Abstracts

Rationale: Topiramate (TPM), a broad spectrum anti-epileptic drug (AED), is approved for initial monotherapy in epilepsy patients (pts) ≥10 y old with partial-onset or primary generalized tonic-clonic seizures (sz) at a dose of 400 mg/day. However, it is unknown if pt characteristics predict individual dose response. This multicenter study was designed to identify pt characteristics predictive of effective target, stabilized monotherapy dosages of TPM. Methods: This is a 24-wk, outpatient, multicenter, open-label trial of TPM monotherapy in pts ≥10 y old with newly diagnosed or relapsing epilepsy with partial-onset or primary generalized tonic-clonic sz. Pts were required to have at least 1 sz in the 3 mos prior to study entry. Investigators titrated pts to an efficacious dose and optimized the TPM monotherapy regimen during the 24-wk trial. The primary endpoint is the mean stabilized dose of TPM during the last 28 days of treatment for pts reporting >3 sz (high-sz-freq pts) vs those reporting 1–3 sz (low-sz-freq pts) during a 3-mo retrospective baseline period; differences were analyzed via analysis of variance. Time to reach stabilized dose was estimated using the Kaplan-Meier method. The use of baseline characteristics to predict the stabilized TPM dose was evaluated using linear regression (for the value of the stabilized dose) and logistic regression (for the probability of reaching the stabilized dose) analyses.Results: Available for analysis were 196 of 415 enrolled pts (mean age 36.1 y; 63% female); 125 (64%) low-sz-freq pts and 71 (36%) high-sz-freq pts. Sixty-eight (54.4%) low-sz-freq pts and 33 (46.5%) high-sz-freq pts met the criteria for the mITT population, defined as all pts treated for ≥12 wks who reached a stabilized dose during the last 28 days prior to the analysis cut-off point. Most pts reached a stable dose of TPM within the first 3 mos of treatment; half of the pts reached a stable dose after ~5 wks (low-sz-freq pts) and 7 wks (high-sz-freq pts). The average stabilized daily dose of TPM was significantly different for the 2 groups; 186mg in the low-sz-freq pts and 248mg in the high-sz-freq pts (P=0.0063). In the mITT population, baseline sz-freq had a significant impact on the stabilized dosage (P<0.01). In the ITT population, both baseline sz-freq (P=0.0306) and sz etiology (P=0.0302) were identified as significant predictors of the probability of reaching a stabilized dose. Most treatment emergent adverse events were mild to moderate; those occurring with cumulative incidence rates >10% in either sz-freq group were paresthesia, anorexia, difficulty with memory, headache, somnolence, fatigue, and dizziness.Conclusions: The stabilized dose of TPM monotherapy in pts with newly diagnosed epilepsy was 186–248 mg/day, with stable TPM target doses achieved within 5-7 wks in 50% of the patients. Baseline sz frequency was predictive of the target dose, with pts having a lower baseline sz frequency requiring a lower TPM dose.