Abstracts

RATIONALE: Oxcarbazepine (OXC) is currently approved as monotherapy or adjunctive therapy in the treatment of partial seizures in adults and as adjunctive therapy in children 4-16 years of age. It was assumed that if plasma levels associated with seizure-control in adults during adjunctive therapy were similar to those associated with seizure-control in the pediatric adjunctive therapy, then plasma levels shown to be effective as monotherapy in adults would be effective as monotherapy in pediatric patients. In this analysis, we determined the efficacious dose range of oxcarbazepine as monotherapy in children based on this pharmacokinetic-bridging approach.
METHODS: OXC plasma concentrations were quantified by the steady-state trough value (Cmin) associated with a constant bid dosing regimen. The distribution of Cmin values was determined for adults on adjunctive therapy at the effective dose range of 600[ndash]2400 mg/day. The distribution of Cmin values was also determined for children on adjunctive therapy at the effective dose range of 8-53 mg/kg/day, which was compared to adult values. Distributions of Cmin values were then determined for adults on monotherapy at the effective dose range of 1200-2400 mg/day. Doses that would produce these Cmin values in children on monotherapy were extrapolated using a pharmacokinetic model. Efficacy of this dose range in children was confirmed using a meta-analysis of seizure data from double-blind monotherapy studies.
RESULTS: From an analysis of the pivotal adjunctive OXC trials in adult patients with medically refractory partial epilepsy, the efficacious plasma OXC trough levels ranged from 4.7 to 17.8 ug/ml with daily doses of 600 mg to 2400 mg. In children, the efficacious plasma trough levels were comparable, ranging from 8.2 to 20.3 ug/ml on daily OXC doses of 8[ndash]53 mg/kg. An analysis of the monotherapy trials of OXC that demonstrated its efficacy in adults with partial epilepsy established that the efficacious trough levels range from 14.5 to 28.2 ug/ml on daily doses of 1200 mg to 2400 mg. This plasma range is achieved in children on OXC as monotherapy at daily doses ranging between 20 and 55 mg/kg. This daily dose range was found to have efficacy in children with partial epilepsy on OXC as monotherapy.
CONCLUSIONS: The levels of OXC at efficacious doses during adjunctive therapy in adults and children are similar. The efficacious dose range of OXC as monotherapy for children with partial onset seizures is 20 to 55 mg/kg/day.
Support: Novartis Pharmaceuticals Corporation
Disclosure: Salary - Novartis Pharmaceutical Corporation; Grant - Novartis Pharmaceutical Corporation; Consulting - Novartis Pharmaceutical Corporation; Stock - Novartis Pharmaceutical Corporation; Honoraria - Novartis Pharmaceutical Corporation