Antiepileptic Drugs, 5th Edition

Zonisamide

92

Chemistry, Biotransformation, and Pharmacokinetics

Jaymin Shah PhD^*

Kent Shellenberger PhD^**

Daniel M. Canafax PharmD^***

* Director. Clinical Pharmacology, Elan Pharmaceuticals, South San Francisco. California

** Vice President, Clinical Affairs, Elan Pharmaceuticals South San Francisco. California

*** Director, Clinical Affairs, Elan Pharmaceuticals, South San Francisco, California

CHEMISTRY

Zonisamide (1,2-benzisoxazole-3-methanesulfonamide) is a broad-spectrum antiepileptic drug (AED) marketed in Japan and South Korea for more than 10 years as Excegran (Dainippon Pharmaceuticals, Osaka, Japan). Zonisamide (Zonegran; Elan Pharmaceuticals, Gainesville, GA) has been approved since March 2000 for marketing in the United States. Zonisamide was first synthesized by Uno and collaborators (1) in 1972. The chemical structure of zonisamide (molecular formula: C₈H₈N₂O₃S; molecular weight, 212.23) is shown inFigure 92.1. The drug appears as nonhygroscopic, white to pale yellow crystals or as a crystalline powder with a slightly bitter taste, and has a melting point of 164°C to 168°C. The pK_a value of zonisamide is 9.66 and its solubility in water (25°C) is pH dependent; at neutral pH, the solubility is approximately 0.78 mg/mL. The drug is undisassociated at acidic pH up to approximately 8, but becomes dissociated above pH 8, leading to increased solubility as the pH increases. Zonisamide is soluble in acetone (1 g/8 mL), but has low solubility in methanol, ethanol, ether, and chloroform (range, 1 g/60 mL to 1 g/1.7 L). The partition coefficient ratio of zonisamide at neutral pH is 1.04 in chloroform/water and 3.24 in 1-octanol/water.

The commercial formulation contains 100 mg of zonisamide and 200 mg total of excipients such as microcrystalline cellulose and sodium lauryl sulfate in a hard gelatin capsule. The encapsulated materials are chemically stable and exhibit no change in dissolution rate unless stored in high humidity and excessive light conditions in a nonprotective package. The commercial product is packaged in a high-density polyethylene bottle and has a documented shelf life of 2 years.

MECHANISM OF ACTION

Voltage-dependent Na⁺ and Ca²⁺ channels have a critical role in neural membrane excitability (2). In vitro pharmacology studies suggest that zonisamide blocks both Na⁺ channels and T-type Ca²⁺ channels, thereby reducing voltage-dependent, transient inward currents. These effects promote stabilizing of neuronal membranes and suppression of neuronal hypersynchronization. Given these effects, it has been suggested that zonisamide disrupts synchronized neuronal

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firing in the seizure forms, thereby limiting the spread of seizures (3). Zonisamide also inhibits carbonic anhydrase activity, but this effect is not thought to be a major contributing factor in producing antiepilepsy activity.

PHARMACOKINETIC OVERVIEW

The pharmacokinetics of zonisamide have been evaluated in numerous studies with volunteers recruited in Japan and the United States. Zonisamide's pharmacokinetic parameters are summarized in Table 92.1. In general, zonisamide has rapid absorption, good bioavailability that is not affected by food, and a long terminal half-life from mixed hepatic (70%) and renal (30%) routes of elimination. The metabolites produced by cytochrome P450 (CYP) 3A4 and 2D6 microsomal enzymes are inactive. After dosing between 200 and 600 mg/day in adults with epilepsy, the resulting zonisamide concentrations are approximately 10 to 30 µg/mL and have a modest relationship between efficacy and adverse events. Drug interactions with zonisamide and the other AEDs are uncommon and of minor clinical significance, except for phenytoin (decreased clearance from zonisamide and increases zonisamide clearance), and phenobarbital and carbamazepine (both increase zonisamide clearance).

In these pharmacokinetic studies, methods for measuring zonisamide levels in various biologic matrices, such as, plasma, serum, and tissue were developed using high-performance liquid chromatography and enzyme-linked assay techniques. These assays were optimized to avoid interference from zonisamide metabolites and other AEDs and their metabolites (4,5, 6). Usual monitoring of zonisamide levels is performed using plasma or serum samples.

ABSORPTION AND BIOAVAILABILITY

After oral doses of radiolabeled zonisamide given in experimental models, absorption from the gastrointestinal tract is rapid and complete as determined by measurement of radioactive drug excretion in bile and urine (7). In a dose escalation study, single oral zonisamide doses of 200, 400, and 800 mg were given to 12 healthy volunteers with a 3-week washout period between doses. Moderately rapid absorption was observed, with the time to maximal plasma concentration (T_max) ranging from 2.4 to 3.6 hours, which was independent of dose size (8). The maximum concentration (C_max) in plasma increases as the dose increases from 200 to 800 mg and ranged from 2.3 to 12 µg/mL (Table 92.1). The elimination half-life is long and appears to be independent of the zonisamide dose, ranging from 49.7 to 62.5 hours. The mean area under the zonisamide concentration-time curve (AUC) is proportional to the dose administered and ranged from 170 to 863 µg/hr/mL.

A multiple dose pharmacokinetic study was conducted in two groups of healthy subjects receiving 400 mg/day dose either as 200 mg twice daily or 400 mg once daily for 35 days in a gradual dose escalation design. At steady state, mean C_max was 30.3 (twice-daily group) and 28.0 µg/mL (once-daily group), reached in 2.1 and 1.8 hours, respectively. The bioavailability of zonisamide with the once-daily regimen is approximately 84% of the twice-daily dosing regimen. At steady state, the fluctuation between peak and trough zonisamide concentrations was 14% for twice-daily (12-hour) dosing and 27% for once-daily (24-hour) dosing (9).

Administration of a single 400-mg dose to patients with refractory epilepsy receiving concomitant AEDs results in

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mean C_max of 5.9 µg/mL that is reached in 3.3 hours and a mean AUC of 213 µg/hr/mL. It is noteworthy that these pharmacokinetic parameters from patient studies are similar to values observed in healthy subjects.

Pharmacokinetic studies of zonisamide have been conducted using either capsule or tablet formulations. At present, an intravenous formulation of zonisamide is not available; therefore, any potential first-pass metabolism has not been assessed. As an indirect measure of bioavailability, [¹⁴C]-zonisamide was given to humans and 65% of the administered radioactivity was recovered in 10 days, indicating that the oral bioavailability of the zonisamide capsule is high (10). The systemic availability of zonisamide is similar with or without administration of the drug with food, except for a slight delay in Tmax to 4 to 6 hours (11).

DISTRIBUTION

Tissue distribution studies of ¹⁴C-zonisamide after single and multiple doses show that the drug is distributed evenly throughout the entire body. The concentrations of radioactivity in various tissues, as a function of time, are similar to the plasma concentrations, except for the liver, kidney, and adrenal concentrations, which are approximately twofold greater than the plasma concentrations. The distribution pattern in the body after repeated doses is similar to that after a single dose. A drug distribution study in the rat brain model shows high concentrations in the cerebral cortex and midbrain (12). Peak radioactivity occurs in most tissues within 3 hours after administering zonisamide and decreases in parallel to the decline in plasma radioactivity. No measurable accumulation of zonisamide is found in the central nervous system. Brain uptake is not through a saturable, carrier-mediated mechanism, but is attributable to lipid-mediated transport (13).

Zonisamide is approximately 40% to 60% bound to human serum albumin. Erythrocytes have a higher affinity than serum albumin for binding zonisamide. There is a dynamic equilibrium between free zonisamide and the drug concentrations in red cells and tissue and on plasma protein binding sites.

The binding capacity of zonisamide in erythrocytes is limited to a maximum of approximately 450 µmol/L (14). Also, saturation of erythrocyte binding occurs at a concentration of approximately 5 µg/mL. These characteristics of zonisamide create a dose-erythrocvtes and dose-whole blood concentration relationship that in the therapeutic range (10 to 30 µg/mL) appears to be nonlinear, whereas the dose-plasma concentration relationship is linear.

Estimates of the plasma Vd/F (apparent oral volume of distribution) after single oral doses range from 1.09 to 1.77 L/kg, indicating that zonisamide is widely distributed outside the plasma compartment. At steady state, the mean plasma Vd for zonisamide is significantly lower than the Vd/F observed for single-dose administration (0.91 versus 1.45 L/kg). The changes observed in the single-dose plasma Vd/F as a function of dose and those observed at steady state are likely produced by the concentration-dependent binding of zonisamide to erythrocytes.

Zonisamide readily penetrates across lipid membranes into various body fluid compartments. The drug also crosses the blood-brain barrier and, in animal studies, the concentration in cerebrospinal fluid is similar to the free fraction in serum (15). Zonisamide crosses the placenta and enters breast milk. Fetal rat concentrations are similar to those in the plasma of the mother, and concentrations in the breast milk are similar to maternal plasma concentrations (16,17). Zonisamide appears to be actively secreted into saliva because saliva levels are higher than the free fraction in serum. It is possible this is the cause of a metallic taste that occasionally is reported by patients taking zonisamide.

Red Blood Cell Binding

Zonisamide, like other sulfonamides, has a high affinity for binding carbonic anhydrase and other red cell components, as opposed to extracellular serum albumin (14); therefore, zonisamide is highly concentrated in erythrocytes (14,18). This results in higher drug concentrations in whole blood than in the plasma. Erythrocyte uptake is best described by the sum of linear passive diffusion and a saturable binding to carbonic anhydrase. Because of this saturable binding, a greater proportion of whole blood to plasma drug concentration is bound to erythrocytes at low concentrations (<5 µg/mL) compared with higher concentrations. Therefore, the erythrocyte to plasma concentration ratio is concentration dependent and produces a degree of apparent concentration nonlinearity at low plasma concentrations. For example, at plasma concentrations of 1 µg/mL, the predicted erythrocyte-plasma ratio is >15, and as plasma concentration increases, this ratio decreases (Table 92.2). The ratio of erythrocyte to plasma drug concentration at steady-state levels of 15 to 20 µg/mL is approximately 4. The erythrocyte uptake of zonisamide has minimal effect on the pharmacokinetic characteristics of the drug at therapeutic steady-state concentrations between 10 and 30 µg/mL.

BIOTRANSFORMATION AND EXCRETION

Zonisamide undergoes significant biotransformation, with various metabolites identified in animal urine. The main

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metabolic pathways in animals include glucuronide conjugation, acetylation, hydroxylation followed by oxidation of the methylene carbon of the sulfamoylmethyl group, finally resulting in loss of the sulfamoylmethyl group, and N-O bond cleavage of the isoxazole ring to produce two ring-cleft metabolites. The hydroxylation and ring-cleft products subsequently are excreted as sulfate or glucuronide conjugates (16,19). The metabolite composition in various body fluids and tissues has been studied in young and adult animal models (12,19). ¹⁴C-zonisamide administered to healthy subjects showed that most of the activity was associated with the intact drug and no appreciable metabolites were present in the plasma (10).

The two primary metabolites identified from human urine are the glucuronide of the open-ring metabolite [2-(sulfamoylacetyl)-phenol-glucuronide] (SMAP) and the Nacetylzonisamide (Figure 92.2). These metabolites, along with unchanged zonisamide in the urine, account for almost all the radioactivity administered. In vitro human liver microsomal studies (20) indicate that CYP is involved in the reductive metabolism of zonisamide. The metabolism of zonisamide to SMAP is almost completely inhibited by anti-CYP3A4 antibody, whereas the anti-CYP2D6 antibody has no effect. Therefore, the 3A subfamily includes the major isoenzymes of the CYP enzymes responsible for the formation of SMAP from zonisamide. These results closely parallel the findings in the rat model, which indicate that CYP3A4 mediates the formation of SMAP (21). At concentrations of 200 µmol/L, which is approximately 40 µg/mL or at the high end of the therapeutic concentration,

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zonisamide had less than a 10% inhibitory effect on several of the CYP isozymes, including CYP3A4 (unpublished data). This inhibition of enzymatic activity is not concentration dependent because the inhibition does not exceed 14% of control levels at concentrations up to 1,000 µmol/L of zonisamide. In humans, repeated administration of the drug does not alter the pharmacokinetic characteristics; therefore, autoinduction of zonisamide metabolism apparently does not occur (18,22).

After a single dose of ¹⁴C-zonisamide in animal models, most (>80%) of the parent drug is eliminated in urine, with a minor fraction (approximately 15% in rats and dogs, 4% in monkeys) eliminated in the feces. Biliary excretion accounts for approximately 22% in rats, a portion of which was eventually eliminated in the feces (7). This suggests that the major route of excretion of zonisamide and its metabolite is by the kidney in animal models. In humans, unchanged zonisamide comprises approximately 30% of total urine radioactivity, N-acetylzonisamide approximately 20%, and the glucuronide of the open-ring metabolite (SMAP) approximately 50% of the total dose administered (10,18). The total excretion of unchanged zonisamide and the conjugated open-ring metabolite of zonisamide accounts for 48% to 60% of the administered dose, suggesting that renal elimination is a major route of excretion in humans and the feces is a minor route of elimination.

CLEARANCE AND HALF-LIFE

Healthy Subjects

In healthy subjects after single zonisamide doses of 200, 400, and 800 mg on three separate occasions with an adequate washout period, the mean half-life of the drug in plasma ranged from 49.7 to 62.5 hours and the apparent oral clearance ranged from 0.25 to 0.32 mL/min/kg (8). In a multiple-dose study with healthy subjects, the mean half-life of zonisamide ranged from 63.0 to 68.6 hours, with apparent oral clearance from 0.143 to 0.17 mL/min/kg (9). The higher plasma clearance from a single dose could be attributable to the nonlinear binding to erythrocytes at low concentrations.

Epileptic Patients Taking Other Antiepileptic Drugs

Studies using pretreatment with phenobarbital or carbamazepine in rats demonstrate a decrease in zonisamide half-life (23). Similarly in humans, an increase in zonisamide plasma clearance and a decrease in half-life is observed with concomitant administration of zonisamide with phenytoin, carbamazepine, phenobarbital, and valproic acid (24). The half-life of zonisamide when given concomitantly with phenobarbital is 38 hours, and is 27 hours when administered concomitantly with phenytoin (25). A similar reduction in the zonisamide half-life to 36 hours is produced by carbamazepine administration (25). These interactions were found after the administration of single zonisamide doses to patients receiving stable doses of the other AEDs. In steady-state drug interaction studies performed in patients with epilepsy receiving stable doses of commonly used AEDs, we observed that in the presence of phenytoin and carbamazepine, the half-life of zonisamide is approximately 27 and 36 hours, respectively, whereas the clearance was increased by 40% to 50%. In contrast to the previous reports, no reduction in the zonisamide half-life (approximately 50 hours) was observed in presence of lamotrigine and valproic acid (26).

Children

Unfortunately, formal zonisamide pharmacokinetic studies have not been conducted in children as yet. Many Japanese trials in children with epilepsy included monitoring steady-state zonisamide blood or serum concentrations. Recent studies showed that serum zonisamide concentrations increased linearly with increasing doses of less than 10 mg/kg/day, and when stabilized at effective doses of 5 to 8 mg/kg/day, the resulting serum zonisamide concentrations were approximately in the range of 10 to 30 µg/mL (27). In addition, dose titration in small increments of 0.5 to 1 mg/kg every 2 weeks is well tolerated, and serum concentrations above 40 µg/mL are more likely to produce adverse effects. It appears that larger zonisamide doses (milligrams per kilogram) are required in children than in adults to achieve equivalent serum drug concentrations, possibly because of increased zonisamide clearance in this population, as seen with the other AEDs (28).

Elderly

The mean plasma C_max for an equivalent dose of zonisamide in elderly subjects (mean age, 69 years; range, 65 to 71 years) is 32.4% higher than that for young adult subjects (mean age, 28 years; range, 21 to 40 years). Conversely, mean AUCs for young and elderly are not different, indicating that the extent of zonisamide absorption is similar for both of these age groups. The mean (standard deviation) zonisamide elimination half-life in the elderly subjects is observed to be 51.9 (23.6) hours, and is somewhat shorter than that in young subjects, 65.7 (11.1) hours (29). The mean Vd is lower in elderly subjects and could account for the decreased plasma half-life in the elderly group. Mean plasma clearance, renal clearance, and the percentage dose excreted unchanged in urine are similar in both age groups, indicating that zonisamide distribution and elimination are not affected by age (30).

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ZONISAMIDE INTERSUBJECT VARIABILITY AND ITS DETERMINANTS

Low (<30%) intersubject zonisamide pharmacokinetic parameter variability occurs in healthy subjects and children with epilepsy (9,31). A somewhat higher degree of variability (approximately 45%) is observed in patients with epilepsy who are concurrently taking other AEDs. This results from effects by the other AEDs combined with the innate interpatient differences in microsomal enzyme activity. Most of the interpatient zonisamide pharmacokinetic variability likely is due to metabolic differences between patients with epilepsy.

The primary metabolites formed from zonisamide degradation in humans are 2-(sulfamoylacetyl)-phenol-glucuronide and N-acetylzonisamide, produced from CYP enzyme alteration of the molecule. Significant genetic polymorphism is observed in both N-acetylation and P450 oxidation (32). For example, N-acetyltransferase activity has a bimodal or possibly trimodal distribution in humans. Similarly, distribution of other P450 hepatic isoenzymes is known to vary across racial groups, such as the variation seen in the frequency of slow and rapid metabolizers for isoenzymes CYP3A4, CYP2D6, and CYP2C19 (33). Predominant intersubject variability commonly is observed for most other AEDs, especially those drugs that have poor aqueous solubility, long elimination half-lives, and CYP-mediated metabolism, and are given concomitantly with medications metabolized by the same pathways.

RELATIONSHIP BETWEEN CONCENTRATION AND DOSE

Clinical studies conducted in adult (34) and pediatric patients (27,31) have demonstrated that steady-state serum drug concentrations increase linearly with increasing dosages above 3 mg/kg/day. Zonisamide concentrations after single doses are not predictive of the eventual steady-state concentrations (35). This appears to result from saturable uptake of zonisamide by red blood cells at approximately 5 µg/mL. The apparent nonlinearity possibly is due to saturable binding of zonisamide to erythrocytes at low concentrations.

A recent report on nonlinear kinetics of zonisamide in patients receiving other AEDs fails to consider this unique red cell binding saturation characteristic of zonisamide (36). Population pharmacokinetic analysis of zonisamide data from clinical studies in patients demonstrates dose-dependent pharmacokinetics of zonisamide with first-order clearance (37). The reported V_max value of 27.6 mg/kg/day is well above the daily maintenance dose of 400 to 600 mg for adults. This dose results in serum drug levels in the desired range of 10 to 30 µg/mL. For clinical purposes, steady-state concentrations can be regarded empirically to be proportional to the dose of zonisamide administered in patients with epilepsy.

RELATIONSHIP BETWEEN CONCENTRATION AND EFFECT

The assessment of zonisamide pharmacodynamic characteristics suggests that both antiepilepsy and drug-related adverse events occur over a wide range of drug concentrations. Zonisamide concentrations greater than 20 µg/mL are associated with reduced seizure rates. Most adverse events occur during the initiation of zonisamide therapy, usually disappearing within the first 4 weeks of treatment. This accommodation or tolerance to zonisamide side effects (mostly neurologic) guided the creation of the current gradual dose titration method that is performed over approximately a 4-week period. It also makes defining a concentration-adverse event relationship difficult.

When the dose of zonisamide is titrated to individual patient requirements based on efficacy and tolerability, the optimal dosage for most adult patients is between 400 and 600 mg/day. These dosages result in serum levels that range from 15 to 30 µg/mL. In contrast, results from a parallel-design study that administered fixed zonisamide doses of 100, 200, and 400 mg/day found no statistically significant relationship between plasma concentrations and clinical response (38). However, in this study, antiepilepsy effects and serum levels did increase as the dose increased (400 > 200 > 100 mg/day). Therefore, patients with low zonisamide levels are more likely to have less antiepilepsy benefits and, conversely, higher drug levels produce more drug-related adverse effects. The interpretation of zonisamide concentrations for each patient should be done in conjunction with their clinical response to the pharmacotherapy.

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