age younger or older than 10 days. The aim of the current study was to characterize the developmental changes in morphine clearance across the entire paediatric age range.


Morphine and morphine-3-glucuronide (M3G) concentration data from 358 (pre)term neonates, infants, children and adults, and morphine concentration data from 117 adolescents were analysed using NONMEM 7.2. Based on available data, two models were developed: I. using morphine data; II. using morphine and M3G data.


In model I, morphine clearance across the paediatric age range was very well described by a BDE function in which the allometric exponent decreased in a sigmoidal manner with bodyweight (BDE model) from 1.47 to 0.88, with half the decrease in exponent reached at 4.01 kg. In model II, the exponent for the formation and elimination clearance of M3G was found to decrease from 1.56 to 0.89 and from 1.06 to 0.61, with half the decrease reached at 3.89 and 4.87 kg, respectively. Using the BDE model, there was no need to use additional measures for size or age.


The BDE model was able to scale both total morphine clearance and glucuronidation clearance through the M3G pathway across all age ranges between (pre)term neonates and adults by allowing the allometric exponent to decrease across the paediatric age range from values higher than 1 for neonates to values lower than 1 for infants and children.


Morphine Preterm Neonate Term Neonate Morphine Concentration Allometric Exponent 
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.



This study was performed within the framework of Top Institute Pharma project number D2-104. The work of C.A.J. Knibbe is supported by the Innovational Research Incentives Scheme (Veni grant, July 2006) of the Dutch Organization for Scientific Research (NWO). The clinical study on morphine pharmacokinetics in older children and adolescents was supported in part by USPHS Grant #UL1 RR026314 from the National Center for Research Resources, NIH and with the Place Outcomes Research Award and Translational Research Award (PI: Sadhasivam) and was supported by the Department of Anesthesia, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA. The authors would like to thank Dr Richard van Lingen, Dr Caroline van der Marel, Professor Imti Choonara and Professor Anne Lynn for their willingness to share their morphine and morphine-3-glucuronide data in children in this project.

Conflicts of interest

Chenguang Wang, Senthilkumar Sadhavisvam, Elke H.J. Krekels, Albert Dahan, Dick Tibboel, Meindert Danhof, Alexander A. Vinks and Catherijne A.J. Knibbe declare no conflicts of interest.


  1. 1.
    Krekels EH, Tibboel D, Danhof M, Knibbe CA. Prediction of morphine clearance in the paediatric population: how accurate are the available pharmacokinetic models? Clin Pharmacokinet. 2012;51(11):695–709. doi: 10.1007/s40262-012-0006-9.PubMedCrossRefGoogle Scholar
  2. 2.
    Bouwmeester NJ, Anderson BJ, Tibboel D, Holford NH. Developmental pharmacokinetics of morphine and its metabolites in neonates, infants and young children. Br J Anaesth. 2004;92(2):208–17.PubMedCrossRefGoogle Scholar
  3. 3.
    Anand KJ, Anderson BJ, Holford NH, Hall RW, Young T, Shephard B, et al. Morphine pharmacokinetics and pharmacodynamics in preterm and term neonates: secondary results from the NEOPAIN trial. Br J Anaesth. 2008;101(5):680–9. doi: aen24810.1093/bja/aen248.PubMedCrossRefGoogle Scholar
  4. 4.
    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. doi: 10.2165/00003088-200948060-000033.PubMedCrossRefGoogle Scholar
  5. 5.
    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. doi: 10.1007/s11095-010-0333-1.PubMedCrossRefGoogle Scholar
  6. 6.
    Mahmood I. Prediction of drug clearance in children from adults: a comparison of several allometric methods. Br J Clin Pharmacol. 2006;61(5):545–57. doi: BCP262210.1111/j.1365-2125.2006.02622.x.PubMedCrossRefGoogle Scholar
  7. 7.
    Mahmood I. Prediction of drug clearance in children: impact of allometric exponents, body weight, and age. Ther Drug Monit. 2007;29(3):271–8. doi: 10.1097/FTD.0b013e318042d3c400007691-200706000-00002.PubMedCrossRefGoogle Scholar
  8. 8.
    Bonate PL. The effect of collinearity on parameter estimates in nonlinear mixed effect models. Pharm Res. 1999;16(5):709–17.PubMedCrossRefGoogle Scholar
  9. 9.
    Khandelwal A, et al. Influence of correlated covariates on predictive performance for different models. 2011; Abstr 2220:20, 2011.Google Scholar
  10. 10.
    Krekels EH, DeJongh J, van Lingen RA, van der Marel CD, Choonara I, Lynn AM, et al. Predictive performance of a recently developed population pharmacokinetic model for morphine and its metabolites in new datasets of (preterm) neonates, infants and children. Clin Pharmacokinet. 2011;50(1):51–63. doi: 10.2165/11536750-000000000-00000.PubMedCrossRefGoogle Scholar
  11. 11.
    Wang C, Peeters MY, Allegaert K, Blusse van 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. doi: 10.1007/s11095-012-0668-x.
  12. 12.
    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. doi: 10.2165/11598180-000000000-00000.PubMedCrossRefGoogle Scholar
  13. 13.
    van Dijk M, Bouwmeester NJ, Duivenvoorden HJ, Koot HM, Tibboel D, Passchier J, et al. Efficacy of continuous versus intermittent morphine administration after major surgery in 0–3-year-old infants; a double-blind randomized controlled trial. Pain. 2002;98(3):305–13.PubMedCrossRefGoogle Scholar
  14. 14.
    Simons SH, van Dijk M, van Lingen RA, Roofthooft D, Duivenvoorden HJ, Jongeneel N, et al. Routine morphine infusion in preterm newborns who received ventilatory support: a randomized controlled trial. JAMA. 2003;290(18):2419–27. doi: 10.1001/jama.290.18.2419.PubMedCrossRefGoogle Scholar
  15. 15.
    van Lingen RA. Pain assessment and analgesia in the newborn: an integrated approach. Rotterdam: Erasmus University; 2000.Google Scholar
  16. 16.
    van der Marel CD, Peters JW, Bouwmeester NJ, Jacqz-Aigrain E, van den Anker JN, Tibboel D. Rectal acetaminophen does not reduce morphine consumption after major surgery in young infants. Br J Anaesth. 2007;98(3):372–9. doi: 10.1093/bja/ael371.PubMedCrossRefGoogle Scholar
  17. 17.
    Lynn AM, Nespeca MK, Bratton SL, Shen DD. Intravenous morphine in postoperative infants: intermittent bolus dosing versus targeted continuous infusions. Pain. 2000;88(1):89–95.PubMedCrossRefGoogle Scholar
  18. 18.
    Choonara I, Lawrence A, Michalkiewicz A, Bowhay A, Ratcliffe J. Morphine metabolism in neonates and infants. Br J Clin Pharmacol. 1992;34(5):434–7.PubMedCrossRefGoogle Scholar
  19. 19.
    Sadhasivam S, Krekels EH, Chidambaran V, Esslinger HR, Ngamprasertwong P, Zhang K, et al. Morphine clearance in children: does race or genetics matter? J Opioid Manage. 2012;8(4):217–26. doi: 10.5055/jom.2012.0119.CrossRefGoogle Scholar
  20. 20.
    Sarton E, Olofsen E, Romberg R, den Hartigh J, Kest B, Nieuwenhuijs D, et al. Sex differences in morphine analgesia: an experimental study in healthy volunteers. Anesthesiology. 2000;93(5):1245–54; discussion 6A.Google Scholar
  21. 21.
    Karlsson MO, Savic RM. Diagnosing model diagnostics. Clin Pharmacol Ther. 2007;82(1):17–20. doi: 610024110.1038/sj.clpt.6100241.PubMedCrossRefGoogle Scholar
  22. 22.
    Brendel K, Comets E, Laffont C, Laveille C, Mentre F. Metrics for external model evaluation with an application to the population pharmacokinetics of gliclazide. Pharm Res. 2006;23(9):2036–49. doi: 10.1007/s11095-006-9067-5.PubMedCrossRefGoogle Scholar
  23. 23.
    Penson RT, Joel SP, Clark S, Gloyne A, Slevin ML. Limited phase I study of morphine-3-glucuronide. J Pharm Sci. 2001;90(11):1810–6.PubMedCrossRefGoogle Scholar
  24. 24.
    Strassburg CP, Strassburg A, Kneip S, Barut A, Tukey RH, Rodeck B, et al. Developmental aspects of human hepatic drug glucuronidation in young children and adults. Gut. 2002;50(2):259–65.PubMedCrossRefGoogle Scholar
  25. 25.
    Edginton AN, Schmitt W, Voith B, Willmann S. A mechanistic approach for the scaling of clearance in children. Clin Pharmacokinet. 2006;45(7):683–704.PubMedCrossRefGoogle Scholar
  26. 26.
    Zaya MJ, Hines RN, Stevens JC. Epirubicin glucuronidation and UGT2B7 developmental expression. Drug Metab Dispos Biol Fate Chem. 2006;34(12):2097–101. doi: 10.1124/dmd.106.011387.PubMedCrossRefGoogle Scholar
  27. 27.
    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: Pharmacomet Syst Pharmacol. 2012;1:e9. doi:
  28. 28.
    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 Pharmacomet Syst Pharmacol. 2012;1:e10.Google Scholar
  29. 29.
    Savic RM, Karlsson MO. Importance of shrinkage in empirical bayes estimates for diagnostics: problems and solutions. AAPS J. 2009;11(3):558–69. doi: 10.1208/s12248-009-9133-0.PubMedCrossRefGoogle Scholar
  30. 30.
    Ince I, de Wildt SN, Wang C,0020Peeters 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. doi: 10.1007/s40262-013-0050-0.

Copyright information

© Springer International Publishing Switzerland 2013

Authors and Affiliations

  • Chenguang Wang
    • 1
    • 2
  • Senthilkumar Sadhavisvam
    • 3
    • 4
  • Elke H. J. Krekels
    • 1
    • 2
  • Albert Dahan
    • 5
  • Dick Tibboel
    • 2
  • Meindert Danhof
    • 1
  • Alexander A. Vinks
    • 4
    • 6
  • Catherijne A. J. Knibbe
    • 1
    • 2
    • 7
    Email author
  1. 1.LACDR, Division of PharmacologyLeiden UniversityLeidenThe Netherlands
  2. 2.Department of Intensive Care and Paediatric SurgeryErasmus MC Sophia Children’s HospitalRotterdamThe Netherlands
  3. 3.Department of AnesthesiaCincinnati Children’s Hospital Medical CenterCincinnatiUSA
  4. 4.Department of PediatricsUniversity of CincinnatiCincinnatiUSA
  5. 5.Department of AnesthesiologyLeiden University Medical CenterLeidenThe Netherlands
  6. 6.Department of Clinical PharmacologyCincinnati Children’s Hospital Medical CenterCincinnatiUSA
  7. 7.Department of Clinical PharmacySt. Antonius HospitalNieuwegeinThe Netherlands

Personalised recommendations