Cenobamate (YKP3089) and Drug-Resistant Epilepsy: A Review of the Literature

Cenobamate (CNB), ([(R)-1-(2-chlorophenyl)-2-(2H-tetrazol-2-yl)ethyl], is a novel tetrazole alkyl carbamate derivative. In November 2019, the Food and Drug Administration approved Xcopri®, marketed by SK Life Science Inc., (Paramus, NJ, USA) for adult focal seizures. The European Medicines Agency approved Ontozry® by Arvelle Therapeutics Netherlands B.V.(Amsterdam, The Neatherlands) in March 2021. Cenobamate is a medication that could potentially change the perspectives regarding the management and prognosis of refractory epilepsy. In this way, this study aims to review the literature on CNB’s pharmacological properties, pharmacokinetics, efficacy, and safety. CNB is a highly effective drug in managing focal onset seizures, with more than twenty percent of individuals with drug-resistant epilepsy achieving seizure freedom. This finding is remarkable in the antiseizure medication literature. The mechanism of action of CNB is still poorly understood, but it is associated with transient and persistent sodium currents and GABAergic neurotransmission. In animal studies, CNB showed sustained efficacy and potency in the 6 Hz test regardless of the stimulus intensity. CNB was revealed to be the most cost-effective drug among different third-generation antiseizure medications. Also, CNB could have neuroprotective effects. However, there are still concerns regarding its potential for abuse and suicidality risk, which future studies should clearly assess, after which protocols should be changed. The major drawback of CNB therapy is the slow and complex titration and maintenance phases preventing the wide use of this new agent in clinical practice.


Introduction
Epilepsy affects more than seventy million individuals worldwide, corresponding to an age-standardized prevalence of 621.5 per 100,000 people [1].Approximately 3 million adults and almost 500,000 children in the United States have epilepsy [2].Increased life expectancies and more people surviving events that can lead to epilepsy are expected to raise the number of people with epilepsy [3].The estimated annual costs in the United States of acute seizure care are around USD 12.5 billion [4].In this context, the burden of drug-resistant epilepsy (DRE) is believed to be significantly higher due to the number of antiseizure medications (ASMs) used concomitantly and the possible high incidence of adverse events [5,6].
Seizure freedom is a primary goal in the treatment of epilepsy.Only half of the individuals with epilepsy will become seizure-free with their first ASM [7].Also, more than one in every three patients with epilepsy will have uncontrolled seizures despite adequate management and anticonvulsant therapy [8].In this context, failure to achieve sustained seizure freedom with the rational use of two anti-seizure drugs administered alone or in combination defines drug-resistant epilepsy [9].
Uncontrolled epilepsy, compared to epilepsy in general, is associated with ten-tofifteen-fold more frequent mortality secondary to traumatic injury, drowning, suicide, and Medicina 2023, 59, 1389 2 of 24 sudden unexpected death from epilepsy (SUDEP) [10].Also, some types of childhood epilepsies are related to neuronal damage leading to epileptic encephalopathy, resulting in lifelong disabilities [11].In addition, low employment rates and lower high school graduation rates can hinder individuals with epilepsy from reaching their maximum potential [12].Therefore, poor control of seizures can lead to a higher risk of experiencing physical and psychological disorders, causing worse healthcare outcomes, increased healthcare needs, and decreased quality of life [13].
Many new ASMs have been discovered during the last three decades, with more than twenty new ASMs approved [14].In this context, these new anticonvulsants have improved the spectrum of side effects, increased routes of administration, and reduced the severity of epilepsy, leading to better compliance and treatment adherence [15,16].But, there were no significant changes in the proportion of individuals affected by DRE.Interestingly, the prevalence of DRE in the 1980s was sixty-three percent, and in 2014 this number was sixty-four percent [17].
In November 2019, the Food and Drug Administration approved the commercialization of cenobamate by SK Life Science Inc., (Paramus, NJ, USA) for adult focal seizures.The European Medicines Agency approved cenobamate by Arvelle Therapeutics Netherlands B.V. (Amsterdam, The Neatherlands) in March 2021 [18].Cenobamate is a medication that could potentially change the perspectives regarding the management and prognosis of refractory epilepsy [19].In this way, this study aims to review the literature on CNB's pharmacological properties, pharmacokinetics, efficacy, and safety.For a complete description of the methodology, read the Supplementary Material, Table S1, Figure S1.

Historical Aspects of Cenobamate
Epilepsy is a neurological disorder characterized by recurrent and unprovoked seizures [20].It is believed that excessive excitability in neural tissues can contribute to the abnormal electrical activities leading to epilepsy [21].ASMs acting on voltage-gated sodium channels have been utilized for the pharmacologic management of epilepsy because these channels are essential for generating and conducting action potentials [22].Also, several point mutations in voltage-gated sodium channels, which exhibit increased persistent sodium currents, have been identified in patients with epilepsy [23].Some ASMs, such as phenytoin and lamotrigine, are known to affect persistent sodium currents [24].
In 1951, during rat studies to develop a new anxiolytic drug, meprobamate was observed to have antiseizure activity [25].Ten years later, Frank Berger at Wallace Laboratories noted the remarkable efficacy of felbamate in controlling abnormal electrical activity in animal models of epilepsy (Figure 1) [26].In 2008, Johnson & Johnson submitted a new application for carisbamate, which was approved by the U.S. Food and Drug Administration [27].But, two years later, carisbamate was removed from the market due to insignificant superiority over a placebo in a randomized controlled trial [28].
Cenobamate (CNB), ([(R)-1-(2-chlorophenyl)-2-(2H-tetrazol-2-yl)ethyl], is a novel tetrazole alkyl carbamate derivative [29].It showed antiseizure activity in the maximal electroshock test and prevented seizures induced by chemical convulsants such as pentylenetetrazol and picrotoxin [30].Also, CNB was reported to be effective in two models of focal seizure, the hippocampal kindled rat and the mouse 6 Hz psychomotor seizure models [31].Moreover, CNB has been reported to effectively and dose-dependently reduce the number and cumulative duration of spike-and-wave discharges characteristic of absence seizures in genetic absence epilepsy rats in the Strasbourg (GAERS) model [32].For further assessment of the antiseizure potencies of alkyl-carbamates, read Table 1 [33].CNB differs from other broad-spectrum ASMs because it has a sustained efficacy and potency in the 6 Hz test regardless of the stimulus intensity.Löscher et al., believed this significant efficacy predicted good outcomes in clinical trials [34].In this way, the 6 Hz test should be studied as a therapy-resistant seizure model, and other ASMs should be assessed for a complete understanding of this model in DRE.Therefore, the significant efficacy of CNB in different models suggests that this drug may have a broad spectrum of activity [35].
The photosensitivity model has been established as a "proof-of-concept" study to achieve a reliable prediction of potential efficacy and chronic-use dosing of the early period of clinical trials with new ASMs.In this model, people with epilepsy are randomly distributed to take the tested drug or placebo as an adjunct single dose.An electroencephalogram (EEG) is used to observe abnormalities in the photoparoxysmal response [36].Trenite et al., performed a single-blind non-randomized study with the photoparoxismal-EEG response (PPR) model in seven individuals with photosensitive epilepsy after oral doses of CNB of 100, 250, and 400 mg or placebo.A complete suppression of PPR response in photosensitive individuals at 250 and 400 mg single doses of CNB was observed.The subjects taking the CNB 100 mg dose had only partially suppressed PPR [37].Thus, these results provide evidence of CNB's potential efficacy in managing seizures in patients with epilepsy and support the clinical trials with this medication.
New methods to determine the plasma levels of CNB were developed to assess the pharmacokinetics of this drug in clinical trials.The first high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was designed [38].Carisbamate was used as the internal standard, and the preparation of plasma samples required the precipitation of proteins by acetonitrile.The calibration curve of this method was linear over a concentration range of 10-5000 ng/mL [39].An achiral LC-MS/MS method was validated in heparinized plasma samples for pharmacokinetic studies.Phenacetin was used as an internal standard, and plasma samples with precipitation of proteins were analyzed.A third method of LC-MS/MS was developed for pharmacokinetic studies of CNB in plasma after administering a single-capsule formulation of 400 mg.The calibration curve range was 0.080-40.0mg/L [40].The fourth method to quantify CNB in human plasma samples was developed using ultra-high-performance liquid chromatography coupled with tandem mass spectrometry.The calibration curve range was 0.050-20.0mg/L [41].
The first CNB trials revealed that more than twenty percent of people with epilepsy became seizure-free.Interestingly, this seizure freedom has never been reported in a placebo-controlled, double-blind trial of anticonvulsive drugs [42].In this context, the FDA decision regarding CNB approval for marketing was remarkable.The advisory board recommended that additional randomized controlled phase 3 trials to investigate the efficacy of CNB were not necessary because of the impressive efficacy data in the phase 2 trials.Also, they replied that open-label safety data should be performed because of some rare cases of drug rash with eosinophilia and systemic symptoms (DRESS) in early trials [43,44].
The development of new routes of drug administration is important for the improvement of adherence.The administration of medications via enteral feeding tubes may be necessary for patients who cannot swallow safely, such as individuals with dysphagia due to cognitive impairment or physical disability.Ferrari et al., studied the recovery of CNB after the administration of a suspension prepared from filmcoated tablets via ex vivo nasogastric and gastrostomy feeding tubes.The authors observed that the mean percentage of recovery from CNB was within the predetermined acceptable range (90.0-110.0%),which can suggest no adhesion or adsorption of CNB to enteral feeding tubes [45].Thus, enteral feeding tubes may be suitable for the administration of CNB.

Pharmacology and Mechanism of Action
CNB's mechanism of action has yet to be completely understood (Table 2).Interestingly, CNB was discovered purely by phenotype-based screening, and its presumed dual mechanism of action was only described years after the first studies [46].CNB can reduce repetitive neuronal firing by inhibiting voltage-gated sodium currents.It may enhance the fast and slow inactivation of sodium channels and potently inhibit the non-inactivating persistent component of the sodium channel current, which has already been observed with other ASMs [47].Noteworthily, CNB had little effect on the peak component of transient sodium currents induced by brief depolarizing step pulses.But, CNB strongly inhibited the noninactivating persistent component of sodium currents [48].Therefore, CNB may modify excitability in principal neurons without compromising inhibitory interneurons [49].Also, CNB was revealed to be a positive allosteric modulator of the γ-aminobutyric acid (GABA) ion channel.This effect was similar for all tested GABAA receptors containing six different alpha subunits (α1β2γ2 or α2-6β3γ2).Nakamura et al., studied the effects of CNB in rat hippocampal CA3 neurons.They observed that CNB had little effect on the peak component of transient sodium current induced by brief depolarizing step pulses.Still, CNB potently inhibited the non-inactivating persistent component of sodium currents.Also, it inhibited the sodium currents evoked by slow voltage-ramp stimuli [48].Noteworthily, the effect of CNB in sodium current in hippocampal rat neurons was concentration-dependent [43].
Sharma et al., assessed the effects of CNB on GABAergic neurotransmission, specifically its effects on GABAA receptors mediating inhibitory postsynaptic currents and tonic conductance in rodent hippocampal neurons.The authors found that CNB is a positive allosteric modulator of high-affinity GABAA receptors, activated by GABA at a site independent of the benzodiazepine binding site, and efficiently enhances tonic conductance inhibition in hippocampal neurons [50].CNB may resemble barbiturate action because of increased tonic and phasic inhibition through GABAA receptor activation [51].It is worth mentioning that these mechanisms were already observed in animal studies with neurosteroids [52].Also, the effect on both phases of GABAA receptor activation could partially explain the efficacy of CNB in managing status epilepticus [53].
The CNB terminal half-life of 50 to 60 h allows this drug to be taken once a day.Noteworthily, this terminal half-life increases with increasing doses of CNB from 30 h (CNB 10 mg) to 76 h (CNB 750 mg).The area under the plasma concentration versus time curve (AUC) increases more than proportionally after the administration of single doses of CNB ranging from 5 to 750 mg.However, after multiple doses of CNB at the steady state, AUC increases linearly with increasing doses within the 50-500 mg/day dose range.Plasma CNB concentrations are steady after approximately two weeks of once-daily dosing.The tablets should be swallowed whole and not crushed or chewed.This drug is extensively metabolized via glucuronidation and oxidation, so drug interactions can occur (Table 3) [32,[54][55][56].CNB pharmacokinetics have been reported to be consistent regarding gender, race, and age.Patients with mild-to-moderate (Clcr 30 to 90 mL/min) and severe (Clcr 30 mL/min) renal impairment and those with mild-to-moderate hepatic impairment should be treated with caution and reduced dose.There are no data regarding CNB's pharmacokinetics in individuals with end-stage renal disease (Clcr < 15 mL/min) undergoing hemodialysis and those with severe hepatic impairment.
Vernillet et al., studied the mass balance and the metabolic profiling of CNB in humans.Eight CNB metabolites (M1, M2a, M2b, M3, M5, M6, M7, and M11) were identified across plasma, urine, and feces.CNB was the main plasma radioactive component, and M1 was the only metabolite detected in plasma (>98% and <2% total radioactivity AUC, respectively).All detected metabolites were found in urine; unchanged CNB accounted for approximately six percent.CNB metabolites appeared to be formed slowly [40].Greene et al., assessed the effect of CNB on the single-dose pharmacokinetics of multiple cytochrome P450 probes in healthy subjects.They observed that CNB induces CYP2B6 activity, exhibits a dosedependent induction of CYP3A4/5 activity, inhibits CYP2C19 activity, and has a negligible effect on CYP2C9 activity [57].
We calculated the chemical and pharmacological properties of CNB using the Swis-sADME tool (Figure 2).These properties can help identify compounds suitable for oral use [58].All the parameters analyzed were within the normal range, except for an insaturation slightly higher than those desired for oral molecules, which can reduce oral bioavailability.Refer to Table 2 for

Clinical Trials
There are 18 clinical trials assessing CNB's efficacy and therapeutic management registered in the ClinicalTrials.govdatabase (Figure 3) (Table 4).Enrollment involved a total of 3964 individuals.Eleven studies evaluated the efficacy of CNB in the management of focal epilepsy.NCT03678753 and NCT03961568 are essential clinical trials because they studied CNB efficacy in primary generalized epilepsy.There are at least five studies awaiting the release of tabular results.

Clinical Trials
There are 18 clinical trials assessing CNB's efficacy and therapeutic management registered in the ClinicalTrials.govdatabase (Figure 3) (Table 4).Enrollment involved a total of 3964 individuals.Eleven studies evaluated the efficacy of CNB in the management of focal epilepsy.NCT03678753 and NCT03961568 are essential clinical trials because they studied CNB efficacy in primary generalized epilepsy.There are at least five studies awaiting the release of tabular results.
We also revised the literature and included the reports already published with cenobamate (YKP3089) (Table 6).

Clinical Trials
There are 18 clinical trials assessing CNB's efficacy and therapeutic management registered in the ClinicalTrials.govdatabase (Figure 3) (Table 4).Enrollment involved a total of 3964 individuals.Eleven studies evaluated the efficacy of CNB in the management of focal epilepsy.NCT03678753 and NCT03961568 are essential clinical trials because they studied CNB efficacy in primary generalized epilepsy.There are at least five studies awaiting the release of tabular results.

Efficacy of Cenobamate
Lattanzi et al., systematically reviewed the results from the studies CO13 and CO17.The pooled estimated risk ratio to achieve seizure freedom for the CNB group compared to the placebo was 3.71 (95%, CI: 1.93-7.14;p < 0.001).Also, seizure frequency reduction by at least 50% occurred during the maintenance phase in 50.1% of the patients randomized to CNB and 23.5% of the placebo-treated participants (RR 2.18, 95% CI 1.67-2.85;p < 0.001).Therefore, adjunctive CNB therapy in adult patients with uncontrolled focal-onset seizures is associated with a greater reduction in seizure frequency than placebo [93].Another metaanalytic study by Zhang et al., with the studies CO13 and CO17 found similar results [94].
Cutillo et al., studied the literature about ASMs and their efficacy for controlling focal to bilateral tonic-clonic seizures.One of the ASMs studied was CNB, which showed significant efficacy compared to placebo (18-59% efficacy above placebo).These results are important because focal to bilateral tonic-clonic seizures are recognized as one of the major risk factors for sudden unexpected death in epilepsy (SUDEP).Therefore, decreasing the incidence of this specific type of focal epilepsy can probably lead to decreased overall mortality by SUDEP [95].

Cost-Effectiveness of Cenobamate
Despite greater efficacy, CNB is still infrequently prescribed.Klein et al., reported that after two years of United States market entry, only less than five percent of adults with focal DRE are treated with CNB.They explained that this possibly occurred due to restrictions to access created by the healthcare system, insufficient post-launch information about efficacy and safety, and limited knowledge about this drug.Also, Klein et al., compared the costs among CNB and other new ASMs approved since 2009, and the cost was similar in the United States and Germany [99].
Flint et al., developed a mapping algorithm to predict SF-6D values in adults with focalonset seizures for use in economic evaluations of CNB [100].This preference-based measure of health-related quality of life can assess six dimensions of health status, including physical functioning, role limitation, social functioning, pain, mental functioning, and vitality [101].The authors found that the mapping algorithm proposed may predict SF-6D values from clinical outcomes in people with epilepsy [100].Therefore, researchers can use outcome data from clinical trials with CNB to facilitate cost-utility analysis.
A Markov model simulation of DRE in Spain was performed to analyze the costeffectiveness of CNB with other ASMs (brivaracetam, eslicarbazepine acetate, lacosamide, and perampanel).The authors found that CNB's daily economically justifiable price of EUR 7.30 is cost-effective for a threshold of EUR 21,000/quality-adjusted life-years.Thus, CNB can produce more health per invested euro.Calleja et al., suggested that CNB therapy can produce an incremental clinical benefit over third-generation ASMs [102].
Laskier et al., estimated the cost-effectiveness of add-on CNB in the UK when used to treat drug-resistant focal seizures in adults.They found that CNB led to cost savings of GBP 51,967 (compared to brivaracetam), GBP 21,080 (compared to eslicarbazepine), GBP 33,619 (compared to lacosamide), and GBP 28,296 (compared to perampanel).They also found an increased cost per quality-adjusted life-year of 1.047 (compared to brivaracetam), 0.598 (compared to eslicarbazepine), 0.776 (compared to lacosamide), and 0.703 (compared to perampanel) per individual over a lifetime time horizon.Therefore, CNB is less costly and more effective when compared to brivaracetam, eslicarbazepine acetate, lacosamide, and perampanel [103].
Villanueva et al., assessed the clinical benefit regarding the number needed to treat (NNT), efficiency, and cost per NNT (CNT) associated with CNB versus third-generation ASMs used in Spain for the adjunctive treatment of focal-onset seizures in patients with DRE.CNB was the ASM associated with the lowest values of NNT at all doses for both fifty-percent responder rate and seizure freedom compared with the alternatives.Also, CNB was the ASM associated with the lowest CNT values at the daily defined dose (DDD) and minimum lacosamide and maximum eslicarbazepine acetate dose for fifty-percent responder rate.Moreover, the maximum dose of CNB was associated with the lowest CNT value at DDD and the minimum dose of lacosamide for seizure freedom [104].

Neuroprotective Potential of Cenobamate
In 2010 (Tenth Eilat Conference on New Antiepileptic Drugs) and 2013 (Eleventh Eilat Conference on New Antiepileptic Drugs), Bialer et al., reported that CNB showed neuroprotective abilities in the hypoxia-induced lethality mice model [105].In this context, Wici ński et al., performed a review of the literature about the neuroprotective effects of CNB.They believe that the pharmacodynamics of CNB may confer excellent neuroprotective properties [106].
There are five main pathways to explain the neuroprotective effect of CNB.First, CNB may inhibit depolarization and signal propagation by blocking voltage-gated sodium channels [107].This can be further enhanced by positive allosteric modulation of GABAA receptors, leading to chloride efflux and hyperpolarizing the membrane [108].Third, CNB, through GABAA receptors, can activate the PI3K/Akt pathway, which, when phosphorylated, can modulate gene transcription and decrease protein degradation, promoting cell survival and self-renewal [109].Fourth, the inhibition of depolarization can prevent voltagegated calcium activation, which does not allow glutamate release in the synaptic cleft and, consequently, excitotoxicity [110].Fifth, the widespread blockade of persistent sodium currents through voltage-gated sodium channels prevents the increased depolarization and activity of central nervous system neurons [106].

Cognition and Cenobamate
Sodium channels play an essential role in dendritic sodium spike generation, related to the Hebbian long-term potentiation of excitatory synaptic transmission and cognitive function [111].Also, dysfunctional GABAergic activity in the pre-frontal cortex may lead to working memory and cognitive impairments [112].
A low rate of cognitive and psychiatric treatment-emergent adverse events was observed during adjunctive CNB treatment in clinical trials.Song et al., studied the effects of CNB on cognitive behaviors and hippocampal long-term potentiation in mice.The authors showed that CNB influenced novel object recognition, object location memory, and Morris water maze performance in mice.Also, CNB suppressed hippocampal excitatory synaptic transmission by reducing the excitability of Schaffer collaterals and interfered with the induction of long-term potentiation [113].Therefore, CNB can potentially affect cognitive function in animal models of epilepsy, but there was no report in the clinical trials.

Electrocardiographic Abnormalities Associated with Cenobamate
Patients treated with CNB may experience a shortening of the QT interval, and this new agent is contraindicated in patients with familial short QT syndrome because of the increased risk of ventricular dysrhythmias and sudden death [75].A dose-dependent QT-interval shortening was observed with CNB.In studies with healthy subjects, the CNB dose of 200 mg/day was associated with QT-interval shortening of more than 20 ms in 33% of the individuals.However, when the dose of CNB was increased to 500 mg/day, 66% of the subjects developed electrocardiographic abnormalities [114].Concurrent use with other drugs that shorten the QT interval (for example, lamotrigine and rufinamide) should be closely monitored.Darpo et al., performed a QT study to assess the effects of therapeutic and supratherapeutic CNB doses (maximum recommended dose, 400 mg/day) on correct QT interval (QTc) in healthy adults.The authors found that CNB had no clinically relevant effects on heart rate or electrocardiographic parameters and no QTc-prolonging effect at therapeutic/supratherapeutic doses [75].

Hepatotoxicity Secondary to Cenobamate
CNB was associated with a low-to-moderate rate of serum aminotransferase elevations during therapy in less than five percent of individuals.The hepatotoxic side effect was usually observed with hypersensitivity reactions such as drug reactions with eosinophilia and systemic symptoms (DRESS) [115].
In a study with 953 CNB users, three presented DRESS and abnormal serum liver enzymes within six weeks of CNB therapy onset [116].However, there were no reports of serum aminotransferase elevations in a larger sample with an adequate titration period [62].
Felbamate is a carbamate anticonvulsant, as is CNB.Felbamate has also already been associated with hepatotoxicity.The black box warning about felbamate has a warning regarding the risk for acute liver failure and that felbamate should only be started in patients with normal liver function [117].Thus, hepatotoxic side effects in the carbamate class can occur.However, there is only a slight association between hepatotoxicity and CNB.
Interestingly, the CNB titration protocol should be cautiously followed because it shows fewer total side effects, including DRESS.Krauss et al., revealed that DRESS syndrome was seen only with a relatively rapid initial titration period [61].The management of CNB-induced DRESS is discontinuing CNB and prescribing corticosteroid therapy and antihistamines [60].
Another important fact regarding CNB prescription is the introduction of this drug in patients already taking another voltage-gated sodium channel blocker.Therefore, a slower titration of CNB is advised, especially in individuals with other voltage-gated sodium channel blocker therapies, as well as stepwise tapering of the previously ineffective agent when starting CNB.This may increase tolerability and reduce the risk of treatment failure due to adverse events [118].

Cenobamate-Induced Movement Disorders
Sáenz-Farret et al., reviewed the literature on movement disorders secondary to antiseizure medications.They found one manuscript of CNZ-induced tremor [119].In a randomized controlled trial of adjunctive CNB in patients with uncontrolled focal seizures, tremor was reported by seven (6.2%) CNB users and by three (2.8%) individuals in the placebo group.A detailed description of phenomenology or localization was not provided [60].In this context, felbamate was reported with akathisia, chorea, and dystonia [120].It is worth mentioning that due to structural similarities between these two medications, these abnormal movements could also be seen with CNB.
A pathophysiological explanation for the development of abnormal movements can be indirectly related to GABAergic neurotransmission.Therefore, case reports of dystonia and tremor will probably be observed in the future, as reported with other ASMs, such as pregabalin [121] and valproate [122].

Pregnancy and Lactation
There are no data regarding the developmental risk associated with using CNB in pregnant women [123].Also, data are unavailable on the presence of CNB in human milk, its effects on breastfed infants, or its effects on milk production [124].However, the administration of CNB in animal studies during pregnancy or throughout lactation significantly increased the risk of developmental abnormalities, such as increased embryofetal mortality, decreased fetal and offspring body weights, and neurobehavioral and reproductive impairment in offspring [53].In a systematic review of breastfeeding while on treatment with antiseizure medications, the authors did not find reports of CNB levels in breastmilk or breastfed infants [125].
CNB may decrease the plasma concentration of oral contraceptives.Therefore, women of reproductive age using oral contraceptives should use dual protection, which can be accomplished by consistently using male/female condoms [54].

Potential for Abuse and Suicidality Risk
CNB is scheduled for class 5 by the Drug Enforcement Administration (DEA).Class 5 is characterized by medications with the least potential for abuse of controlled substances.The ASMs developed before 2006 were standardly classified as class 5 [126].This scheduling is based on the adverse effects observed in clinical studies with debatable applicability to patients with epilepsy.DEA scheduling has significant drawbacks, such as apprehension by patients in using a medication related to addiction, low storage of the medication by pharmacies, and patients with epilepsy being unable to refill prescriptions until they have used up their existing pills.These factors probably affected access to CNB and led some individuals to discontinue or even avoid this medication [127].Noteworthily, the discontinuation of CNB should be performed gradually to reduce the risk of withdrawal syndrome and increased seizure frequency.
The allosteric modulation of GABAA receptors by CNB occurs at a site independent of the benzodiazepine binding site.So, the risk of inducing dependence, withdrawal symptoms, and tolerance is lower with CNB than with benzodiazepines [50].CNB's potential for abuse and dependence was observed in animal models, which has been further assessed with studies using alprazolam and placebo as comparators.In this single-dose, randomized, double-blind, placebo-controlled crossover study (YKP3089C024), CNB's abuse potential profile was significantly lower than that of alprazolam.Euphoric mood was observed in 2% of placebo, 19% of alprazolam 1.5 mg, 17.4% of alprazolam 3 mg, 0% of CNB 200 mg, and 18% of CNB 400 mg patients [32].
Most ASMs have a class of warning by the U.S. Food and Drug Administration for increased suicidality risk (suicidal ideation and behavior).This is based on a retrospective meta-analysis of randomized clinical trials of eleven ASMs approved between 1990 and 2007, comparing suicidality in patients treated with ASMs and placebo [126].Klein et al., recently reviewed all randomized, placebo-controlled phase 2 and 3 studies of new ASMs to compare suicidality rates between patients treated with ASMs and with placebo to determine whether these agents are associated with increased risk for suicidality.There was no evidence of increased risk of suicidal ideation (ASMs and placebo overall risk ratio, 0.75; 95% CI, 0.35-1.60)or attempt (risk ratio, 0.75; 95% CI, 0.30-1.87)overall or for any individual drug.The authors found no current evidence that CNB and other ASMs (eslicarbazepine, perampanel, brivaracetam, and cannabidiol) increase suicidality in epilepsy and merit a suicidality class warning [128].

Expert Recommendations
For instance, it is evident that, similarly to lamotrigine, the risk of allergic and immunologic adverse events can be markedly reduced by a very cautious and slow titration [129].A more gradual titration schedule was developed to reduce the incidence of side effects associated with CNB.This schedule was investigated in Study CO21.CNB dosing approved by the U.S. Food and Drug Administration protocol is shown below (Table 7).
Patients should be advised against engaging in activities requiring mental alertness, such as operating vehicles or machinery, until the response to CNB has been determined during the titration phase.Concomitant use with other central nervous system depressants or alcoholic beverages may have additive sedative side effects, which should be advised.Also, patients should be monitored for the emergence or worsening of depression and/or any unusual changes in mood or behavior, as well as suicidal thoughts or behavior [130].Moreover, it is worth remembering that individuals with DRE usually take many other ASMs, and there is a significant risk of interactions (Figure 4).
To prevent pharmacodynamic adverse events, decreasing the baseline medication as early as possible during the titration of CNB is helpful so that such side effects due to interactions can be avoided and individual adherence is improved.It may also be helpful to measure the plasma levels of the concomitant medication to assess the individual course closely.
mg once daily Observation: Cenobamate maximum dosage recommended is 400 mg once daily.Above cenobamate 250 once daily, there is a significant incidence of side effects.a https://www.xcopri.com(accessed on 30 May 2023).
Patients should be advised against engaging in activities requiring mental alertness, such as operating vehicles or machinery, until the response to CNB has been determined during the titration phase.Concomitant use with other central nervous system depressants or alcoholic beverages may have additive sedative side effects, which should be advised.Also, patients should be monitored for the emergence or worsening of depression and/or any unusual changes in mood or behavior, as well as suicidal thoughts or behavior [130].Moreover, it is worth remembering that individuals with DRE usually take many other ASMs, and there is a significant risk of interactions (Figure 4).[131].A summary of the main takeaway points is provided in Table 8.

Elderly
Individuals should be monitored for central nervous system and cognitive adverse events and monitored carefully for potential drug-drug interactions.
Woman of child-bearing age Women who are actively seeking to become pregnant or who are pregnant should consider a different ASM.
Who is not a candidate for CNB therapy?
Patients who require an immediate effect from an ASM.Also, individuals with a history of DRESS or severe hypersensitivity reactions to other drugs.
What is the target CNB dose?
CNB 200 mg/day should be the initial target dose.But, initial signs of efficacy have been reported early in the titration period.
When should the pill be taken?Dose at bedtime to alleviate adverse events.

Counseling patients about common adverse effects
Advise the patients to inform their provider if adverse effects occur.Adverse effects include somnolence (dose-dependent), dizziness (dose-dependent), fatigue (dose-dependent), diplopia (dose-dependent), headache, and nausea.
Adjusting concomitant ASM This will depend on the dose/concentration of the ASM and the dose of CNB.

Future Perspectives
DRE commonly requires polytherapy.But, clinicians have scarce guidance on how to approach polytherapy for epilepsy.So, a systematic evaluation of the possibilities for polytherapy in the treatment of uncontrolled seizures should be performed.CNB revealed significant efficacy for these refractory cases.Therefore, studies with CNB as monotherapy and polytherapy should be continuously performed.
Another important aspect to evaluate in future studies is the CNB spectrum of action.CNB should be assessed in generalized epilepsy, specific epilepsy syndromes, and even other comorbidities.Since the other alkyl carbamate derivatives demonstrated efficacy for managing anxiety and neuropathic pain, it is possible that CNB could also be efficacious in treating these conditions.Moreover, special patient groups such as infants, children, elderly, and patients with epilepsy and other comorbid conditions should be included in the coming clinical trials.CNB non-linear kinetics may cause more-than-proportional drug concentrations at high doses with frequent possible intolerable neurological adverse effects.Further studies are required to better-characterize pharmacokinetic and pharmacodynamics interactions with co-administered medications and the relationships between plasma CNB concentrations and clinical effects.
Continuing safety data with open-label trials are recommended through drug surveillance activities during routine clinical use.The need for a slow titration is still a significant drawback of CNB for the management of patients with status epilepticus, episodes of cluster seizures, and acute repetitive seizures.Therefore, further studies with fast titration or even developing an acute formulation with similar features should be developed.
Network meta-analysis showed significant superiority of CNB when compared with other third-generation ASMs.Head-to-head trials with different ASMs should be performed to support these findings.Moreover, the clinical databases with CNB trials should be assessed for highly efficacious combinations of ASMs.It would be important to highlight some clinical findings or even genetic features leading to good outcomes with CNB therapy.
In Study CO17, people with epilepsy taking only one ASM were included.In this way, some specialists believe that a higher proportion of less-severe epilepsy was included in this pivotal trial.Another discussed point in CO13 and CO17 was the relatively short titration and maintenance phases.The individuals with epilepsy in these trials reached a steadystate concentration within ten days.Thus, the interpretation of short-term adjunctive trials is challenging and sensitivity analyses for differences in baseline seizure frequency would have been beneficial in these trials.

Conclusions
CNB is a highly effective drug in managing focal onset seizures, with more than twenty percent of individuals with DRE achieving seizure freedom.This finding is remarkable for the antiseizure medication literature and combines with the approval for marketing after the impressive efficacy data of the phase 2 trials.The CNB mechanism of action is still poorly understood, but it is associated with transient and persistent sodium currents and GABAA receptors.In animal studies, CNB showed sustained efficacy and potency in the 6 Hz test regardless of the stimulus intensity.CNB was revealed to be the most cost-effective drug among different third-generation ASMs.However, there are still concerns regarding the potential for abuse and suicidality risk, which future studies should clearly assess, and protocols should be changed.The major drawback of CNB therapy is the slow and complex titration and maintenance phases preventing the wide use of this new agent in clinical practice.

Figure 4 .
Figure 4. Effects of cenobamate (CNB) on drug levels of antiseizure medications (ASMs).For ASMs whose metabolism can be increased by CNB, consider increasing the dose of the ASM.For ASMs whose metabolism can be decreased by CNB, consider reducing the dose of the ASM.

Table 1 .
Antiseizure potencies of alkyl-carbamates in mouse and rat models by Löscher et al. [33] adapted by Rissardo et al. a,b .

Table 1 .
Antiseizure potencies of alkyl-carbamates in mouse and rat models by Löscher et al. [33] adapted by Rissardo et al. a,b .

Table 2 .
Pharmacological properties of cenobamate a .
The objective of this expanded access program is to continue providing treatment with CNB to patients with focal epilepsy that were enrolled in the SK Life Science Inc clinical trials Abbreviations: CNB: cenobamate; CYP: cytochromes P450; DRE: drug-resistant epilepsy; PPR: photoparoxismalelectroencephalogram response (PPR) model.

Table 5 .
Cont.Treatment-resistant (≥3 seizures per month) despite treatment with one to three ASMs.b Seizures despite treatment with at least one ASM within the past two years and taking stable doses of one to three concomitant ASMs.
Abbreviations: ASM: antiseizure medication; CNB: cenobamate; DB: double-blind; DR: dose-response; DRE: drug-resistant epilepsy; EEG: electroencephalogram; FBM: felbamate; FDA: U.S. Food and Drug Administration; ITT: intention-to-treat; m-ITT: modified intention-to-treat; mITT-M = modified intention-to-treat-maintenance phase; NA: not available/not reported; OLE: open-label extension; PB: phenobarbital; PHT: phenytoin; R: randomized; TEAE: treatment-emergent adverse event; VGB: vigabatrin.a c Initial starting dose of 100 mg/day with a faster titration schedule of 100 mg increments weekly was amended to an initial starting dose of 50 mg/day with a slower up-titration after a blinded review of the first nine patients.d Based on seizure frequency per 28 days.e Responder rate defined as ≥50% reduction in seizure frequency.* Significant at 0.05 level.

Table 7 .
Cenobamate dosing approved according to U.S. Food and Drug Administration protocol a.Steinhoff et al., provided practical guidance for managing adults receiving adjunctive CNB to treat focal epilepsy Observation: Cenobamate maximum dosage recommended is 400 mg once daily.Above cenobamate 250 once daily, there is a significant incidence of side effects.a https://www.xcopri.com(accessed on 30 May 2023).

Table 8 .
Takeaways by Steinhoff et al. [131] adapted by Rissardo et al.Who is a candidate for CNB treatment?Any adults with uncontrolled focal onset seizures.