ZONISAMIDE - A REVIEW OF ITS PHARMACODYNAMIC AND PHARMACOKINETIC PROPERTIES, AND THERAPEUTIC POTENTIAL IN EPILEPSY

Zonisamide is a 1.2 benzisoxazole derivative and the first agent of th is chemical class to be developed as an antiepileptic dry. It has show n activity in various animal models of epilepsy, and although a detail ed mode of action awaits clarification it appears to block the propaga tion/spread of seizure discharges and to suppress the epileptogenic fo cus. Clinical experience with zonisamide in Japan has documented its e fficacy in the treatment of partial seizures (partial-onset generalise d tonic-clonic, simple partial and/or complex partial seizures), and t o a more variable extent, generalised tonic-clonic, generalised tonic (mainly seen in symptomatic generalised epilepsies including Lennox-Ga staut Syndrome) and compound/combination seizures (including those ref ractory to treatment with other antiepileptic drugs). Other generalise d seizure types have also responded to therapy with zonisamide, althou gh only small patient numbers were studied. Zonisamide has demonstrate d efficacy equivalent to that of carbamazepine in patients with (mainl y) partial seizures, and to that of valproic acid in a small study of children (n = 32) with generalised seizures. Animal studies suggest th at zonisamide possesses a more favourable therapeutic index than most other antiepileptic drugs. However, clinical trials conducted to date, have not confirmed any overt tolerability advantage. Indeed, whereas the recommended therapeutic plasma zonisamide concentration is 20 mg/L , clinical investigations have associated adverse events with plasma z onisamide concentrations of >30 mg/L. suggesting the usefulness of the rapeutic drug monitoring. Moreover, although plasma concentrations of zonisamide are empirically regarded to be proportional to therapeutic doses in patients in Japan, nonlinear pharmacokinetics have been repor ted for this drug in patients in the US and may further complicate its use in this patient population. Additional pharmacokinetic studies wi ll help to establish the change in pharmacokinetic profile that occurs with dosage titration in patients outside Japan. Among 700 patients t reated with zonisamide in Europe/US, a high incidence of renal calculi (1.9%) has been noted however, the causal relationship to zonisamide is disputed. Indeed, although urinary lithiasis has also been recorded for patients in Japan, the aetiology, incidence and spontaneous regre ssion of this condition suggest that it is not a serious problem for t his patient population. Until this difference is clarified, it is like ly that zonisamide will find its greatest use in the treatment of pati ents in Japan. Like many other established antiepileptic drugs, availa ble data suggest the propensity for zonisamide to alter the pharmacoki netic profile of other anticonvulsant agents, although severe interact ions appear to be unlikely. The ultimate positioning of zonisamide in the therapy of epilepsy awaits clearer definition of its pharmacokinet ic, efficacy (particularly in comparison with other antiepileptics) an d tolerability profiles. At present therefore, available data do not s upport the use of this drug in individuals outside of Japan, except in formal clinical studies involving careful monitoring. However, for pa tients in Japan with epilepsies refractory to established therapy, zon isamide would appear a valid alternative, particularly in the treatmen t of partial seizures.