An evaluation of zonisamide, including its long-term efficacy, for the treatment of focal epilepsy

ABSTRACT

Introduction: About 70 million people worldwide are estimated to suffer from epilepsy. Despite a large variety of old and new antiepileptic drugs on the market, about 30% of people with epilepsy do not become seizure-free with medical treatment. This is a major individual and public health burden. Most of these difficult-to-treat patients are having focal seizures. Zonisamide is effective against focal seizures in adults and children and, thus, a therapeutic option for such patients. Its safety profile needs special attention.

Areas covered: Herein, the authors discuss the pharmacology, clinical efficacy and the adverse effects of zonisamide. The article is derived from clinical trial data, long-term studies, meta-analyses, review articles, text books, webpages, and official license information.

Expert opinion: Zonisamide has proven to be efficacious in focal epilepsy in children and adults, although it is not more effective than carbamazepine or other antiepileptic drugs. It is also effective in generalized epilepsy and in several other conditions of the CNS. Its safety profile may prevent it from becoming a first-line drug for focal epilepsy or any other indication.

KEYWORDS:

• Cognitive adverse effect
• drug safety
• epilepsy
• gastrointestinal adverse effects
• long-term efficacy
• mechanism of action
• monotherapy
• pharmacokinetics
• psychiatric adverse effects
• retention rate

1. Introduction

Epilepsy is one of the most common neurological diseases, with a prevalence of 0.5 % in Western countries and up to 1.3 % in developing countries. It has been estimated that 70 million people worldwide are affected by the disease [1,2]. The incidence vs. age curve is U-shaped, which means that most new cases appear among newborns and children, and among people aged 65 years and older [1,2]. This is because epilepsy can have different etiologies, and congenital brain damage and stroke are among the most common ones.

Epilepsy comprises numerous different seizure types and syndromes as classified by the International League Against Epilepsy (ILAE)[3]. A principal distinction is made between focal onset seizures (starting in a circumscribed part of the brain) and generalized seizures (starting in both hemispheres simultaneously). Focal and generalized seizures are further subdivided. Treatment guidelines recommend that treatment with one drug (monotherapy) should be preferred. In fact, about 90% of those patients that become seizure-free with pharmacological treatment, do so on monotherapy[4].

Antiepileptic drugs (AEDs) act through a multitude of pharmacological mechanisms, e.g. by blocking of voltage-dependent sodium and calcium ion channels as well as by direct actions on gamma-amino-butyric acid (GABA) and glutamate receptors, thereby suppressing repetitive neuronal firing and restoring the balance between inhibitory and excitatory activity. AEDs reduce the number of epileptic seizures, but they do not cure the disease. Hence, treatment is often lifelong. Unfortunately, only 60–70% of all people with epilepsy become seizure-free. The remainder are mostly patients with focal seizures [5–8]. These patients are commonly categorized as having difficult-to-treat or drug-resistant epilepsy and use often a combination therapy of two or more AEDs [6]. They may also be referred to non-pharmacological treatment such as the ketogenic diet, vagus nerve stimulation or epilepsy surgery. The socioeconomical and medical consequences of uncontrolled epilepsy are a major burden for affected individuals and their relatives, and a considerable cost factor from a public health point of view [9–11].

During the past 30 years, many new AEDs have been marketed. This review summarizes the key characteristics of Zonisamide (ZNS) as a therapeutic option in focal epilepsy.

2. Overview of the market

Despite almost 30 first-, second-, and third generation AEDs on the market and despite adequate treatment, 30–40% of people with epilepsy do not become seizure free even after trying two or more AEDs either in monotherapy or in combination [6]. Moreover, even the highest reported long-term retention rates of AEDs seldom exceed 70%; most AEDs have much lower retention rates [12]. The main reasons for stopping treatment are lack of therapeutic effect, and adverse drug reactions. Thus, there is a need for more effective medications, preferably with improved adverse effect profiles.

At least 16 new compounds are currently under clinical development, most of them for the treatment of focal seizures. These drugs include cenobamate (blocks the persistent Na⁺-current in inactive sodium channels), ganaxolone and Sage-547 (analogues of allopregnanolone, an endogenous neurosteroid), padsevonil (3rd generation SV2A-modulator) and several repurposed compounds or derivatives of old compounds like everolimus, fenfluramine, valnoctamide and others. For a complete overview, see Golyala and Kwan (2017) or Bialer et al. (2018) [13,14]. In addition, some already marketed AEDs are being studied in order to extend their license, including ZNS and cannabidiol (see www.clinicaltrials.gov).

3. Chemistry

The IUPAC name for ZNS is 1-(1,2-Benzoxazol-3-yl)methanesulfonamide; the CAS number is 68,291–97-4. Its empirical formula is C₈H₈N₂O₃S and its molecular weight is 212.23 (see Box 1). ZNS is a white, odorless and tasteless powder that is moderately soluble in water (0.8 mg/mL) and has a pKa of 9.7 [15]. Its ATC-code is N03AX15.

4. Pharmacodynamics

ZNS was discovered by serendipity in 1974 during routine testing of 1,2-benzisoxazole derivatives for psychiatric disorders. Animal experiments revealed its antiepileptic properties [16]. ZNS blocks voltage-dependent sodium and T-type calcium ion channels. It enhances GABA-mediated inhibition by increasing presynaptic GABA release and inhibiting its re-uptake from the synaptic cleft. It also reduces glutamate-induced excitation and is a weak inhibitor of carboanhydrase [17]. It is not exactly known how much each of these mechanisms contribute to the clinical efficacy of ZNS, but it is likely that these multiple mechanisms of action contribute to its broad-spectrum clinical efficacy. ZNS is effective in both generalized and focal onset seizures, which makes it a treatment option for most epileptic seizure types.

In addition to its antiepileptic properties, ZNS has demonstrated neuroprotective properties in experimental models of different conditions of the brain [18,19]. It also acts as an inhibitor of monoamine oxidase B (MAO-B), delays dopamine transporter reduction in Parkinson’s disease, and alleviates Parkinsonian motor symptoms [20–22]. ZNS has also shown some efficacy as a treatment for migraine and obesity [23,24].

5. Pharmacokinetics and metabolism

After oral dosing, ZNS is completely absorbed. The rate and extent of absorption are dose-proportional in the range of 200–600 mg while drug exposure (c_max, AUC) becomes greater with higher doses. Maximum serum concentrations appear after 2.4–3.6 hours. Concomitant food intake increases t_max but does not reduce the extent of absorption. The usual maintenance dose for adults with epilepsy is 200–500 mg/day [25,26].

97% of an orally administered dose is renally excreted, 30–35% as zonisamide, 15–20% as N-acetyl zonisamide, and 50% as the glucuronide of the main metabolite, 2–sulfamoylacetyl phenol (SMAP). The conversion of ZNS to SMAP is mediated by cytochrome P450 (CYP) 3A4. All metabolites of ZNS are pharmacologically inactive [26,27].

Although the metabolism of ZNS involves cytochrome P450 (CYP), the number of documented pharmacokinetic drug-drug interactions with ZNS is low. Enzyme inducers like phenytoin, phenobarbital or carbamazepine accelerate the metabolism of ZNS. Initial reports that ZNS may increase the serum concentrations of phenytoin could not be reproduced by later studies. ZNS does not affect the metabolism of oral contraceptives or other drugs [15,27].

ZNS is evenly distributed in the entire body and has an apparent volume of distribution at steady-state of 0.91 L/kg. The degree of protein binding is 40–60%, and a considerable proportion of the drug is also bound to erythrocytes. However, at therapeutically relevant serum concentrations, the latter has minimal impact on ZNS pharmacokinetics [15,27].

The plasma half-life of ZNS is very long, ranging from 50 to 88 hours[15]. Thus, time to steady-state is 10–14 days.

No formal pharmacokinetic studies in children have been published. Naturalistic studies indicate a higher clearance than in adults, decreasing with older age [28,29]. In children ≥6 years, the recommended dose is 6–8 mg/kg/d although a lower dose of 3–4 mg/kg/d may provide equally good efficacy with improved tolerability [25,30].

Several different methods for measuring ZNS concentrations in serum or plasma have been published. The suggested reference range is 10–38 mg/L (45–180 µmol/L) [31].

6. Clinical efficacy

The clinical efficacy of ZNS as a treatment for focal epilepsy is well-documented. At the time of writing this review, www.clinicaltrials.gov lists 11 completed clinical studies in children (0–17 years) and 45 completed clinical studies in adults (18–65 years), of which five and 10, respectively, in focal epilepsy. Four pivotal trials with a total of 845 patients demonstrated the clinical efficacy of ZNS as add-on treatment for focal epilepsy in adults [32–35]. In these trials, ZNS produced responder rates of 21% to 67% and reduced the median frequency of all focal seizures by 26% to 73%. The proportion of patients achieving complete freedom from seizures was reported in two of these studies and stated as 5% and 6%, respectively [32,33]. In addition, one pivotal trial proved its efficacy in monotherapy [36], and one in the pediatric population [37]. The monotherapy trial was a head-to-head comparison with carbamazepine where 177 out of 223 patients (79.4%) in the ZNS group (200–500 mg/d) became seizure-free for at least 26 weeks. This result was non-inferior to carbamazepine. The ILAE concluded in 2013 that ZNS has level A evidence for efficacy/effectiveness in focal epilepsy in adults, both as add-on treatment and as initial monotherapy [38]. In the pediatric trial (207 patients aged 6–17 years), ZNS was titrated to 8 mg/kg/d over 8 weeks. During the following 12- week observation period, responder rates of 50% (ZNS) and 31% (placebo) were observed.

A recent meta-analysis by the Cochrane collaboration calculated the overall risk ratio (RR) vs. placebo for at least 50% reduction of focal seizures with ZNS add-on treatment at a dose of 100–500 mg/day as 1.86 (95% CI 1.63 to 2.22). The number needed to treat (NNT) was calculated as six, i.e. six patients needed to be treated for every additional patient with at least 50% seizure reduction [39]. Eight studies with a total of 1 636 patients were included in that meta-analysis.

The long-term efficacy of ZNS in focal epilepsy in both children and adults has been examined in open label extensions of pivotal trials and other prospective studies with six to 36 months follow-up. These studies showed no loss of effect during the observation period, not even in patients with difficult-to-treat (‘therapy-refractory’) focal epilepsy [40–43]. Median seizure reduction rates varied between 46 and 66% (the common definition for treatment response is ≥50% seizure reduction).

A network meta-analysis of new AEDs that had been compared to carbamazepine in controlled clinical trials found no differences regarding 6- and 12-month freedom from focal seizures between ZNS, levetiracetam, lacosamide and eslicarbazepine vs. carbamazepine[44].

In contrast to controlled clinical trials undertaken for regulatory purposes, the long-term retention rate in everyday clinical practice is a much more realistic and suitable measure of a drug’s effectiveness, i.e. its combined therapeutic efficacy and tolerability [12]. For ZNS, 1-year retention rates in the range of 45–60% have been reported by various studies [45–47]. This rate is lower than the rates reported for other second generation AEDs such as oxcarbazepine, lamotrigine or levetiracetam. On the other hand, the retention rate of ZNS is remarkably stable once the first year has passed. 2-year- and 3-year retention rates of 60% have been reported for ZNS [12,48]. One study even reported a 6-year retention rate of 55%[49]. This is presumably due to the fact that discontinuation of ZNS usually occurs after few months of treatment: 10 months on average if it was for lack of efficacy (46% of the discontinuations) and 6 months for adverse effects (30%), eight months if both occurred (16%), and one month if other reasons applied (8%) [12].

Several clinical studies indicate that ZNS is also effective against absence seizures, tonic-clonic seizures, myoclonic seizures and in pediatric epilepsy syndromes such as Lennox-Gastaut Syndrome, West Syndrome and Ohtahara Syndrome [45,50,51]. ZNS is at present only available as oral capsules. Accordingly, no data on the clinical use of ZNS in status epilepticus has been published so far [52].

7. Safety and tolerability

Adverse reactions induced by ZNS are mainly gastrointestinal or CNS-related. In controlled clinical trials, adverse reactions occurring with a higher frequency than placebo included anorexia/weight loss, nausea, dizziness, ataxia, nystagmus, confusion, memory difficulties, concentration difficulties, mental slowing, agitation, depression, suicidal ideation, speech abnormalities, verbal expression difficulties, somnolence, and fatigue [26]. Often, adverse effects occur during the initial dose escalation phase and resolve either spontaneously or after drug withdrawal. However, cognitive and mood effects usually persist, even after one year of treatment [53]. The long half-life of ZNS is a disadvantage when the drug needs to be discontinued immediately due to serious adverse reactions.

Adverse effects on cognition and mood are common with ZNS, and cognitive and psychiatric adverse effects are the most frequent reasons for discontinuation of ZNS treatment [54–56]. A retrospective review of 1694 patients using different AEDs found that the frequency of cognitive adverse reactions to ZNS was 15%, which was the next highest rate after topiramate (22%), an AED that is well-known for its negative effects on cognition[54]. Of note, another study concluded that the emergence of psychiatric or cognitive adverse reactions does not necessarily require high serum levels, as the affected patients did only achieve 50% of the maximum ZNS serum level in control patients [56]. In a prospective randomized study, 47% of patients reported dose-dependent cognitive adverse effects after one year and 15% experienced mood changes. The cognitive adverse effects were mainly decreased verbal long-term memory as well as decreased verbal fluency and mental flexibility. These effects were seen at doses of 300 mg/day or higher[53]. Systematic monitoring of cognitive functions has been suggested as a tool to improve treatment outcome [57,58].

ZNS is usually prescribed as add-on treatment. However, adverse cognitive effects from AEDs worsen as the total drug load increases [59], and this applies also to ZNS[54]. One study that examined the frequency of intolerable adverse cognitive effects (IACEs) in patients with a total drug load of at least two AEDs showed that ZNS had the next highest IACE rate (10%) after topiramate (26%) [60]. Both ZNS and topiramate have in common a sulfa moiety which is suspected to increase GABA activity especially in the prefrontal cortex.

In pediatric RCTs, mostly gastrointestinal, psychiatric or cognitive adverse effects were reported, and higher doses were associated with a higher risk of adverse effects [61].

Rarely, ZNS may induce visual hallucinations, probably due to its ability to increase dopaminergic transmission[62]. Accordingly, psychosis as well has been associated with the use of ZNS[55].

It has been reported that 24% (99% CI: 2–46%) of ZNS-treated patients develop weight loss, and losses may reach up to 8 kg [63,64]. In children, weight loss ≥5% has been observed in approximately 35%[65]. ZNS has been studied as an anti-obesity drug but as yet it has not become an established treatment [24,66].

Like other inhibitors of carboanhydrase, ZNS may induce nephrolithiasis. The FDA-approved SPC states that nephrolithiasis was observed in 4% of adults and in 8% of pediatric patients in the clinical development program[26]. In long-term studies, 1.2–1.4% of the patients developed symptomatic kidney stones and 2.6% developed asymptomatic nephrolithiasis. These frequencies translate to ‘common’ according to the standard categories of adverse drug reaction frequency issued by the Council for International Organizations of Medical Sciences (CIOMS). Data are mixed as to whether this adverse drug reaction is dose-dependent or not [67,68].

No firm conclusions can yet be drawn regarding the teratogenic potential of ZNS, but data from the North American Antiepileptic Drug Pregnancy Registry suggest a low risk, with no major congenital malformations occurring in 90 monotherapy exposures [69].

ZNS is a sulfonamide. Hence, moderate and severe allergic reactions do occur. A recent meta-analysis concluded that of all AEDs, ZNS has the highest risk of potentially life-threatening allergic reactions like Steven-Johnson syndrome and toxic epidermal necrolysis [70].

The adverse effect profile of ZNS shows similarities to topiramate which in principle is structurally unrelated but also has a sulfonamide moiety and acts as an inhibitor of carboanhydrase. Like ZNS, topiramate can induce weight loss, kidney stones as well as cognitive and psychiatric adverse reactions [71].

In a recent comparative network meta-analysis of AEDs for focal epilepsy, ZNS obtained one of the lowest positions in a ranking of being the best therapeutic option in terms of tolerability [72].

8. Regulatory affairs

ZNS was launched in Japan in 1989 by Dainippon, subsequently in Korea (1990), in the US (2000) and in the European Union (2005). It is now marketed by Eisai under the trademarks Zonegran® (Asia, Europe, US) and Excegran® (Japan, South Korea, Turkey). In Japan, ZNS is licensed for generalized and focal seizures, both in monotherapy and as add-on treatment in children and adults. In the US, ZNS is only licensed for adjunctive therapy of focal seizures in adults over 16 years [26]. In Europe, ZNS is licensed as monotherapy in newly diagnosed adults and as an add-on therapy in adults and children aged six years and older [25]. In Japan, ZNS is also marketed by Dainippon Sumitomo as Trerief® for the treatment Parkinson’s disease and parkinsonism in dementia with Lewy bodies [73,74]. A number of generic formulations of ZNS are available, e.g. in the EU and the US.

9. Conclusion

ZNS has multiple mechanisms of action and is efficacious in focal seizures in adults. Its efficacy is non-inferior to that of carbamazepine, but not better than that of any competitor. ZNS is licensed for both add-on treatment and as monotherapy (EU, Japan) for focal seizures. In addition, it is licensed for focal epilepsy in children in the EU (add-on treatment) and Japan (monotherapy). Its safety profile is characterized by gastrointestinal, neuropsychiatric and cognitive adverse effects. Kidney stones are common, and both moderate and severe allergic reactions do occur. The long-term retention rate of ZNS is comparably low at 45–60%.

10. Expert opinion

As about 30% of people with epilepsy do not become seizure-free with medical treatment, there is a clear need for antiepileptic drugs that are more efficacious and better tolerated. While ZNS acts on several different molecular targets and is clearly efficacious in different seizure types and epilepsy syndromes, its clinical effectiveness in terms of responder rate, NNT or retention rate is at best average, compared to other AEDs. The long half-life allows for once-daily dosing and provides very small peak-trough fluctuations of the serum concentration, but it can also be unfortunate when treatment needs to be stopped immediately due to acute adverse drug reactions.

Post-marketing surveillance studies suggest that the safety profile of ZNS may be considered a challenge that requires careful patient selection and clinical monitoring. Cognitive slowing and other neurological or psychiatric adverse effects are frequently seen in everyday clinical practice and lead often to discontinuation of the drug. Symptomatic kidney stones are common. Despite these disadvantages, and although there is a considerable lack of head-to-head comparisons of ZNS with other second- and third generation AEDs, ZNS is certainly an option for difficult-to-treat patients that have not responded to or not tolerated treatment with first-line AEDs like carbamazepine, levetiracetam or lamotrigine.

Two large patient groups in epilepsy are children and elderly patients. Both are particularly vulnerable for cognitive adverse reactions. In the EU and Japan, ZNS is licensed for the treatment of focal epilepsy in pediatric patients and it is likely that this indication will be expanded to other markets. The same applies for the monotherapy indication. Due to its adverse effect profile however, ZNS is not a first-line treatment for focal seizures and it is unlikely that it will become one. Consequently, ZNS is being studied in other indications. It may become a treatment of second or third choice for various types of generalized epilepsy. Thanks to its multiple mechanisms of action, ZNS may also have beneficial effects in other conditions of the central nervous system. It is already licensed for Parkinson’s disease and parkinsonism in Lewy body dementia (at present only in Japan), and it may have potential as a treatment for parkinsonian symptoms induced by antipsychotics. Moreover, ZNS is currently being studied as a treatment of alcohol dependency. However, its tolerability issues may prevent it from becoming a first-line drug in any of these or other potential indications.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Box 1. Drug summary box

Table

Drug name	Zonisamide
Phase	Launched
Indication	Focal and generalized epilepsy; Parkinson’s disease
Pharmacology	Sodium- and calcium channel blocker; GABAergic; anti-glutamatergic; carboanhydrase inhibitor; MAO-B inhibitor
Route of administration	Oral
Chemical structure
Pivotal trials	Phase III (add-on)[32–35] Phase III (children)[37] Phase III (monotherapy)[36]

Additional information

Funding

This manuscript has not been funded.