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

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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.

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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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Authors and Affiliations

  1. LACDR, Division of Pharmacology, Leiden University, Leiden, The Netherlands

    Chenguang Wang, Elke H. J. Krekels, Meindert Danhof & Catherijne A. J. Knibbe

  2. Department of Intensive Care and Paediatric Surgery, Erasmus MC Sophia Children’s Hospital, Rotterdam, The Netherlands

    Chenguang Wang, Elke H. J. Krekels, Dick Tibboel & Catherijne A. J. Knibbe

  3. Department of Anesthesia, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

    Senthilkumar Sadhavisvam

  4. Department of Pediatrics, University of Cincinnati, Cincinnati, OH, USA

    Senthilkumar Sadhavisvam & Alexander A. Vinks

  5. Department of Anesthesiology, Leiden University Medical Center, 2300 RC, Leiden, The Netherlands

    Albert Dahan

  6. Department of Clinical Pharmacology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

    Alexander A. Vinks

  7. Department of Clinical Pharmacy, St. Antonius Hospital, P.O. Box 2500, 3430 EM, Nieuwegein, The Netherlands

    Catherijne A. J. Knibbe

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  1. Chenguang Wang
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Correspondence to Catherijne A. J. Knibbe.

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Wang, C., Sadhavisvam, S., Krekels, E.H.J. et al. Developmental Changes in Morphine Clearance Across the Entire Paediatric Age Range are Best Described by a Bodyweight-Dependent Exponent Model. Clin Drug Investig 33, 523–534 (2013). https://doi.org/10.1007/s40261-013-0097-6

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