Abstracts

RATIONALE: Antiepileptic drugs (AEDs) are typically titrated according to clinical response. For newer AEDs, titration targets are generally doses proven to be effective in clinical trials, as opposed to [dsquote]therapeutic[dsquote] plasma concentrations. Nonetheless, information about the relationship between AED plasma concentrations and dose may be helpful to clinicians. However, data on the plasma concentrations observed with newer AEDs used as monotherapy are limited.
METHODS: Two double-blind studies have evaluated four different dosages of topiramate (TPM) as monotherapy in patients with newly or recently diagnosed epilepsy. In Study 1, patients with newly or recently diagnosed ([lt]3 yrs) localization-related epilepsy were randomized to treatment with 50 or 500 mg/day TPM (25 or 200 mg/day TPM if body weight [lt]50 kg). In Study 2, patients with newly diagnosed ([lt]3 mos) epilepsy were randomized to double-blind treatment with the investigator[scquote]s choice of standard therapy (carbamazepine or valproate) or two dosages of TPM (100 or 200 mg/day). Both studies were fixed-dose studies, precluding the determination of a traditional [dsquote]therapeutic range.[dsquote] Blood was drawn for plasma concentrations at the last study visit.
RESULTS: Dose vs. mean (SD) plasma concentrations ( [mu]g/mL) were: TPM 50, 1.6 (1.0); TPM 100, 3.8(1.6); TPM 200, 6.4 (3.1); and TPM 500, 12.4 (6.6). Dose vs. 6-mo seizure-free rates were: TPM 50, 39%; TPM 100, 49%; TPM 200, 44%; and TPM 500, 54%. In Study 1, plasma concentrations were grouped into three subgroups of equal size ([lt]1.76 [mu]g/mL; 1.77-9.91 [mu]g/mL; [gt]9.91 [mu]g/mL), regardless of dose assignment. A correlation was observed between plasma concentration strata and time to 1st seizure: (84 days, 194 days, 451 days, respectively; p=0.015). Nonetheless, scatterplots of plasma concentrations vs. time to 1st seizure showed considerable intra-individual variability.
CONCLUSIONS: These data illustrate the linearity of TPM dose vs. plasma concentration when used as monotherapy. Although a dose effect is observed in plasma concentrations and therapeutic response, a [dsquote]therapeutic range[dsquote] has not been defined. Rather, TPM dose should be individualized according to clinical response.
Support: The R. W. Johnson Pharmaceutical Research Institute
Disclosure: Salary - Neto, Wu, Wang, & Pledger- Pharmaceutical Research Institute(PRI); Grant - Clinical Studies- Pellock- from Ortho McNeil; Stock - Neto, Wu, Wang, & Pledger; Honoraria - Pellock, Ortho McNeil