Abstracts

Zonisamide (ZNS) is a sulfonamide antiepileptic drug, approved for both monotherapy and add-on therapy in Japan. The drug is also approved in the United States, but only for add-on therapy. ZNS has been reported to have a weak effect of inhibiting carbonic anhydrase, much less compared to acetazolamide. While serum ZNS levels have been available for monitoring in Japan (reference range 10-30 mcg/ml in Keio University Hospital), no previous studies have documented the extent of metabolic acidosis in epilepsy patients, from the inhibition of carbonic anhydrase, especially in correlation with serum levels.
Medical records were retrospectively reviewed on four patients (2 male, 2 female, 2-11 years old), who received ZNS for add-on therapy, monitored with serum ZNS levels and bicarbonate levels (HCO3^-). All patients had partial epilepsy, and received care for epilepsy at Keio University Hospital, Tokyo, Japan. No patient had any known inborn errors of metabolism. All patients received valproate prior to and during the treatment with ZNS. Two of the four also received clobazam. All patients had multiple simultaneous measurements of serum ZNS levels and HCO3^-. Serum ZNS levels were correlated with changes in HCO3^-.
The range of ZNS dosage was 0-10 mg/kg/day, and ZNS level was 0-34.5 mcg/ml. Increased ZNS levels correlated with greater decrease in HCO3^-, in three out of four patients. Two of these three patients had sedation from high ZNS levels, and the sedation improved with reduction in the ZNS dosage. The single patient, who did not have any decrease in HCO3^- from ZNS, had renal stones. No stones were seen in the other patients. No other major side effects were seen during the study period, such as liver dysfunction, renal failure, bone marrow suppression, allergic reaction, or interstitial pneumonitis. Reduction in seizure frequency was seen in the three patients who had decreased HCO3^- with higher ZNS levels, but not in the single patient, who did not have any decrease in HCO3^-.
Although the inhibition of carbonic anhydrase has been reported as weak with ZNS, we found a trend towards a decrease in HCO3^- with ZNS in three of the four patients studied. Higher ZNS levels correlated with a greater decrease in HCO3^-, which suggest a dose-related effect. As decreased HCO3^- may worsen acidosis in patients at risk, measuring HCO3^-, and ZNS levels, may be recommended in ZNS therapy. Measuring HCO3^- and ZNS levels may also help guide monitoring other side effects such as sedation.