Pharmacokinetic drug interactions in children taking oxcarbazepine.
OBJECTIVE
Our objective was to evaluate the drug-drug interactions of oxcarbazepine with coadministered antiepileptic drugs in children.


METHODS
In a clinical trial, pediatric patients receiving an oxcarbazepine dose titrated to 30 to 46 mg. kg(-1). d(-1) given twice daily had 1 to 4 blood samples collected per patient for population pharmacokinetic analysis of oxcarbazepine's major bioactive 10-monohydroxy metabolite. With the use of NONMEM, 7 concomitant antiepileptic drugs and 12 additional covariates were examined for their effects on the pharmacokinetics of 10-monohydroxy metabolite. In addition, for each concomitant antiepileptic drug, the ratio of its mean concentration with coadministration of oxcarbazepine to that without coadministration at baseline was calculated to evaluate the effect of oxcarbazepine on the coadministered antiepileptic drugs.


RESULTS
The population pharmacokinetic data for 10-monohydroxy metabolite consisted of a total of 376 observations from 109 patients, aged 3 to 17 years. Body surface area and 3 antiepileptic drugs (carbamazepine, phenobarbital, and phenytoin) were significant predictors of the apparent clearance of 10-monohydroxy metabolite, whereas height was a significant predictor of apparent volume. Weight-normalized clearance of 10-monohydroxy metabolite was higher in young children than in older children and adults. Carbamazepine, phenobarbital, or phenytoin administered with oxcarbazepine increased the apparent clearance of 10-monohydroxy metabolite by 31% to 35%, whereas carbamazepine levels decreased by 15% and phenobarbital levels increased by 14%.


CONCLUSIONS
Oxcarbazepine has a low propensity to inhibit or induce oxidative enzymes. Young children could be given higher milligrams-per-kilogram oxcarbazepine doses than older children and adults to achieve the same mean steady-state concentration of 10-monohydroxy metabolite. The adjustment is based simply on body size.
Sallas
William M
WM
Norvastis Pharmaceuticals Corporation, East Hanover, NJ 07936-1080, USA. william.sallas@pharma.novartis.com
Milosavljev
Slavica
S
D'souza
Joseph
J
Hossain
Mohammad
M
D000293:Adolescent; D000465:Algorithms; D000704:Analysis of Variance; D000927:Anticonvulsants / Q000009:adverse effects* / Q000493:pharmacokinetics*; D002220:Carbamazepine / Q000009:adverse effects* / Q000031:analogs & derivatives*; D002648:Child; D002675:Child, Preschool; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004347:Drug Interactions; D005260:Female; D006801:Humans; D008297:Male; D008954:Models, Biological; D000078330:Oxcarbazepine; D011153:Population; D011786:Quality Control
D000927:Anticonvulsants; D002220:Carbamazepine; D000078330:Oxcarbazepine