Zonisamide Treatment Research Articles

Open Label Trial of the Tolerability and Efficacy of Zonisamide in the Treatment of Alcohol Dependence

Objectives: The objectives of this study are to assess the tolerability and efficacy of the anticonvulsant zonisamide in an open label trial of the treatment of alcohol dependence. Methods: In this trial, zonisamide (400-mg daily) was administered to alcohol-dependent subjects (ADS) (n = 16) over 13 weeks. The mean daily consumption of standard alcoholic drinks and performance on a verbal fluency task, the COWAT, and on a measure of attention and visuomotor speed, the DSMT were assessed, and the occurrence of adverse events was monitored weekly. Results: The mean number of drinks consumed daily was significantly reduced from baseline levels during the treatment period. Performances on the COWAT and on the DSMT were not significantly reduced by zonisamide treatment. Overall, zonisamide was well tolerated by the study subjects. Conclusion: These results indicate that zonisamide administration may not impair verbal fluency in ADS, and are consistent with other studies that found zonisamide administration may reduce alcohol intake.

The antiepileptic drug zonisamide inhibits MAO-B and attenuates MPTP toxicity in mice: Clinical relevance

Zonisamide is an FDA-approved antiepileptic drug that blocks voltage-dependent Na + channels and T-type Ca 2+ channels and improves clinical outcome in Parkinson's disease (PD) patients when used as an adjunct to other PD therapies. Zonisamide also modifies dopamine (DA) activity, provides protection in ischemia models and influences antioxidant systems. Thus, we tested it for its ability to protect DA neurons in a mouse model of PD and investigated mechanisms underlying its protection. Concurrent treatment of mice with zonisamide and 1-methyl-4-phenyl-1,2,3,6-tetraydropyridine (MPTP) attenuated the reduction in striatal contents of DA, its metabolite DOPAC and tyrosine hydroxylase (TH). We also discovered that zonisamide inhibited monoamine oxidase B (MAO-B) activity in vitro with an IC 50 of 25 μM, a concentration that is well within the therapeutic range used for treating epilepsy in humans. Moreover, the irreversible binding of systemically administered selegiline to MAO-B in mouse brain was attenuated by zonisamide as measured by ex vivo assays. Zonisamide treatment alone did not produce any lasting effects on ex vivo MAO-B activity, indicating that it is a reversible inhibitor of the enzyme. Consistent with the effects of zonisamide on MAO-B, the striatal content of 1-methyl-4-phenylpyridinium (MPP +), which is derived from the administered MPTP via MAO-B actions, was substantially reduced in mice treated with MPTP and zonisamide. The potency and reversibility with which zonisamide blocks MAO-B may contribute to the ability of the drug to improve clinical symptoms in PD patients. The results also suggest that caution in its use may be necessary, especially when administered with other drugs, in the treatment of epilepsy or PD.

Idiopathic Hemifacial Spasm Responsive to Zonisamide

We describe a patient with idiopathic hemifacial spasm (HFS) that was responsive to zonisamide treatment. A 65-year-old woman presented with a 4-year history of left-sided HFS developing gradually, starting from the upper facial muscles. After several analyses, the diagnosis of idiopathic HFS was made, and the clonazepam treatment (0.5 mg every 8 hours) was started, without a complete remission of symptoms. Therefore, zonisamide (150 mg twice a day for a 6-week period) was added, with a complete resolution. The rechallenge with zonisamide after its dechallenge confirmed its effectiveness. During follow-up, the patient remained symptom-free, with no adverse drug reactions. We suggest that zonisamide could represent a useful therapeutic option in the treatment of idiopathic HFS.

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The impact of zonisamide on weight. A clinical study in 103 patients with epilepsy

To investigate the impact of zonisamide (ZNS) on body weight in patients with epilepsy. A retrospective chart analysis of weight changes after initiation of ZNS (103 patients; 54 female; age 17-68 years). For 31 patients follow-up data after ZNS-withdrawal were available. Patients were categorized according to body-mass-index (BMI) <20, 20-25, and >25 kg/m(2). Body weight before ZNS was 78.6 +/- 16.0 kg (range 45-120 kg), BMI 26.5 +/- 5.2 kg/m(2) (range17.6-41.3 kg/m(2)). Within 13 +/- 7.2 months of treatment, mean body weight decreased by -3.7% +/- 9.1%, showing high interindividual variability (-36% to +32%). Weight loss >5% was documented in 35%, weight gain >5% in 14% of patients. Weight loss was more prominent in patients being overweight prior to treatment onset. At the end of follow-up, patients with overweight had decreased by number. Weight changes under ZNS were not correlated to ZNS daily dosage. Following discontinuation of ZNS treatment weight loss proved to be reversible. Zonisamide reduced weight in 35% of patients, especially in patients with overweight prior to treatment. Weight loss is reversible following discontinuation of treatment with ZNS.

Long-term safety and efficacy of zonisamide in patients with refractory partial-onset epilepsy

To investigate whether zonisamide remains effective and well tolerated in the treatment of refractory partial epilepsy during long-term treatment and with flexible dosing in clinical practice. Patients with refractory partial epilepsy who completed a fixed-dose, randomized, double-blind clinical trial were recruited in an open-label extension study with adjustment of zonisamide and other antiepileptic drug dosage according to the treating physician's usual clinical practice. An intention-to-treat analysis of 317 patients showed that zonisamide was well tolerated with a predictable safety profile. Patient retention rates at 1, 2 and 3 years were 65.3%, 44.5% and 28.8%, respectively. Zonisamide treatment was associated with a maintained reduction in seizure frequency, with some patients achieving prolonged periods of seizure freedom. Flexible dosing with zonisamide demonstrated a good safety profile and sustained efficacy in the long-term adjunctive treatment of refractory partial epilepsy.

Zonisamide decreases cortical excitability in patients with idiopathic generalized epilepsy

Objective To evaluate changes in cortical excitability after long-term zonisamide (ZNS) administration. Methods Fifteen drug-naïve idiopathic generalized epilepsy (IGE) patients (8 male, mean age 24.9 years) were enrolled. The transcranial magnetic stimulation (TMS) parameters obtained using two Magstim 200 stimulators were resting motor threshold (RMT), motor evoked potential (MEP) amplitudes, cortical silent period (CSP), intracortical inhibition (ICI), and intracortical facilitation (ICF). TMS parameters were compared before and after ZNS administration. Results All patients were administered ZNS monotherapy (200 mg/day) for 8 weeks. No patient reported seizures during the study period. After ZNS treatment MEP amplitudes were significantly reduced in right (−34.2%) and left hemispheres (−37.0%) (Wilcoxon’s signed rank test after Bonferroni’s correction for multiple comparisons, P < 0.05). Mean RMT, CSP, and ICI/ICF were not changed by ZNS ( P > 0.05). Conclusions These findings suggest that ZNS decreases cortical excitability in patients with IGE and a MEP amplitude is a useful TMS parameter for evaluating changes in cortical excitability induced by ZNS. Significance The findings in this study are helpful to understand how ZNS affects the excitability of the motor cortex in patients with IGE.

Open-label, long-term safety study of zonisamide administered to children and adolescents with epilepsy

Background Zonisamide is licensed in the EU and USA for the adjunctive treatment of partial-onset seizures in adults but there are few data about its use in children. Aims To assess the long-term safety and efficacy of zonisamide in children and adolescents. Methods Zonisamide-naïve patients ( n=109, aged 3–15 years, weight ⩾12.5 kg) with a clinical diagnosis of epilepsy (⩾4 seizures/month, receiving 1–2 antiepileptic drugs [AEDs] daily) received zonisamide once or twice daily in an open-label trial. The starting dose was 1 mg/kg/day, increased by 2 mg/kg/day every 1–2 weeks at the investigator's discretion to an initial maximum of 12 mg/kg/day. The occurrence of adverse events (AEs) was the primary safety measure. Efficacy was measured via the reductions in seizure frequency and via investigator- and carer-rated global assessment ratings. Results The mean dose received was 8.5 mg/kg/day. Of the 109 children, 52 (48%) completed 15 months’ treatment. Treatment-related AEs, mostly mild-to-moderate in severity, were reported by 58 patients. Seven patients discontinued due to treatment-related AEs. Serious AEs (pancreatitis, decreased sweating, and vertigo) were reported by three patients. A significant ( p=0.033) median reduction in ‘all seizure’ frequency of 2.60 seizures per week was observed. Additionally, a significant ( p=0.029) median reduction of 1.80 seizures/week in ‘complex partial’ seizures was reported. Improvements in investigator- and carer-rated global assessments were noted. Conclusions Zonisamide treatment was generally well tolerated and was associated with significant reductions in seizure frequency in this pediatric population with a variety of both partial and generalized medically refractory epilepsy syndromes.

Preventing effects of a novel anti-parkinsonian agent zonisamide on dopamine quinone formation

The neurotoxicity of dopamine (DA) quinones as dopaminergic neuron-specific oxidative stress is considered to play a role in the pathogenesis and/or progression of Parkinson's disease (PD), since DA quinones conjugate with several key PD pathogenic molecules ( e.g., tyrosine hydroxylase, α-synuclein and parkin) to form protein-bound quinone (quinoprotein) and consequently inhibit their functions. Zonisamide (ZNS) is used as an anti-epileptic agent but also improved the cardinal symptoms of PD in recent clinical trials in Japan. To evaluate the effects of ZNS on excess cytosolic free DA-induced quinone toxicity, we examined changes in DA quinone-related indices after ZNS treatment both in in vitro cell-free system and in cultured cells. Co-incubation of DA and ZNS in a cell-free system caused conversion of DA to stable melanin via formation of DA-semiquinone radicals and DA chrome. Long-term (5 days) treatment with ZNS decreased quinoprotein and increased DA/DOPA chromes in dopaminergic CATH.a cells. ZNS significantly inhibited quinoprotein formation induced by treatment with tetrahydrobiopterin and ketanserin that elevate cytosolic free DA in the cells. Our results suggest that the novel anti-parkinsonian agent ZNS possesses preventing effects against DA quinone formation induced by excess amount of cytosolic DA outside the synaptic vesicles.

Neuroleptic Malignant Syndrome‐like State in an Epileptic Patient with Organic Brain Comorbidity Treated with Zonisamide and Carbamazepine

Neuroleptic Malignant Syndrome‐like State in an Epileptic Patient with Organic Brain Comorbidity Treated with Zonisamide and Carbamazepine

Zonisamide and renal calculi in patients with epilepsy: how big an issue?

ABSTRACTObjectives: To determine the prevalence of renal calculi in patients treated with zonisamide during randomized, controlled and open-label clinical trials, and from post-marketing surveillance data.Methods: Reports of renal calculi from four placebo-controlled double-blind trials of zonisamide, their long-term open-label treatment extension phases, and the US/European zonisamide clinical trial programme were reviewed. One double-blind study and its extension included routine ultrasound screening to identify asymptomatic calculi. Post-marketing surveillance data were also investigated, as was concomitant treatment with topiramate.Results: No symptomatic renal calculi were reported during four randomized double-blind, placebo-controlled trials involving 848 subjects (including 498 zonisamide recipients) treated for up to 3 months. In long-term extension studies with treatment for up to 24 months, symptomatic renal calculi were reported in 9/626 (1.4%) patients. Pooled safety data from all US/European clinical trials identified 15/1296 (1.2%) patients with symptomatic renal calculi during treatment for up to 8.7 years. Post-marketing surveillance revealed nine cases from 59 667 patient-years of exposure in the USA, and 14 from 709 294 patient-years of exposure in Japan; only one case occurred during concomitant topiramate and zonisamide treatment. No imbalance in electrolyte levels was found from 35 patients receiving such co-treatment in clinical trials.Conclusions: The available data suggest that the risk of developing renal calculi during zonisamide treatment is low. Data are insufficient to determine whether concomitant treatment with topiramate increases the risk of renal stones.

Long-term use of zonisamide in refractory childhood-onset epilepsy

This open label study examined the long-term efficacy and safety of zonisamide as adjunctive therapy in mentally retarded and multiple-handicapped patients with severe childhood-onset epilepsy. The study included 24 patients (mean age 12.5 years, range 2–40 years) which had different severe epilepsy syndromes (75% focal, 12.5% generalized, 12.5% refractory status epilepticus) refractory to at least 6 (median 10) anti-epileptic drugs. All patients were followed for at least 18 months after beginning of zonisamide treatment. Mean duration of zonisamide therapy was 55 weeks (range 5–168 weeks) and mean maintenance dosage was 7.7 mg/kg/day (range: 4–16 mg/kg/day). The patients received an average of 1.9 (range 1–3) concomitant antiepileptic drugs. The initial response rate defined as a⩾50% reduction of seizure frequency after 8 weeks was 58.3% (14 of 24 patients). Four of 14 initial responders developed loss of efficacy during long-term treatment. The retention rate after 18 months was 41.7% (10 of 24 patients). One patient (4.2%) became completely seizure-free after initiation of zonisamide treatment and remained seizure-free for the entire observation period of 18 months. Overall, zonisamide was well tolerated. Side effects were observed in 46% of patients and were mild to moderate. They mostly occurred during titration and subsided in maintenance dosing. Only in two patients (8.3%) zonisamide therapy was discontinued due to side effects (loss of appetite). No serious side effects were observed. These results are similar to the findings of Japanese studies suggesting that long-term use of adjunctive zonisamide therapy may be beneficial for treating mentally retarded, multiple handicapped patients with highly refractory childhood-onset epilepsy.

Psychosis Following Initiation of Zonisamide

Back to table of contents Previous article Next article Letters to the EditorFull AccessPsychosis Following Initiation of ZonisamideCLARA THOMPSON MICHAEL M.D.JENNIFER L. STARR M.D.,CLARA THOMPSON MICHAEL M.D.Search for more papers by this authorJENNIFER L. STARR M.D.Search for more papers by this author,Published Online:1 Apr 2007AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail To the Editor: Zonisamide is a novel anticonvulsant used as adjunctive treatment in combination with other antiepileptic medications for partial seizures. We present a case report of a patient who developed psychotic symptoms after initiation of zonisamide and stabilized only after zonisamide cessation, psychiatric hospitalization, and antipsychotic medication treatment.“Ms. A” was a 50-year-old Caucasian female with a 41-year history of seizures refractory to multiple antiepileptic regimens, mild mental retardation, and no previous psychiatric history. Phenytoin, primidone, and vagal nerve stimulator placement 30 months before her admission led to improved seizure control, with no apparent psychiatric symptoms. Eight months before hospitalization, phenytoin was discontinued and zonisamide was added, titrated to 300 mg/day with subsequent variation between 200 mg/day to 400 mg/day.Ms. A’s family reported that within two to three weeks of starting zonisamide, she became hostile, irritable, and isolative. Over six months, her family relationships worsened as these behaviors continued. Two weeks before admission, Ms. A was observed in an emergency room as being belligerent, paranoid, and reporting auditory and visual hallucinations. She had called police about family, refused to bathe, perseverated about medication, and limited eating and drinking. She was instructed to discontinue zonisamide.Upon psychiatric admission, valproic acid was started for seizure control; primidone and vagal nerve stimulation continued. Ms. A received olanzapine, which was increased over four days to 15 mg qhs. During her initial three inpatient days, she was agitated, paranoid, intrusive, and periodically combative, requiring seclusion.Ms. A’s psychosis gradually resolved over four weeks. Upon discharge she displayed perseveration and mild irritability, but demonstrated no paranoia, delusions, or hallucinations. Discharge medications were olanzapine, primidone, and valproic acid. Zonisamide has been used in Japan and Korea for over 15 years. Several Japanese-language case studies report psychosis and/or mania with zonisamide (1 – 3) . Psychosis incidence in one study ranged from 1.9% to 2.3% of patients treated with zonisamide (2) . In another study of 74 patients, incidence of psychosis ranged from 13% to 18% (1) . One-half of these episodes occurred within one year following zonisamide initiation, and 11 out of 14 occurred within three years. Patients who experienced psychosis were younger than those who did not. A 12-year-old child whose psychosis subsided with cessation was retried with zonisamide until her psychosis became irreversible. Previous reports noting poor correlation between starting zonisamide and psychosis onset could not definitively conclude that zonisamide was the causative agent (1 , 4) . We cannot rule out that our patient’s symptoms resulted from interictal psychosis. However, her 41-year seizure history, previously unaccompanied by psychosis, leads us to believe that this psychotic episode is related to zonisamide treatment. Zonisamide is used increasingly in the United States for seizure control and, off-label, for weight loss. We agree with Japanese recommendations that zonisamide be halted in epileptic patients with new-onset psychosis and not be retried.Salt Lake City, UtahDr. Michael’s daughter is employed by GlaxoSmithKline. Dr. Starr reports no competing interests.The authors thank Susan Schulman, C.C.R.A., for assistance with preparation of this report.

Long term use of zonisamide in refractory childhood-onset epilepsy

We present data of our open label study of zonisamide as adjunctive treatment in 24 patients (mean age 12.5 years) with different epilepsy syndromes, all refractory to at least 6 antiepileptic drugs (median 10). Mean duration of zonisamide therapy was 55 weeks (5–168); mean maintenance dosage was 7.7mg/kg/day (4–16mg/kg/day). The initial response rate (more than 50% seizure reduction after two month) was 58.3% (=14 patients), 41.7% (=10 patients) have been still on zonisamide treatment after 18 month, with one patient (=4.2%) still seizure free. Zonisamide was overall well tolerated. We observed mild to moderate side effects in 46%. Only in one patient loss of appetite as a side effect led to discontinuation of the treatment. Side effects (decreased appetite, constipation, nausea, behavioural change and seizure aggravation) occurred mostly during titration of the medication and resolved on maintenance dosage.

Zonisamide for Migraine Prophylaxis in Refractory Patients

Zonisamide is a new antiepileptic drug with multiple mechanisms of action and a favourable pharmacokinetic profile. Preliminary data suggest that zonisamide may be effective in migraine prophylaxis. We evaluated the efficacy and tolerability of zonisamide for migraine prophylaxis in refractory patients. We reviewed the charts of adult patients with International Headache Society-defined episodic migraine (EM) or with transformed migraine (TM) according to the Silberstein-Lipton criteria, who had been treated with zonisamide at our out-patient clinic for at least 60 days. Demographic data, zonisamide dosage and duration of treatment were collected and analysed. Headache frequency, attack duration, headache severity and headache-related disability before and after treatment initiation with zonisamide were compared. Thirty-three patients were included in the study (average age 43.9 +/- 8.4 years; 23 (70%) with TM and 10 (30%) with EM). The patients had failed an average of 6.2 migraine prophylactic drugs prior to zonisamide. The average zonisamide daily dose was 337.9 +/- 146.3 mg and the average duration of treatment was 186.4 +/- 174.0 days. The average number of days with headache per month was reduced in the entire study population from 20.7 +/- 9.5 before zonisamide treatment to 18.0 +/- 11.3 after its initiation (P = 0.06) [in TM from 24.7 +/- 7.3 to 21.0 +/- 10.7 (P = 0.06); in EM from 11.6 +/- 7.6 to 11.0 +/- 9.7 (P = NS)]. No significant changes in other headache parameters were found. Fourteen patients (42.4%) reported adverse events (AEs), the most common of which was fatigue. Most patients (12/14, 85.7%) rated AEs as mild or moderate. In this group of refractory migraine patients, zonisamide therapy did not result in a statistically significant beneficial effect on headache or on associated symptoms.

An Open Prospective Study of Zonisamide in Acute Bipolar Depression

To examine the effectiveness and safety of zonisamide in the treatment of acute bipolar depression. An open-label, prospective, nonrandomized, 8-week study conducted in bipolar outpatients (type I, type II, or not otherwise specified) with depressive symptoms. No patient was manic or mixed at study entry. Previous treatments were continued unchanged, but no new treatments were allowed. Montgomery Asberg Depression Rating Scale and the Mania Rating Scale from the Schedule of Affective Disorders and Schizophrenia-Change Version were used. Twenty patients (10 men, 10 women) with bipolar disorder (17 type I, 2 type II, 1 NOS), aged 38.1 +/- 8.81 years, received zonisamide at mean dose of 222.5 +/- 85.1 mg/d. Mean Montgomery Asberg Depression Rating Scale scores improved significantly from baseline to endpoint (mean difference = -8.4, 95% confidence interval [4.1, 12.6], P = 0.001). Ten patients (50%) terminated early due to adverse effects, mostly side effects including nausea/vomiting, cognitive impairment, and sedation. One patient experienced increased suicidal ideation, and one patient experienced hypomania. This study suggests improvement of depressive symptoms in this sample with 8 weeks of open-label zonisamide treatment.

Practical prescribing and long-term efficacy and safety of zonisamide

Long-term efficacy, tolerability and safety of antiepileptic drug (AED) therapy is essential given the chronic nature of epilepsy. Zonisamide (Zonegran ®), a novel AED with a broad range of mechanisms of action contributing to its antiseizure efficacy, has been evaluated extensively for the long-term management of epilepsy. Open-label extension studies in the United States and Europe suggest continued efficacy of zonisamide in long-term treatment without development of adverse events further to those seen in registration studies. Baseline seizure frequency is reduced by approximately 40–70% during long-term treatment for up to 2 years, and 30–50% of patients attain ≥50% reduction in seizure frequency across all categories of seizure and durations of treatment. Preliminary data indicate a progressive decline in seizure frequency with continued zonisamide treatment. Zonisamide is well tolerated in long-term use, with a trend towards decreasing incidence of generally mild adverse events over time and a low rate of withdrawal during chronic use. Nephrolithiasis and other serious adverse events are infrequent, and can be minimised by appropriate management and patient education. This profile of maintained efficacy, tolerability and safety during sustained administration in combination with other AEDs supports zonisamide as a valuable adjunctive agent in the long-term management of refractory partial epilepsy.

Zonisamide in the management of epilepsy—Japanese experience

Zonisamide (Zonegran ®), a novel antiepileptic drug (AED) approved in Europe for the adjunctive treatment of refractory partial seizures in adults, has undergone extensive evaluation in pre- and post-marketing double-blind and open-label studies in Japan (where zonisamide is used widely to treat partial and generalised seizures in adults and children). These data indicate that the clinical benefit of zonisamide extends across a range of seizure types and patient ages. In an analysis based on a mixture of controlled and open studies in adults and children with partial seizures, 51–57% responded to zonisamide treatment (achieving ≥50% reduction in baseline seizure frequency). Efficacy extends across a range of generalised seizures and 22–66% of adults and children experiencing tonic–clonic, tonic, clonic, myoclonic or absence seizures responded to treatment. Even greater responder rates have been reported when zonisamide was used as monotherapy for partial seizures and generalised seizures in patients refractory to other AEDs or with newly diagnosed epilepsy. Zonisamide is also efficacious in paediatric epilepsy syndromes, including Lennox-Gastaut Syndrome, West Syndrome and Ohtahara Syndrome. Across the spectrum of epilepsy syndromes studied, zonisamide is well-tolerated with a low incidence of adverse events, which are generally mild and CNS-related. These data indicate that zonisamide represents a valuable broad-spectrum option for the treatment of epilepsy.

Differential effects of vigabatrin and zonisamide on the neuropeptide Y system in the hippocampus of seizure prone gerbil

Changed neuropeptide Y (NPY) system in the hippocampus has been reported in various experimental epileptic models. However, there have been little data concerning the alteration in the NPY system in the epileptic hippocampus following treatment of anti-epileptic drugs (AEDs). In the present study, therefore, we performed analyses of effects of vigabatrin (VGB) and zonisamide (ZNS) treatment on the NPY system in the hippocampus of the seizure sensitive (SS) gerbils. In SS gerbil, NPY immunoreactivity in the hippocampus was lower than that in seizure resistant gerbil. Following VGB treatment, the number of NPY immunoreactive neurons and NPY mRNA expression were increased in the hilus and the hippocampus proper. In contrast, ZNS treatment markedly elevated only the density of NPY immunoreactive fibers in the dentate gyrus, not in the hippocampus proper, as compared with saline-treated animals. These patterns were observed in the dose-dependent manners. These findings suggest that AEDs treatments may distinctly affect the NPY system in the SS gerbil hippocampus.

Lack of Clinically Significant Pharmacokinetic Interactions Between Zonisamide and Lamotrigine at Steady State in Patients With Epilepsy

The present study was designed to assess the effect of the addition of zonisamide (ZNS) on lamotrigine (LTG) disposition and the safety of the combination under steady-state conditions in patients with epilepsy. A secondary objective was to characterize ZNS pharmacokinetics (PK) in the presence of LTG. Twenty subjects (male and female 18 to 55 years old) stabilized on LTG monotherapy (150-500 mg/d) took part in a 2-center, open-label, 1-way drug interaction study. ZNS was gradually increased to 200 mg twice daily over a 3-week period, and 3 PK profiles were performed: on days -7 and -1 to assess the PK of oral LTG administered alone and on day 35, after 14 days of ZNS at the maximal tolerated dose, to evaluate the effect of ZNS on LTG PK and to characterize ZNS PK in the presence of LTG. Eighteen subjects completed the study. Steady-state dosing of ZNS did not significantly affect the mean Cmin (mean +/- SD: 2.8 +/- 1.4 vs 3.5 +/- 2.4 microg/mL), Cmax (5.1 +/- 3.0 vs 5.1 +/- 3.0 microg/mL), AUC0-12 (45.5 +/- 22.6 vs 50.3 +/- 32.1 microg.h/mL), and CL/F (2778.5 +/- 1368.5 vs 3052.1 +/- 2744.9 mL/h) of LTG measured before (day -1) and after (day 35) ZNS administration, respectively. Further, 90% confidence intervals for the geometric mean ratios (day 35/day -1) fell within the no-effect range of 0.80-1.25. The fraction of dose of total and unconjugated LTG excreted in urine was not significantly different between baseline and ZNS treatment, but the renal clearance of LTG decreased significantly with ZNS dosing (P = 0.01). On the other hand, the PK parameters measured for ZNS in the presence of LTG were consistent with an absence of LTG effect on ZNS PK. The coadministration of ZNS and LTG was generally well tolerated. Steady-state safety and PK of LTG and ZNS are not affected significantly when these two drugs are coadministered at clinically relevant doses, indicating that no dosage adjustment of either drug should be required when they are used in combination.