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Prediction of Morphine Clearance in the Paediatric Population

How Accurate are the Available Pharmacokinetic Models?

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Abstract

The pharmacokinetics of morphine in paediatrics have been widely studied using different approaches and modelling techniques. In this review, we explore advantages and disadvantages of the different data analysis techniques that have been applied, with specific focus on the accuracy of morphine clearance predictions by reported paediatric pharmacokinetic models. Twenty paediatric studies reported a wide range in morphine clearance values using traditional, rather descriptive methods. Clearance values were expressed per kilogram bodyweight, while maturation in clearance was described by comparing mean clearance per kilogram bodyweight between age-stratified subgroups. Population modelling allows for the analysis of sparse data, thereby limiting the burden to individual patients. Using this technique, continuous maturation profiles can be obtained on the basis of either fixed allometric scaling or comprehensive covariate analysis. While the models based on fixed allometric scaling resulted in complex maturation functions, all three paediatric population models for morphine yielded quite similar clearance predictions. The largest difference in clearance predictions between these three population models occurred in the first months of life, particularly in preterm neonates. Morphine clearance predictions by a physiologically based pharmacokinetic model were based on many continuous equations describing changes in underlying physiological processes across the full paediatric age range, and resulted in similar clearance predictions as well. However, preterm neonates could not be integrated in this model. In conclusion, the value of paediatric pharmacokinetic models is mostly dependent on clearance predictions and population concentration predictions, rather than on the individual description of data. For most pharmacokinetic models, however, the assessment of model performance was very limited and the accuracy of morphine clearance predictions as well as population concentration predictions was confirmed by formal evaluation and validation procedures for only one model.

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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.

Conflict of interest

All authors declare no conflicts of interest that are directly relevant to the content of this review.

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Authors and Affiliations

  1. Division of Pharmacology, Leiden/Amsterdam Center for Drug Research, Leiden, The Netherlands

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

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

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

  3. Department of Clinical Pharmacy, St. Antonius Hospital, PO Box 2500, 3430 EM, Nieuwegein, The Netherlands

    Catherijne A. J. Knibbe

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  1. Elke H. J. Krekels
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Correspondence to Catherijne A. J. Knibbe.

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Krekels, E.H.J., Tibboel, D., Danhof, M. et al. Prediction of Morphine Clearance in the Paediatric Population. Clin Pharmacokinet 51, 695–709 (2012). https://doi.org/10.1007/s40262-012-0006-9

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