PHARMACOKINETICS OF OXCARBAZEPINE DURING ADJUNCTIVE THERAPY IN PEDIATRIC PATIENTS WITH INADEQUATELY CONTROLLED PARTIAL SEIZURES
Abstract number :
1.287
Submission category :
Year :
2003
Submission ID :
644
Source :
www.aesnet.org
Presentation date :
12/6/2003 12:00:00 AM
Published date :
Dec 1, 2003, 06:00 AM
Authors :
Surinder Mangat, Cixuang Zheng, Sebastien Balez, Jerry R. Nedelman Novartis Pharma AG, Novartis Pharma AG, East Hanover, NJ; Novartis Pharma SAS, Novartis Pharma SAS, Rueil, France
To determine the pharmacokinetics of oxcarbazepine in pediatric patients during adjunctive therapy and to compare observed plasma concentrations to predictions based on a pharmacokinetic model for older pediatric patients (Sallas W 1999;40:Suppl.7:102).
In this open-label study, patients 1 month to [lt]4 years of age with partial seizures taking up to two concomitant antiepileptic drugs (AEDs) were allocated into two groups: 1) those receiving at least one enzyme-inducing AED (carbamazepine, phenobarbital or phenytoin), and 2) those receiving no AEDs or only non-enzyme-inducing AEDs. Dosing with oxcarbazepine was initiated on Day 1 at 10 mg/kg/day, and was increased by 10 mg/kg/day every 5 days, to a maximum dose of 60 mg/kg/day. Blood samples for analysis of the main active metabolite of oxcarbazepine, the monohydroxy derivative (MHD) were obtained on Day 5 (pre-dose), Day 10 (0.5h postdose), Day 20 (2h postdose) and Day 30 (5-8h postdose). Predicted MHD concentrations were determined from a pharmacokinetic model previously fitted to 109 patients 3 to 17 years of age on both enzyme-inducing and non-enzyme-inducing AEDs. According to that model, clearance and volume of distribution for MHD depend on body surface area (BSA) and height (HT), respectively. Thus, concentrations were predicted based on the median body size for the younger patients in this study.
Pharmacokinetic data were obtained for 21 out of 24 enrolled patients. Observed MHD concentrations were consistent with predicted concentrations. Median baseline BSA, HT, and weight for the 21 patients were 0.51 m2, 83 cm, and 11 kg, respectively. For patients of this size whether or not receiving enzyme-inducing AEDs, the previous model predicts trough (predose) MHD concentrations at 10 mg/kg/day dose to be 10.73 [micro]mol/L and 15.20 [micro]mol/L, respectively. Sixteen of 21 patients provided trough samples, defined as 10 [ndash] 14 hour post dose. Observed mean [plusmn] SD trough MHD concentrations were 11.86 [plusmn] 7.23 for patients on enzyme-inducing AEDs (n=9) and 17.11 [plusmn] 4.94 for patients not on enzyme-inducing AEDs (n=7). Further details, including population-pharmacokinetic modeling of the new data, will be presented.
Concentrations of the oxcarbazepine active metabolite MHD for patients 1 month to [lt]4 years of age on oxcarbazepine therapy were predictable by extrapolating a model based on patients 3 to 17 years of age.
[Supported by: Novartis Pharma]