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01-06-2009 | Original Research Article

Morphine Glucuronidation in Preterm Neonates, Infants and Children Younger than 3 Years

Authors: Dr Catherijne A. J. Knibbe, Elke H. J. Krekels, Johannes N. van den Anker, Joost DeJongh, Gijs W. E. Santen, Monique van Dijk, Sinno H. P. Simons, Richard A. van Lingen, Evelyne M. Jacqz-Aigrain, Meindert Danhof, Dick Tibboel

Published in: Clinical Pharmacokinetics | Issue 6/2009

Abstract

Background and objective

A considerable amount of drug use in children is still unlicensed or off-label. In order to derive rational dosing schemes, the influence of aging on glucuronidation capacity in newborns, including preterms, infants and children under the age of 3 years was studied using morphine and its major metabolites as a model drug.

Methods

A population pharmacokinetic model was developed with the nonlinear mixed-effects modelling software NONMEM® V, on the basis of 2159 concentrations of morphine and its glucuronides from 248 infants receiving intravenous morphine ranging in bodyweight from 500 g to 18 kg (median 2.8 kg). The model was internally validated using normalized prediction distribution errors.

Results

Formation clearances of morphine to its glucuronides and elimination clearances of the glucuronides were found to be primarily influenced by bodyweight, which was parameterized using an allometric equation with an estimated exponential scaling factor of 1.44. Additionally, a postnatal age of less than 10 days was identified as a covariate for formation clearance to the glucuronides, independent of birthweight or postmenstrual age. Distribution volumes scaled linearly with bodyweight.

Conclusions

Model-based simulations show that in newborns, including preterms, infants and children under the age of 3 years, a loading dose in µg/kg and a maintenance dose expressed in µg/kg^1.5/h, with a 50% reduction of the maintenance dose in newborns younger than 10 days, results in a narrow range of morphine and metabolite serum concentrations throughout the studied age range. Future pharmacodynamic investigations are needed to reveal target concentrations in this population, after which final dosing recommendations can be made.

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Title: Morphine Glucuronidation in Preterm Neonates, Infants and Children Younger than 3 Years
Authors: Dr Catherijne A. J. Knibbe
Elke H. J. Krekels
Johannes N. van den Anker
Joost DeJongh
Gijs W. E. Santen
Monique van Dijk
Sinno H. P. Simons
Richard A. van Lingen
Evelyne M. Jacqz-Aigrain
Meindert Danhof
Dick Tibboel
Publication date: 01-06-2009
Publisher: Springer International Publishing
Published in: Clinical Pharmacokinetics / Issue 6/2009
Print ISSN: 0312-5963
Electronic ISSN: 1179-1926
DOI: https://doi.org/10.2165/00003088-200948060-00003

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Morphine Glucuronidation in Preterm Neonates, Infants and Children Younger than 3 Years

Abstract

Background and objective

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background and objective

Methods

Results

Conclusions

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