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

被引:115
作者
PETERS, DH
SORKIN, EM
机构
[1] Adis International Limited, Auckland, Private Bag 65901, 41 Centorian Drive, Mairangi Bay
关键词
D O I
10.2165/00003495-199345050-00010
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Zonisamide is a 1.2 benzisoxazole derivative and the first agent of this chemical class to be developed as an antiepileptic dry. It has shown activity in various animal models of epilepsy, and although a detailed mode of action awaits clarification it appears to block the propagation/spread of seizure discharges and to suppress the epileptogenic focus. Clinical experience with zonisamide in Japan has documented its efficacy in the treatment of partial seizures (partial-onset generalised tonic-clonic, simple partial and/or complex partial seizures), and to a more variable extent, generalised tonic-clonic, generalised tonic (mainly seen in symptomatic generalised epilepsies including Lennox-Gastaut Syndrome) and compound/combination seizures (including those refractory to treatment with other antiepileptic drugs). Other generalised seizure types have also responded to therapy with zonisamide, although only small patient numbers were studied. Zonisamide has demonstrated efficacy equivalent to that of carbamazepine in patients with (mainly) partial seizures, and to that of valproic acid in a small study of children (n = 32) with generalised seizures. Animal studies suggest that 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 zonisamide concentrations of >30 mg/L. suggesting the usefulness of therapeutic 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 reported for this drug in patients in the US and may further complicate its use in this patient population. Additional pharmacokinetic studies will help to establish the change in pharmacokinetic profile that occurs with dosage titration in patients outside Japan. Among 700 patients treated 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 regression of this condition suggest that it is not a serious problem for this patient population. Until this difference is clarified, it is likely that zonisamide will find its greatest use in the treatment of patients in Japan. Like many other established antiepileptic drugs, available data suggest the propensity for zonisamide to alter the pharmacokinetic profile of other anticonvulsant agents, although severe interactions appear to be unlikely. The ultimate positioning of zonisamide in the therapy of epilepsy awaits clearer definition of its pharmacokinetic, efficacy (particularly in comparison with other antiepileptics) and tolerability profiles. At present therefore, available data do not support the use of this drug in individuals outside of Japan, except in formal clinical studies involving careful monitoring. However, for patients in Japan with epilepsies refractory to established therapy, zonisamide would appear a valid alternative, particularly in the treatment of partial seizures.
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页码:760 / 787
页数:28
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