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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

Abstract

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.

Methods

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.

Results

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.

Conclusion

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.

Keywords

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.

Notes

Acknowledgments

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.

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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

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