Abstracts

RATIONALE: Baseline antiepileptic drug (AED) load is believed to increase CNS toxicity of subsequent add-on AED therapy due to pharmacodynamic interactions. Although neurotoxicity is often managed by slowing titration and/or reducing dose of the newly added agent, the importance of concomitant reducing AED co-therapy has not been well established in clinical trials. To evaluate whether co-therapy reduction improves topiramate (TPM) tolerability, we compared a dose-management strategy of allowing flexible co-therapy dosing to a regimen in which co-therapy doses were fixed. Preliminary analyses performed during validation of data from this novel open-label study, which randomized investigators to treatment groups, are presented.
METHODS: Eligible subjects for this 20-wk, open-label study were adults with partial-onset seizures despite treatment with [gt]1 AED. TPM was titrated at physician discretion; recommended starting dose was 25 mg/day with weekly 25-mg/day increases for the first 4 wk and subsequent increments of 25-50 mg/day weekly as needed. Investigators were randomized to a group allowed to manage treatment-emergent adverse events (AEs) by reducing co-therapy doses (Flex-Dose) or one not allowed to adjust co-therapy doses (Fixed-Dose). If AEs necessitated co-therapy reduction, the Fixed-Dose subject exited randomized treatment. Primary study endpoint was the percentage of subjects exiting randomized treatment due to AEs.
RESULTS: Preliminary analyses of data from the first 315 subjects who had received [gt]1 TPM dose were performed. Demographics for the two groups were similar. Overall, 58% of subjects were female; mean age was 39 yrs. Of Flex-Dose subjects, 9% exited randomized treatment due to AEs vs 18% of Fixed-Dose subjects (P=0.035). AEs were similar in incidence but tended to be more intense with fixed co-therapy: AEs of marked severity were reported by 4% (Flex-Dose) vs 7% (Fixed-Dose). The most common AEs were dizziness (8%) and somnolence (10%). Cognitive effects were generally mild and reported by [lt]5% of subjects. Co-therapy was reduced in 38% of Flex-Dose subjects; 5% had co-therapy discontinued and achieved TPM monotherapy. Median TPM dose at Week 20 was 250 mg/day (Flex-Dose) and 200 mg/day (Fixed-Dose).
CONCLUSIONS: When initiated as adjunctive therapy, TPM is better tolerated when co-therapy dosages are reduced to manage AEs. These data with TPM support the contribution of pharmacodynamic interactions to the side effect profile associated with AED adjunctive therapy.
Support: Ortho-McNeil Pharmaceutical.
Disclosure: Salary - Hulihan, Kamin, Karim, Olsen- Ortho-McNeil Pharmaceutical. Grant - Naritoku- Clinical Investigations. Stock - Hulihan, Kamin, Karim, Olsen- Ortho-McNeil Pharmaceutical.