Journal Article

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

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

2009

Overview

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.

• Publisher: Springer International Publishing,Adis International,Wolters Kluwer Health, Inc,Springer Nature B.V
• Subject: Age Factors / Biological and medical sciences / Child, Preschool / Complications and side effects / Dosage and administration / Drug metabolism / Drugs / Female / General pharmacology / Glucuronides - metabolism / Glucuronosyltransferase - metabolism / Humans / Infant / Infant, Newborn / Infant, Premature - metabolism / Internal Medicine / Male / Medical sciences / Medicine / Medicine & Public Health / Metabolic Clearance Rate - physiology / Morphine / Morphine - metabolism / Original Research Article / Pharmacokinetics. Pharmacogenetics. Drug-receptor interactions / Pharmacology. Drug treatments / Pharmacology/Toxicology / Pharmacotherapy