Abstract
Synopsis
Zonisamide is a 1,2 benzisoxazole derivative and the first agent of this chemical class to be developed as an antiepileptic drug. 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.
Pharmacodynamic Properties
The antiepileptic effects of zonisamide have been demonstrated in animal models of epilepsy through study of electroencephalographic (EEG) activity and the symptoms of induced seizures. Indeed, assessment of EEG recordings of focal and secondarily generalised seizures evoked by a variety of stimuli in the cortex or subcortex of cats and/or rats administered zonisamide revealed attenuation or abolition of seizure activity and its spread. In most animal models, afterdischarges were shortened in duration and their thresholds elevated.
Zonisamide has also shown activity in animal studies which have concentrated on the symptoms of induced seizures. Thus, zonisamide consistently prevented the tonic extensor component of maximal electroshock seizures, attenuated or controlled fully kindled seizures and abolished the maximal seizures induced by pentylenetetrazole. In contrast, zonisamide neither had effect on the minimal seizures induced by pentylenetetrazole, nor on convulsive death induced by strychnine.
In the above studies zonisamide demonstrated an antiepileptic profile most similar to that of phenytoin or carbamazepine.
The pharmacodynamic profile of zonisamide in animal models of epilepsy suggests that the anticonvulsant action of this drug involves blockade of the spread or propagation of seizure discharges and suppression of the epileptogenic focus. While full details of its mode of action are unknown, inhibition of neuronal voltage-dependent sodium and/or T-type calcium channels has been suggested.
There appears to be a wide margin between doses of zonisamide that are effective in animal models of epilepsy and those that produce adverse effects in the central nervous system (CNS) of animals, both in terms of signs of CNS effects and changes in EEG activity. Moreover, compared with other antiepileptic drugs, zonisamide showed less of a propensity to induce CNS effects. In accordance with such findings, acute lethal toxicity of zonisamide occurred at doses greater than most standard antiepileptic drugs. With regard to motor function, zonisamide depressed the feline flexor reflex, but was without effect on neuromuscular transmission.
Pharmacokinetic or pharmacodynamic tolerance to the anticonvulsive effects of zonisamide in animal models does not appear to occur with repeated administration, or in the presence of drugs that inhibit or induce microsomal enzymes.
Pharmacokinetic Properties
The pharmacokinetic profile of zonisamide has been assessed in volunteers in Japan or the US. Peak plasma concentrations (Cmax) following oral zonisamide ranged from 2.3 mg/L after a 200mg dose to 12.5 mg/L after an 800mg dose and were achieved within 2.4 to 3.6 hours in healthy volunteers in the US; area under the plasma concentration-time curve (AUC) increased dose-proportionally. The presence of food does not affect the rate or extent of zonisamide absorption. Zonisamide was highly concentrated in erythrocytes, with concentrations exceeding those in plasma by 4- to 9-fold in healthy volunteers in Japan. The blood pharmacokinetic profile of zonisamide (400mg) in patients with refractory epilepsy receiving concurrent anticonvulsive medication in the US, showed similarities to that in healthy volunteers with evidence of erythrocyte accumulation.
In Japan, repeat administration of zonisamide at dosages of up to 13 mg/kg/day to children, and 18.6 mg/kg to adults, resulted in plasma concentrations linearly proportional to the dose given; however, when administered in a multiple dose regimen to patients in the US, zonisamide exhibited nonlinear pharmacokinetics. Indeed, at steady-state, the clearance of zonisamide 200 to 600mg twice daily was only 42% of that following administration of a single 400mg dose. In clinical studies, plasma zonisamide concentrations of 7 to 40 mg/L have been associated with antiepileptic effects in patients receiving concomitant anticonvulsant therapies, although most patients showed signs of toxicity with doses resulting in plasma levels of >30 mg/L. Based on these results, a target steady-state plasma zonisamide concentration of 20 mg/L has been suggested.
Although no human data are available regarding the volume of distribution (Vd) of zonisamide at steady-state, Vd values were reduced from 1.8 L/kg after a single 200mg dose to 1.2 L/kg after an 800mg dose in studies which recruited volunteers in the US, reflecting nonlinear binding to erythrocytes. For the purpose of therapeutic monitoring, it is recommended that zonisamide concentrations are determined in plasma or serum. Plasma protein binding of zonisamide is nonsaturable and is not extensive (<50%) over therapeutic plasma concentrations.
In studies which recruited volunteers in the US, the plasma clearance rate was 1.34 L/h at doses of 200 or 400mg, but clearance was reduced by 22% after a dose of 800mg. Plasma elimination half-life ranged from 50 to 68 hours after single oral doses of 200 to 800mg.
Urinalysis has revealed that zonisamide undergoes biotransformation by acetylation and also cleavage of the isoxazole ring followed by conjugation with glucuronic acid. In Japan, the parent drug and glucuronide conjugate have accounted for almost 50% of a 200mg dose recovered in the urine of volunteers. In animal studies, an appreciable portion of zonisamide has been recovered from faeces; however, whether this route is of importance in man awaits clarification. Available data suggest that disposition of single dose zonisamide is unaffected by the presence of renal dysfunction in volunteers in the US.
Clinical Efficacy
Most of the published clinical trials of zonisamide have been conducted in Japan. Supportive clinical trials conducted later in the US and Europe have generally not been published in full. This review has therefore focused on the efficacy of zonisamide in patients recruited to clinical studies in Japan.
The efficacy of zonisamide has been demonstrated in a total of 1008 adults or children with various epilepsies (mainly refractory to treatment), recruited to a series of predominantly non-comparative clinical trials in Japan. In this population, oral administration of zonisamide at mean dosages of 5.9 to 8.8 mg/kg/day resulted in mean serum concentrations of about 20 mg/L. Efficacy, defined as a reduction in seizure frequency of ⩾50% compared with baseline, varied with seizure type, seizure frequency and number of concomitant antiepileptic medications. In this analysis zonisamide was particularly beneficial in the treatment of partial seizures (partial-onset generalised tonic-clonic, simple and/or complex seizures) with efficacy rates (⩾50% reduction in seizure frequency compared with baseline) of 50 to 60%. Zonisamide was also effective, although to a more variable degree, in the treatment of generalised or compound/combination seizures. In large patient groups (n ⩾ 46) efficacy rates were 59% for those with generalised tonic-clonic seizures, 26% for those with generalised tonic seizures and 41% for those with compound/combination seizures. Other generalised seizures also responded to therapy with zonisamide although the patient population was relatively small (n ⩽ 10); notably zonisamide was effective in the treatment of West Syndrome and Lennox-Gastaut Syndrome. In the long term (⩾1 year), efficacy rates for zonisamide in 155 epileptic patients exceeded 60%, except in patients with generalised tonic (40%) or compound/combination seizures (50%). In comparative clinical trials conducted in Japan, the efficacy of zonisamide was judged equivalent to that of carbamazepine in patients with predominantly partial epilepsies, and valproic acid in limited numbers of paediatric patients (n = 32) with convulsive or nonconvulsive generalised seizures. In broad agreement with these findings, superior efficacy has been attributed to zonisamide when compared with placebo in a European study of patients with complex partial seizures. Furthermore, the efficacy of zonisamide in the treatment of partial seizures has also been documented in a noncomparative study conducted in the US.
Tolerability
In a series of principally noncomparative clinical trials which recruited 1008 adults or children with epilepsy in Japan, zonisamide was associated with an adverse event rate of 51% and a withdrawal rate of 18% in the presence of 0 to ⩾3 concomitant antiepileptic drugs. Principal adverse events were drowsiness (24% of patients), ataxia (13%), loss of appetite (11%), gastrointestinal problems (7%), loss of or decreased spontaneity (6%), and slowing of mental activity (5%). Increased serum transaminase enzyme activity or leucopenia necessitated the withdrawal of 2% of patients. Monotherapy/polytherapy (considered together) was associated with marginally greater incidences of adverse events (particularly drowsiness), than monotherapy alone. In a comparative clinical trial conducted in patients in Japan, the tolerability profile for zonisamide was comparable with that for carbamazepine, although ataxia was noted more frequently with carbamazepine and anorexia occurred more frequently with zonisamide.
Most of the adverse events recorded in a placebo-controlled investigation conducted in Europe and a noncomparative investigation conducted in the US related to the nervous or gastrointestinal systems. However, renal calculi were noted for 4 of 113 patients (3.5%) in the latter study (2 with familial association), and for 13 of 700 patients (1.9%). recruited to nonconiparative studies conducted in the US/Europe. Nevertheless, a causal relationship to zonisamide is disputed. Indeed, differences in the incidence of urinary lithiasis appear to exist, since renal calculi were noted infrequently (0.2%) among 1008 patients in Japan and affected patients showed spontaneous regression of this condition with a familial predisposition.
Zonisamide adversely affected specific cognitive function such as acquisition and consolidation in patients in the US at plasma concentrations of >30 mg/L; however, other findings suggested tolerance to the adverse cognitive effects observed.
Dosage and Administration
Zonisamide is available in Japan in tablet (100mg) or powder form (200 mg/g) and may be orally administered once daily or in 2 or 3 divided doses. In Japan, the recommended initial adult dosage is 100 to 200 mg/day, increasing if necessary to 200 to 400 mg/day (maximum 600 mg/day). Children in Japan may be treated initially with dosages of 2 to 4 mg/kg/day, increasing to 4 to 8 mg/kg/day (maximum 12 mg/kg/day). Dosage adjustments may be made at 1- to 2-week intervals and optimum therapy may be achieved through monitoring of plasma/serum concentrations. No dosage recommendations are available for patients in countries other than Japan.
Zonisamide should not be abruptly discontinued and should be administered with caution to patients with hepatic dysfunction and pregnant women.
Blood zonisamide concentrations may alter with concomitant administration of other antiepileptic drugs. Indeed, blood AUC values for zonisamide were greater in the presence of carbamazepine than in the presence of phenytoin, and phenobarbital has been associated with increased zonisamide plasma clearance. Studies which have evaluated the effects of zonisamide on the disposition of other concomitant antiepileptic drugs have shown inconsistent findings. Together, these results suggest that severe interactions are unlikely to occur between zonisamide and other antiepileptic drugs although dosage adjustment may be necessary with polytherapy.
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Various sections of the manuscript reviewed by: S. Berent, Department of Neurology and Psychiatry, College of Pharmacy, University of Michigan Medical Center, Ann Arbor, Michigan, USA; D.W. Chadwick, The University of Liverpool, Mersey Regional Department of Medical and Surgical Neurology, Walton Hospital, Liverpool, England; E.M. Cornford, Neuropharmacology Laboratories, West Los Angeles Veterans Administration Center, Los Angeles, California, USA; M. Dam, University Clinic of Neurology, Hvidovre Hospital, Hvidovre, Copenhagen, Denmark; M.J. Eadie, Department of Medicine, Clinical Science Building, Royal Brisbane Hospital, Brisbane, Queensland, Australia; G.H. Fromm, Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA; M. Kimura, Department of Pharmaceutical Services, Hiroshima University Hospital, Hiroshima, Japan; H. Meinardi, Institut voor epilepsiebestrijding, Heemstede, The Netherlands; H. Oguni, Department of Paediatrics, Tokyo Women’s Medical College, Tokyo, Japan; L.M. Ojemann, Epilepsy Center, Harborview Medical Center, Seattle, Washington, USA; F. Pisani, Clinica Neurologica 1, Policlinico Universitario, Contesse-Messina, Italy; J.C. Sackellares, Department of Neurology, University of Michigan Medical Center, Ann Arbor, Michigan, USA; M. Seino, National Epilepsy Center, Shizuoka Higashi Hospital, Shizuoka, Japan; Y. Wada, Department of Neuropsychiatry, Kanazawa University School of Medicine, Kanazawa, Japan.
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Peters, D.H., Sorkin, E.M. Zonisamide. Drugs 45, 760–787 (1993). https://doi.org/10.2165/00003495-199345050-00010
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DOI: https://doi.org/10.2165/00003495-199345050-00010