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Pharmacokinetic drug interactions in children taking oxcarbazepine
William M Sallas1, Slavica Milosavljev, Joseph D'souza
1Norvastis Pharmaceuticals Corporation, East Hanover, NJ 07936-1080, USA. william.sallas@pharma.novartis.com
Insights
Oxcarbazepine has minimal drug interactions in children. Dosing adjustments for oxcarbazepine (OXC) in young children are based on body size, not age, to maintain therapeutic levels.
Area of Science:
- Pharmacology
- Pediatric Pharmacology
- Drug Metabolism
Background:
- Oxcarbazepine (OXC) is an antiepileptic drug frequently used in children.
- Understanding its drug-drug interactions (DDIs) with coadministered antiepileptic drugs (AEDs) is crucial for safe and effective treatment.
- Pediatric populations may exhibit different pharmacokinetic profiles compared to adults.
Purpose of the Study:
- To evaluate the pharmacokinetic drug-drug interactions between oxcarbazepine and commonly used antiepileptic drugs in pediatric patients.
- To identify factors influencing the metabolism of oxcarbazepine's active metabolite, 10-monohydroxy metabolite (MHD).
- To establish appropriate dosing guidelines for oxcarbazepine in children based on age and body size.
Main Methods:
- Population pharmacokinetic analysis of MHD was performed using data from 109 pediatric patients (aged 3-17 years).
- The influence of 7 concomitant AEDs and 12 covariates on MHD pharmacokinetics was assessed using NONMEM.
- Ratios of AED concentrations with and without oxcarbazepine were calculated to determine OXC's effect on coadministered AEDs.
Main Results:
- Body surface area, carbamazepine, phenobarbital, and phenytoin significantly affected MHD clearance.
- Weight-normalized clearance of MHD was higher in younger children.
- Coadministration with carbamazepine, phenobarbital, or phenytoin increased MHD clearance by 31-35%; carbamazepine levels decreased by 15%, and phenobarbital levels increased by 14%.
Conclusions:
- Oxcarbazepine demonstrates a low potential for inhibiting or inducing oxidative enzymes.
- Higher weight-normalized oxcarbazepine doses are recommended for young children compared to older children and adults to achieve equivalent MHD concentrations.
- Dosing adjustments for oxcarbazepine in pediatric patients should primarily be based on body size.
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.