Randomized, controlled, dose-ranging trial of carisbamate for partial-onset seizures

Faught, Edward; Holmes, Gregory L.; Rosenfeld, William E.; Novak, Gerald; Neto, Walter Krause; Greenspan, Andrew; Schmitt, Jens; Yuen, Eunice; Reines, Scott A.; Haas, Magali

doi:10.1212/01.wnl.0000334751.89859.7f

Cited by 42 publications

(57 citation statements)

References 9 publications

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“…Despite its disparity with previous preclinical work, the equivocal antiepileptic effect of CRS we found in rpFPI-PTE was not inconsistent with that observed in populations of partial-onset pharmacoresistant epilepsy patients in add-on clinical trials (Faught et al, 2008;Sperling et al, 2010), because large effects of CRS were not seen in either case. No clinical data are available to assess the performance of CRS on patients with pharmacoresistant epilepsy caused by head trauma, and neither our study nor the add-on clinical trials of CRS in pharmacoresistant epilepsies may reflect the performance of CRS on pharmacoresponsive epilepsy patients.…”

contrasting

confidence: 99%

Antiepileptic and Antiepileptogenic Performance of Carisbamate after Head Injury in the Rat: Blind and Randomized Studies

Eastman

Verley

Fender

et al. 2010

J Pharmacol Exp Ther

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Carisbamate (CRS) exhibits broad acute anticonvulsant activity in conventional anticonvulsant screens, genetic models of absence epilepsy and audiogenic seizures, and chronic spontaneous motor seizures arising after chemoconvulsant-induced status epilepticus. In add-on phase III trials with pharmacoresistant patients CRS induced Ͻ30% average decreases in partial-onset seizure frequency. We assessed the antiepileptogenic and antiepileptic performance of subchronic CRS administration on posttraumatic epilepsy (PTE) induced by rostral parasaggital fluid percussion injury (rpFPI), which closely replicates human contusive closed head injury. Studies were blind and randomized, and treatment effects were assessed on the basis of sensitive electrocorticography (ECoG) recordings. Antiepileptogenic effects were assessed in independent groups of control and CRS-treated rats, at 1 and 3 months postinjury, after completion of a 2-week prophylactic treatment initiated 15 min after injury. The antiepileptic effects of 1-week CRS treatments were assessed in repeated measures experiments at 1 and 4 months postinjury. The studies were powered to detect ϳ50 and ϳ40% decreases in epilepsy incidence and frequency of seizures, respectively. Drug/vehicle treatment, ECoG analysis, and [CRS] plasma determination all were performed blind. We detected no antiepileptogenic and an equivocal transient antiepileptic effects of CRS despite [CRS] plasma comparable with or higher than levels attained in previous preclinical and clinical studies. These findings contrast with previous preclinical data demonstrating large efficacy of CRS, but agree with the average effect of CRS seen in clinical trials. The data support the use of rpFPI-induced PTE in the adolescent rat as a model of pharmacoresistant epilepsy for preclinical development.

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contrasting

confidence: 99%

Antiepileptic and Antiepileptogenic Performance of Carisbamate after Head Injury in the Rat: Blind and Randomized Studies

Eastman

Verley

Fender

et al. 2010

J Pharmacol Exp Ther

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“…In these clinical trials, carisbamate demonstrated a good central nervous system (CNS) side effect profile, with mild to moderate dose-dependent somnolence and dizziness when given adjunctively with two or three concomitant antiepileptic drugs. Similarly, discontinuation rates due to CNSrelated adverse effects were relatively low, and were highest (19%) at the maximal dose tested (i.e., 1600 mg/day) [15]. When given as monotherapy in a migraine prophylaxis trial that failed to show efficacy, carisbamate was also well tolerated at doses up to 600 mg/day [17].…”

Section: Introductionmentioning

confidence: 92%

“…It also has been shown to attenuate alcohol intake in animals [2,14]. In human investigations in patients with epilepsy, carisbamate (200-1600 mg/day) has shown antiepileptic efficacy in some but not all studies [15,16]. In these clinical trials, carisbamate demonstrated a good central nervous system (CNS) side effect profile, with mild to moderate dose-dependent somnolence and dizziness when given adjunctively with two or three concomitant antiepileptic drugs.…”

Section: Introductionmentioning

confidence: 99%

Cognitive effects of carisbamate in randomized, placebo-controlled, healthy-volunteer, multidose studies

Meador¹,

Brashear²,

Wiegand³

et al. 2011

Epilepsy & Behavior

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“…2-4 Although there was a trend for better seizure control with higher doses of carisbamate, given the dose-related reduction in tolerability, carisbamate is no longer being evaluated for this indication. [2][3][4] Pharmacokinetic (PK) studies in humans indicate carisbamate is rapidly absorbed with mean peak plasma concentrations observed around 0.5 to 2 hours following a single oral dose of 500 mg. 5 Oral bioavailability was estimated to be approximately 94%. 6 Coadministration with food does not alter the PK of carisbamate to a clinically relevant level.…”

mentioning

confidence: 99%

“…1 In 4 doubleblind, placebo-controlled studies in adult patients with partial-onset seizures that have been conducted to date, carisbamate failed to consistently demonstrate a significant treatment difference relative to placebo across the dose ranges assessed. [2][3][4] Although there was a trend for better seizure control with higher doses of carisbamate, given the dose-related reduction in tolerability, carisbamate is no longer being evaluated for this indication. [2][3][4] Pharmacokinetic (PK) studies in humans indicate carisbamate is rapidly absorbed with mean peak plasma concentrations observed around 0.5 to 2 hours following a single oral dose of 500 mg. 5 Oral bioavailability was estimated to be approximately 94%.…”

mentioning

confidence: 99%

Effect of Mild and Moderate Hepatic Impairment on the Pharmacokinetics and Safety of Carisbamate

Moore

Zannikos

Solanki

et al. 2012

The Journal of Clinical Pharma

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This open-label, parallel-group study was designed to characterize the pharmacokinetics (PK) of carisbamate in participants with mild or moderate hepatic impairment versus those with normal hepatic function. Healthy (n = 10) and hepatic-impaired (n = 20) participants received a single 200-mg oral dose of carisbamate. Serial PK blood samples were collected up to 120 hours postdose. A modest increase in mean area under the plasma concentration-time curve from 0 to infinity (AUC(∞)) was observed for the mild impairment group compared with the normal group (ratio of geometric means ~116%), while mean maximum plasma concentration (C(max)) values were similar (ratio of geometric means ~94%). The AUC(∞) value for the moderate hepatic-impaired group was approximately 207% that of the normal group, while there was a smaller increase in C(max) (~118%) compared with the normal group. Mean half-life (t(1/2)) values were prolonged in the moderate impairment group (21 hours) relative to the normal group (11 hours). There was a decrease in apparent clearance (CL/F) and an increase in AUC(∞u) (AUC(∞) × % drug unbound). The percentage of carisbamate unbound to proteins did not change across the groups, suggesting the increases in AUC(∞) were due to decreased intrinsic hepatic clearance. Carisbamate 200 mg was well tolerated.

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Randomized, controlled, dose-ranging trial of carisbamate for partial-onset seizures

Abstract: Carisbamate at doses of 300, 800, and 1,600 mg/d was effective as adjunctive therapy for reducing the frequency of partial-onset seizures.

Cited by 42 publications

References 9 publications

Antiepileptic and Antiepileptogenic Performance of Carisbamate after Head Injury in the Rat: Blind and Randomized Studies

Antiepileptic and Antiepileptogenic Performance of Carisbamate after Head Injury in the Rat: Blind and Randomized Studies

Cognitive effects of carisbamate in randomized, placebo-controlled, healthy-volunteer, multidose studies

Effect of Mild and Moderate Hepatic Impairment on the Pharmacokinetics and Safety of Carisbamate

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