Zonisamide

Zonisamide is a benzisoxazole derivative. It is an anti-epileptic medicine with weak carbonic anhydrase activity in-vitro. It is chemically unrelated to other anti-epileptic agents.

The mechanism of action of zonisamide is not fully elucidated, but it appears to act on voltage-sensitive sodium and calcium channels, thereby disrupting synchronised neuronal firing, reducing the spread of seizure discharges and disrupting subsequent epileptic activity. Zonisamide also has a modulatory effect on GABA-mediated neuronal inhibition.

Pharmacodynamic effects

The anticonvulsant activity of zonisamide has been evaluated in a variety of models, in several species with induced or innate seizures, and zonisamide appears to act as a broad-spectrum anti-epileptic in these models. Zonisamide prevents maximal electroshock seizures and restricts seizure spread, including the propagation of seizures from cortex to sub-cortical structures and suppresses epileptogenic focus activity. Unlike phenytoin and carbamazepine however, zonisamide acts preferentially on seizures originating in the cortex.

Absorption

Zonisamide is almost completely absorbed after oral administration, generally reaching peak serum or plasma concentrations within 2 to 5 hours of dosing. The first-pass metabolism is believed to be negligible. Absolute bioavailability is estimated to be approximately 100%. Oral bioavailability is not affected by food, although peak plasma and serum concentrations may be delayed.

Zonisamide AUC and C_max values increased almost linearly after single dose over the dose range of 100-800 mg and after multiple doses over the dose range of 100-400 mg once daily. The increase at steady state was slightly more than expected on the basis of dose, probably due to the saturable binding of zonisamide to erythrocytes. Steady state was achieved within 13 days. Slightly greater than expected accumulation occurs relative to single dosing.

Distribution

Zonisamide is 40-50% bound to human plasma proteins, with in vitro studies showing that this is unaffected by the presence of various antiepileptic medicinal products (i.e., phenytoin, phenobarbitone, carbamazepine, and sodium valproate). The apparent volume of distribution is about 1.1–1.7 l/kg in adults indicating that zonisamide is extensively distributed to tissues. Erythrocyte/plasma ratios are about 15 at low concentrations and about 3 at higher concentrations.

Biotransformation

Zonisamide is metabolised primarily through reductive cleavage of the benzisoxazole ring of the parent drug by CYP3A4 to form 2-sulphamoylacetylphenol (SMAP) and also by N-acetylation. Parent drug and SMAP can additionally be glucuronidated. The metabolites, which could not be detected in plasma, are devoid of anticonvulsant activity. There is no evidence that zonisamide induces its own metabolism.

Elimination

Apparent clearance of zonisamide at steady-state after oral administration is about 0.70 l/h and the terminal elimination half-life is about 60 hours in the absence of CYP3A4 inducers. The elimination half-life was independent of dose and not affected by repeat administration. Fluctuation in serum or plasma concentrations over a dosing interval is low (<30%). The main route of excretion of zonisamide metabolites and unchanged drug is via the urine. Renal clearance of unchanged zonisamide is relatively low (approximately 3.5 ml/min); about 15-30% of the dose is eliminated unchanged.

Linearity/non-linearity

Zonisamide exposure increases with time until steady state is achieved by approximately 8 weeks. When comparing the same dose level, subjects of higher total body weight appear to have lower steady-state serum concentrations, but this effect appears to be relatively modest. Age (≥12 years) and gender, after adjustment for body weight effects, have no apparent effect on zonisamide exposure in epileptic patients during steady-state dosing. There is no need for dose adjustment with any of the AEDs including CYP3A4 inducers.

Pharmacokinetic/pharmacodynamic relationship

Zonisamide lowers the 28-day average seizure frequency and the decrease is proportional (log-linear) to zonisamide average concentration.

Special patient groups

In subjects with renal impairment

Renal clearance of single doses of zonisamide was positively correlated with creatinine clearance. The plasma AUC of zonisamide was increased by 35% in subjects with creatinine clearance <20 ml/min.

Patients with an impaired liver function

The pharmacokinetics of zonisamide in patients with impaired liver function have not been adequately studied.

Elderly

No clinically significant differences were observed in the pharmacokinetics between young (aged 21-40 years) and elderly (65-75 years).

Children and adolescents (5-18 years)

Limited data indicate that pharmacokinetics in children and adolescents dosed to steady state at 1, 7 or 12 mg/kg daily, in divided doses, are similar to those observed in adults, after adjustment for bodyweight.

Findings not observed in clinical studies, but seen in the dog at exposure levels similar to clinical use, were liver changes (enlargement, dark-brown discolouration, mild hepatocyte enlargement with concentric lamellar bodies in the cytoplasm and cytoplasmic vacuolation) associated with increased metabolism.

Zonisamide was not genotoxic and has no carcinogenic potential.

Zonisamide caused developmental abnormalities in mice, rats, and dogs, and was embryolethal in monkeys, when administered during the period of organogenesis at zonisamide dosage and maternal plasma levels similar to or lower than therapeutic levels in humans.

In a repeated-dose oral toxicity study in juvenile rats, at exposure levels similar to those observed in paediatric patients at the maximum recommended dose, decreases in body weight and changes in renal histopathology and clinical pathology parameters and behavioural changes were observed. Changes in renal histopathology and clinical pathology parameters were considered to be related to carbonic anhydrase inhibition by zonisamide. The effects at this dose level were reversible during the recovery period. At a higher dose level (2-3-fold systemic exposure compared to therapeutic exposure) renal histopathological effects were more severe and only partially reversible. Most adverse effects observed in the juvenile rats were similar to those seen in the repeated-dose toxicity studies of zonisamide in adult rats, but renal tubular hyaline droplets and transitional hyperplasia were observed in the juvenile study only. At this higher dose level, juvenile rats showed a decrease in growth, learning, and developmental parameters. These effects were considered likely related to the decreased body weight and exaggerated pharmacologic effects of zonisamide at the maximum tolerated dose.

In rats, decreased numbers of corpora lutea and implantation sites were observed at exposure levels equivalent to the maximum therapeutic dose in humans; irregular oestrus cycles and a decreased number of live foetuses were observed at exposure levels three times higher.