Abstracts

To explore the relationship between therapeutic effects of topiramate (TPM) as monotherapy and plasma concentrations. A randomized, double-blind trial compared TPM titrated, based on tolerability, to target maintenance dosages of 50 or 400 mg/day in patients with epilepsy diagnosed [underline][lt][/underline]3 months before study entry or patients who had relapsed while not receiving AED therapy. 470 adults and children ([underline][gt][/underline]6 yrs old) were randomized to double-blind treatment after any emergency or temporary AED was withdrawn. Plasma concentrations were measured during stabilization after titration (Day 127 or last study visit for early withdrawals). Efficacy measured as time to 1^st seizure and the probability of being seizure-free were evaluated as a function of plasma concentration. In the primary efficacy analysis, TPM titrated to a target maintenance dosage of 400 mg/day was significantly more effective than 50 mg/day in time to 1^st seizure. The first titration step with a significant between-group difference was at 100 vs. 25 mg/day. Mean final dosage and mean stabilized plasma concentrations were 43 mg/day and 1.9 [micro]g/ml in the TPM 50 group, and 309 mg/day and 11.7 [micro]g/ml in the group with a titration target of 400 mg/day. The [sim]7-fold difference between groups in final dosage and plasma concentration is consistent with linear kinetics of TPM. Time to 1st seizure vs. TPM plasma concentration strata ([lt]2, 2-[lt]10, [ge]10 [micro]g/ml) favored higher concentrations (p=0.029). In post-hoc analyses, estimated seizure-free rates at 6 months also showed concentration-dependent effect. The effective range for most patients appeared to be 4-10 [micro]g/ml [ndash] plasma levels achievable with 100-300 mg/day TPM. Incremental therapeutic gain was relatively small at concentrations [gt]10 [micro]g/ml. The most common treatment-emergent adverse events were paresthesia, headache, upper respiratory tract infection, dizziness, somnolence, fatigue, appetite decrease and weight loss. Discontinuations due to cognitive-related dysfunction were 7% with the higher TPM dose and 2% with 50 mg/day TPM. The therapeutic effects of TPM as monotherapy in epilepsy are both dose- and concentration-dependent. Based on these data, 100-300 mg/day and 4-10 [micro]g/ml appear to be effective when TPM is initiated as monotherapy and titrated according to clinical response. (Supported by Johnson [amp] Johnson Pharmaceutical Research [amp] Development, L.L.C.)