Morphine glucuronidation in preterm neonates, infants and children younger than 3 years.
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 microg/kg and a maintenance dose expressed in microg/kg1.5/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.
Knibbe
Catherijne A J
CA
Department of Clinical Pharmacy, St Antonius Hospital, 3430 EM Nieuwegein, the Netherlands. c.knibbe@antoniusziekenhuis.nl
Krekels
Elke H J
EH
van den Anker
Johannes N
JN
DeJongh
Joost
J
Santen
Gijs W E
GW
van Dijk
Monique
M
Simons
Sinno H P
SH
van Lingen
Richard A
RA
Jacqz-Aigrain
Evelyne M
EM
Danhof
Meindert
M
Tibboel
Dick
D
D000367:Age Factors; D002675:Child, Preschool; D005260:Female; D020719:Glucuronides / Q000378:metabolism*; D014453:Glucuronosyltransferase / Q000378:metabolism; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007234:Infant, Premature / Q000378:metabolism*; D008297:Male; D008657:Metabolic Clearance Rate / Q000502:physiology; D009020:Morphine / Q000378:metabolism*
D020719:Glucuronides; D009020:Morphine; C491474:UGT2B7 protein, human; D014453:Glucuronosyltransferase