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Randomized, concentration-controlled trial of topiramate in refractory focal epilepsy

From the Department of Clinical Pharmacology (Drs. Christensen, Andreasen, and Poulsen), Aarhus University, and Departments of Neurology (Drs. Christensen and Dam) and Clinical Biochemistry (Dr. Pulsen), Aarhus University Hospital, Denmark.

Address correspondence and reprint requests to Dr. J. Christensen, Department of Clinical Pharmacology, Bartholin Building, Aarhus University, 8000 Aarhus C, Denmark; e-mail: Jakob{at}farm.au.dk

Objective: To establish the concentration response of topiramate in patients with refractory focal epilepsy.

Methods: Sixty-five patients with more than eight seizures during an 8-week baseline were randomized to three prespecified plasma levels (low, 6 µmol/L [2 mg/L]; medium, 31 µmol/L [10.5 mg/L]; and high, 56 µmol/L [19 mg/L]). Topiramate treatment was titrated to one of the prespecified plasma levels during an 8-week titration period, followed by a 12-week observation period.

Results: The overall median (25th to 75th percentile) reduction in seizures during the observation compared with baseline was 50% (9.5 to 90%). In the individual groups, the median reduction was as follows: low, 39% (13 to 70%); medium, 85% (41 to 96%); and high, 39% (2.0 to 81%). The primary outcome of the trial was the comparison of seizure reduction (Mann–Whitney U test) between the low and the medium group (p = 0.03). Comparisons between the other groups were as follows: medium vs high (p = 0.05) and low vs high (p = 0.81). Psychiatric adverse events and adverse events related to the CNS were the most frequently encountered. Most adverse events showed concentration response, particularly between low and medium levels.

Conclusions: Patients assigned to the medium plasma level (31 µmol/L [10.5 mg/L]) had the best seizure outcome. Patients in the medium and high groups experienced more adverse events than patients in the low group. Optimal treatment response is thus most likely found at plasma concentrations higher than 6 µmol/L (2 mg/L), but no further increase in efficacy seems to occur at concentrations above 31 µmol/L (10.5 mg/L).

Received October 7, 2002. Accepted in final form July 22, 2003.

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