Physiologically Based Pharmacokinetic Modeling of Lacosamide in Patients With Hepatic and Renal Impairment and Pediatric Populations to Support Pediatric Dosing Optimization.

PURPOSE: Lacosamide (LCM) is a new-generation anti-seizure medication that is efficacious in patients with focal seizures with or without secondary generalization. Until now, the efficacy, safety, and tolerability of LCM are still lacking in Chinese epilepsy patients, particularly for pediatric populations and patients with renal or hepatic impairment. METHODS: This study was conducted to develop a physiologically based pharmacokinetic (PBPK) model to characterize the pharmacokinetics of LCM in Chinese populations and predict the pharmacokinetics of LCM in Chinese pediatric populations and patients with renal or hepatic impairment. Using data from clinical investigations, the developed PBPK model was validated by comparing predicted and observed blood concentration data. FINDINGS: Doses should be reduced to approximately 82%, 75%, 63%, and 76% of the Chinese healthy adult dose in patients with mild, moderate, and severe renal impairment and end-stage renal disease; and approximately 89%, 72%, and 36% of the Chinese healthy adult dose in patients with Child Pugh-A, B, and C hepatic impairment. For pediatric populations, intravenous doses should be adjusted to 1.75 mg/kg for newborns, 2.5 mg/kg for toddlers, 2.2 mg/kg mg for preschool and school age, and 2 mg/kg mg for adolescents to achieve an equivalent plasma exposure of 2 mg/kg LCM in adults. The oral doses should be adjusted to 20 mg for toddlers, 32 mg for preschool, 45 mg for school age, and 95 mg for adolescents to achieve an approximately equivalent plasma exposure of 100 mg LCM in adults. IMPLICATIONS: The PBPK model of LCM can be utilized to optimize dosage regimens for special populations.

Pitfalls of using video-EEG for a trial endpoint in children aged <4 years with focal seizures.

OBJECTIVE: Double-blind, randomized, and placebo-controlled trial SP0967 (NCT02477839/2013-000717-20) did not demonstrate superior efficacy of lacosamide versus placebo in patients aged ≥1 month to <4 years with uncontrolled focal seizures, per ≤72 h video-electroencephalogram (video-EEG)-based primary endpoints (reduction in average daily frequency of focal seizures at end-of-maintenance [EOM] versus end-of-baseline [EOB], patients with ≥50% response). This was unexpected because randomized controlled trial SP0969 (NCT01921205) showed efficacy of lacosamide in patients aged ≥4 to <17 years with uncontrolled focal seizures. SP0969's primary endpoint was based on seizure diary instead of video-EEG, an issue with the latter being inter-reader variability. We evaluated inter-reader agreement in video-EEG interpretation in SP0967, which to our knowledge, are the first such data for very young children with focal seizures from a placebo-controlled trial. METHODS: Local investigator and central reader agreement in video-EEG interpretation was analyzed post hoc. RESULTS: Analysis included 105 EOB and 98 EOM video-EEGs. Local investigators and central reader showed poor agreement based on ≥2 focal seizures at EOB (Kappa = 0.01), and fair agreement based on ≥2 focal seizures at EOM (Kappa = 0.23). Local investigator and central reader seizure count interpretations varied substantially, particularly for focal seizures, but also primary generalized and unclassified epileptic seizures, at both timepoints. INTERPRETATION: High inter-reader variability and low inter-reader reliability of the interpretation of seizure types and counts prevent confident conclusion regarding the lack of efficacy of lacosamide in this population. We recommend studies in very young children do not employ video-EEGs exclusively for accurate study inclusion or as an efficacy measure.

Efficacy and tolerability of adjunctive lacosamide in patients aged <4 years with focal seizures.

OBJECTIVE: Primary objective was to evaluate efficacy of lacosamide administered concomitantly with 1-3 antiseizure medications in young children with uncontrolled focal (partial-onset) seizures. METHODS: Double-blind, parallel-group trial (SP0967: NCT02477839/2013-000717-20) conducted between June 2015 and May 2020 at hospitals and clinics in 25 countries. Patients (aged ≥1 month to <4 years) with uncontrolled focal seizures were randomized 1:1 to adjunctive lacosamide or placebo using an interactive voice/web response system and stratified by age. After a 20-day titration period, patients who reached target-dose range (8-12 mg/kg/day) entered a 7-day maintenance period. Region-specific primary efficacy variables were based on ≤72-h video-electroencephalograms: change in average daily frequency (ADF) of electrographic focal seizures as measured on end-of-maintenance video-electroencephalogram versus end-of-baseline video-electroencephalogram (United States); 50% responder rate (≥50% reduction in ADF of focal seizures) during maintenance (European Union). RESULTS: In total, 255 patients were randomized (lacosamide/placebo: 128/127) and received ≥1 trial medication dose. Percentage reduction in ADF of focal seizures for lacosamide (116 patients) versus placebo (120 patients) was 3.2% (95% confidence interval = -13.6 to 17.5, p = 0.69). 50% responder rate was 41.4% for lacosamide (116 patients), 37.5% for placebo (120 patients) (p = 0.58). Treatment-emergent adverse events were reported by 44.5% of lacosamide-treated patients (placebo 51.2%). INTERPRETATION: Adjunctive lacosamide did not show superior efficacy versus placebo in young children with focal seizures. However, efficacy variables were potentially affected by high variability and low reliability between readers in video-electroencephalogram interpretation. Lacosamide was generally well tolerated; safety profile was acceptable and consistent with that in adults and children aged ≥4 years.

Efficacy and Tolerability of Adjunctive Brivaracetam in Patients with Focal-Onset Seizures on Specific Concomitant Antiseizure Medications: Pooled Analysis of Double-Blind, Placebo-Controlled Trials.

INTRODUCTION: This article aimed to assess the efficacy and tolerability of adjunctive brivaracetam (BRV) in adults with focal-onset seizures on specific concomitant antiseizure medications (ASMs) taken as part of their treatment regimen. METHODS: This was a post hoc analysis of pooled data from double-blind, placebo-controlled trials (N01252/NCT00490035, N01253/NCT00464269, and N01358/NCT01261325) in patients with uncontrolled focal-onset seizures randomized to BRV (50-200 mg/day) or placebo on the most common concomitant ASMs at trial initiation. RESULTS: Nine concomitant ASMs were analyzed: carbamazepine (CBZ), lamotrigine (LTG), valproate (VPA), oxcarbazepine (OXC), topiramate (TPM), phenytoin (PHT), lacosamide (LCM), clobazam (CLB), and phenobarbital (PHB). Reduction over placebo in focal-onset seizure frequency per 28 days with BRV ranged from 11.7% (concomitant OXC) to 33.5% (concomitant PHB). The median percentage reduction from baseline in focal-onset seizure frequency per 28 days ranged from 25.5% to 42.8% in patients on BRV (placebo 4.4-21.2%); 50% responder rates ranged from 31.9% to 44.9% in patients on BRV (placebo 11.4-25.2%). In patients on BRV, seizure freedom ranged from 1.4% (concomitant PHT) to 12.5% (concomitant LCM); seizure freedom ranged from 0% to 1.2% in patients on placebo. All efficacy endpoints analyzed were consistently numerically higher in patients on BRV versus placebo. The overall incidence of treatment-emergent adverse events (TEAEs) was generally similar across subgroups by specific concomitant ASMs in patients on BRV (range 60.8-74.5%) or placebo (range 53.8-66.7%). Drug-related TEAEs were numerically higher across all subgroups by concomitant ASM in patients on BRV (range 35.2-48.3%) versus placebo (range 23.9-37.1%). Discontinuations due to TEAEs ranged from 2.9% to 13.3% in patients on BRV and was 0-5.7% for patients taking placebo across subgroups. CONCLUSION: BRV was efficacious and well tolerated regardless of the specific concomitant ASMs used as part of their treatment regimen. These data show that in patients with focal-onset seizures, BRV provides additional efficacy to a broad range of ASMs.

Case 321: Leigh Syndrome.

HISTORY: A 9-month-old preterm male infant born at 33 weeks gestation presented with a 2-month history of developmental decline. The parents reported that over the past several months, they noted regression of milestones, where the infant stopped smiling, crying, expressing himself, or making eye contact. The parents also reported that the infant had multiple seizures during which he would wake up stiff and stare into space for 10-20 seconds while his lips would become blue. The parents were referred to a neurologist, where physical examination was notable for hypotonia. Electroencephalography (EEG) revealed frequent bilateral parietal epileptiform discharges. The patient was subsequently started on lacosamide. The patient's medical history was notable for abnormally low citrulline levels at birth, with negative results of urea cycle disorder testing at the time, along with left inguinal hernia repair performed 3 months ago. More recent laboratory analysis had shown persistently elevated serum lactate and alanine levels. There was no history of travel, recent infection, or vaccine administration. MRI of the brain with spectroscopy was performed for further evaluation.

Greater need for treatment optimization in patients with epilepsy initiating adjunctive therapy: Results of a retrospective claims analysis of antiseizure medication drug load in the United States.

BACKGROUND: This retrospective, observational study used US claims data to assess changes in antiseizure medication (ASM) drug load for a cohort of patients with epilepsy. METHODS: Adults (≥18 years) with a diagnosis of epilepsy (ICD-10 code G40.xxx) who started new adjunctive ASM treatment with one of 4 branded (brivaracetam, eslicarbazepine, lacosamide, perampanel) or 4 unbranded (carbamazepine, lamotrigine, levetiracetam, topiramate) ASMs between January 1, 2016 and December 31, 2020 were identified from IBM MarketScan® research databases (primary study population). Patients must have been continuously enrolled 360 days before the start of the new ASM (eligibility period). Follow-up was from the start of new ASM until Day 540 (∼18 months). The primary endpoint was concomitant ASM drug load, which included all ASMs except the new (comparator) ASM. A sensitivity analysis population included adults with epilepsy who were continuously enrolled for ≥ 180 days during at least one calendar year in the study period (2016-2020), whether or not the comparator ASM was new or existing during that period. Total ASM drug load, which included comparator ASM and concomitant ASMs, was assessed in the sensitivity analysis population. RESULTS: In total, 21,332 patients were included in the primary study population, of which 5767 initiated branded ASMs and 15,565 initiated unbranded ASMs. A total of 392,426 patients were included in the sensitivity analysis population during at least one calendar year 2016-2020. Concomitant ASM drug load increased in the 360 days prior to new ASM start and slightly declined thereafter. Mean concomitant ASM drug load for the primary population was 1.6 (SD 1.8) at new ASM start. Concomitant drug load was higher among those starting branded ASM comparators compared to those starting unbranded comparators. Mean total ASM drug load for patients increased over time and was approximately double for patients exposed to branded ASMs (mean range 2.1 to 2.7) compared to that of patients exposed to any unbranded ASM (mean range 1.0 to 1.3). CONCLUSION: Concomitant ASM drug load increased prior to addition of new ASM, with higher increases observed among patients starting branded vs unbranded ASMs, followed by slight decreases thereafter. Total drug load increased linearly among all patients. These findings underscore the need for ongoing ASM regimen evaluation and treatment optimization in patients with epilepsy.

How to handle a missed or delayed dose of lacosamide in pediatric patients with epilepsy? a mode-informed individual dosing.

This study aims to investigate the effects on the pharmacokinetic (PK) of lacosamide (LCM), and to guide the individual dosing regimens for children and ones with poor medication adherence. Population PK research was performed based on 164 plasma samples of 113 pediatric patients aged from 1.75 to 14.42 years old. The PK characteristic of LCM was developed by a one-compartment model with first-order elimination. The typical value of apparent clearance (CL) and apparent volume of distribution (Vd) was 1.91 L·h-1 and 56.53 L respectively. In the final model, the variability of CL was significantly associated with the body surface area (BSA) and elevated uric acid (UA) level. In contrast, the impact of some prevalent anti-seizure medicines, such as valproic acid, levetiracetam, oxcarbazepine, lamotrigine, and perampanel, and gene polymorphisms of Cytochrome P450 (CYP)2C19, ATP-binding cassette (ABC)B1, and ABCC2 had no clinical significance on the PK parameters of LCM. BSA-based dosing regimen of LCM was provided according to Monte Carlo simulation approach; while the dosage should reduce half in patients with an UA level of more than 400 µmol·L-1 comparing with an UA level of 100 µmol·L-1. Individualize remedial doses of about 0.5- to 1.5-fold of regular doses were recommended in six common scenarios of missed or delayed doses, that depended on the delayed time. In current study, the population PK model of LCM in children with epilepsy was developed successfully. The BSA-based dosing regimen and individualized remedial strategy were recommended to guarantee the precise administration of LCM.

Use of lacosamide for focal epilepsy in a child with kidney failure undergoing peritoneal dialysis.

BACKGROUND: Lacosamide (LCM) has become commonly used for focal onset seizures due to its high tolerability and low drug interactions. Unlike patients on hemodialysis (HD), pharmacokinetic data and dosing recommendations for patients undergoing peritoneal dialysis (PD) are scant. CASE REPORT: A 2-year-old girl with end-stage kidney disease undergoing PD suffered prolonged focal onset seizures. The patient had congenital anomalies of the kidney and urinary tract associated with branchio-oto-renal syndrome due to an EYA1 gene mutation. She also had neurological sequelae from post-resuscitation encephalopathy at the age of one month. Antiseizure medication with few drug interactions, less impact on the neurodevelopmental state and possibility of intravenous administration was preferred. LCM met those criteria and was carefully administered. Although the patient had recurrent prolonged seizures during the titration periods, LCM could be continued without any apparent side effects. The blood levels of LCM increased linearly to the optimal level. We confirmed excretion of LCM in the PD fluid. Kidney transplantation was done three months after and her seizures were well controlled. CONCLUSIONS: LCM might be a promising option for patients undergoing PD. Due to the lower removal efficacy in PD compared with in HD, close attention should be paid to possible drug excess.

Therapeutic monitoring of lacosamide, perampanel, and zonisamide during breastfeeding.

OBJECTIVE: To provide additional information on the transport of the new anti-seizure medications lacosamide, perampanel, and zonisamide in breast milk and breastfed infants. METHODS: Between 2013 and 2022, concentrations of anti-seizure medications were measured in six women with epilepsy (each drug in two patients) using high-performance liquid chromatography. Additionally, concentrations were determined after two consecutive pregnancies in women receiving lacosamide and one woman receiving zonisamide. In all cases, anti-seizure medication concentrations were measured in the maternal serum and breast milk, and five cases, in the infant serum. RESULTS: For lacosamide, the ratios of breast milk/maternal serum concentration varied between 0.77 and 0.93, the ratios of infant/maternal serum concentrations were 0.16 and 0.35, and the ratios of infant serum/milk concentrations were 0.21 and 0.38. For perampanel, the ratios of breast milk/maternal serum concentration were 0.01 and 0.10 and the ratio of infant/maternal serum concentration was 0.36. For zonisamide, the ratios of breast milk/maternal serum concentration varied between 0.76 and 1.26, the ratios of infant/maternal serum concentrations between 0.44 and 0.85, and the ratios of infant serum/milk concentrations between 0.55 and 1.05. CONCLUSIONS: Breastfeeding is recommended for women using lacosamide, perampanel, and zonisamide. However, the actual exposure can only be accurately evaluated by determining the serum concentration of anti-seizure medication in breastfed infants.

Clinical characteristics of acute lacosamide poisoning: Pavia Poison Control Centre experience.

AIMS: Lacosamide is a third-generation antiepileptic drug used as adjunctive therapy for partial seizures. Since its approval in 2008 very few cases of lacosamide overdose have been described in literature. The aim of our study was to evaluate clinical characteristics of acute lacosamide poisoning. METHODS: A retrospective observational study was performed including all cases of acute lacosamide poisoning referred to Pavia Poison Control Centre from January 2012 to December 2021. For each patient age, sex, ingested dose, coingestants, clinical manifestations, treatment and outcome were collected. RESULTS: A total of 31 subjects (median age 39 years, [interquartile range: 26.5-46.5]; females 22/31) were included. The median lacosamide ingested dose was 1500 mg [650-2800]. In 35.5% of cases lacosamide was the single ingested substance, while in 64.5% coingestants were also present. Coingestants varied from a minimum of 1 to a maximum of 3, with the more common being benzodiazepines and valproic acid. Clinical manifestations were present in 87% patients the most common were: vomiting (29%); seizures (29%), coma (25.8%), drowsiness (25.8%), confusion (12.9%), agitation (12.9%), tachycardia (12.9%), tremors (9.7%), bradycardia (9.7%), headache (6.5%) and hypertension (3.2%). The median lacosamide ingested dose was significantly higher in patients that experienced coma compared to patient who did not (2800 vs. 800 mg; P = .0082). Orotracheal intubation was necessary in 32.3% of patients. All patients fully recovered. CONCLUSION: Lacosamide acute overdose may lead to a severe clinical picture. Dentral nervous system symptoms predominated, particularly seizures and coma occurred in a high percentage of cases.

Efficacy of Lacosamide and Rufinamide as Adjuncts to Midazolam-Ketamine Treatment Against Cholinergic-Induced Status Epilepticus in Rats.

Benzodiazepine pharmacoresistance develops when treatment of status epilepticus (SE) is delayed. This response may result from gamma-aminobutyric acid A receptors (GABAAR) internalization that follows prolonged SE; this receptor trafficking results in fewer GABAAR in the synapse to restore inhibition. Increase in synaptic N-methyl-D-aspartate receptors (NMDAR) also occurs in rodent models of SE. Lacosamide, a third-generation antiseizure medication (ASM), acts on the slow inactivation of voltage-gated sodium channels. Another ASM, rufinamide, similarly acts on sodium channels by extending the duration of time spent in the inactivation stage. Combination therapy of the benzodiazepine midazolam, NMDAR antagonist ketamine, and ASMs lacosamide (or rufinamide) was investigated for efficacy against soman (GD)-induced SE and neuropathology. Adult male rats implanted with telemetry transmitters for monitoring electroencephalographic (EEG) activity were exposed to a seizure-inducing dose of GD and treated with an admix of atropine sulfate and HI-6 1 minute later and with midazolam monotherapy or combination therapy 40 minutes after EEG seizure onset. Rats were monitored continuously for seizure activity for two weeks, after which brains were processed for assessment of neurodegeneration, neuronal loss, and neuroinflammatory responses. Simultaneous administration of midazolam, ketamine, and lacosamide (or rufinamide) was more protective against GD-induced SE compared with midazolam monotherapy. In general, lacosamide triple therapy had more positive outcomes on measures of epileptogenesis, EEG power integral, and the number of brain regions protected from neuropathology compared with rats treated with rufinamide triple therapy. Overall, both drugs were well tolerated in these combination models. SIGNIFICANCE STATEMENT: We currently report on improved efficacy of antiseizure medications lacosamide and rufinamide, each administered in combination with ketamine (NMDAR antagonist) and midazolam (benzodiazepine), in combatting soman (GD)-induced seizure, epileptogenesis, and brain pathology over that provided by midazolam monotherapy, or dual therapy of midazolam and lacosamide (or rufinamide) in rats. Administration of lacosamide as adjunct to midazolam and ketamine was particularly effective against GD-induced toxicity. However, protection was incomplete, suggesting the need for further study.

Imperatorin interacts additively with novel antiseizure medications in the mouse maximal electroshock-induced seizure model: an isobolographic transformation.

BACKGROUND: Anticonvulsant effects of imperatorin (IMP) have been experimentally confirmed earlier, but no information is available on the interaction profiles of this naturally occurring coumarin when combined with novel antiseizure medication (ASMs). This study aimed to determine the effects of IMP on the anticonvulsant effects of lacosamide (LCM), oxcarbazepine (OXC), pregabalin (PGB), and topiramate (TPM) in the maximal electroshock-induced seizure (MES) model in mice. METHODS: The anticonvulsant effects exerted by novel ASMs (LCM, OXC, PGB, and TPM) when combined with constant doses of IMP (25 and 50 mg/kg) underwent isobolographic transformation to precisely classify the observed interactions in the mouse MES model. Total brain concentrations of ASMs were measured with high-pressure liquid chromatography to exclude the pharmacokinetic nature of interactions among IMP and the tested ASMs. RESULTS: IMP (50 mg/kg) significantly enhanced (p < 0.01) the anticonvulsant potency of LCM, OXC, PGB, and TPM in the mouse MES model. IMP (25 mg/kg) mildly potentiated the anticonvulsant action of LCM, OXC, PGB, and TPM, but no statistical significance was reported for these combinations. The isobolographic transformation of data from the MES test revealed that the interactions of novel ASMs with IMP were additive. Moreover, IMP (50 mg/kg) did not affect the total brain content of any of the novel ASMs in experimental mice. CONCLUSIONS: The additive interactions of IMP with LCM, OXC, PGB, and TPM in the mouse MES model accompanied by no pharmacokinetic changes in the total brain content of ASMs are worthy of recommendation for further studies.

A real-world comparison among third-generation antiseizure medications: Results from the COMPARE study.

OBJECTIVE: There are few comparative data on the third-generation antiseizure medications (ASMs). We aimed to assess and compare the effectiveness of brivaracetam (BRV), eslicarbazepine acetate (ESL), lacosamide (LCM), and perampanel (PER) in people with epilepsy (PWE). Efficacy and tolerability were compared as secondary objectives. METHODS: This multicenter, retrospective study collected data from 22 Italian neurology/epilepsy centers. All adult PWE who started add-on treatment with one of the studied ASMs between January 2018 and October 2021 were included. Retention rate was established as effectiveness measure and described using Kaplan-Meier curves and the best fitting survival model. The responder status and the occurrence of adverse events (AEs) were used to evaluate efficacy and safety, respectively. The odds of AEs and drug efficacy were estimated by two multilevel logistic models. RESULTS: A total of 960 patients (52.92% females, median age = 43 years) met the inclusion criteria. They mainly suffered from structural epilepsy (52.29%) with monthly (46.2%) focal seizures (69.58%). Compared with LCM, all the studied ASMs had a higher dropout risk, statistically significant in the BRV levetiracetam (LEV)-naïve (hazard ratio [HR] = 1.97, 95% confidence interval [CI] = 1.17-3.29) and PER groups (HR = 1.64, 95% CI = 1.06-2.55). Women were at higher risk of discontinuing ESL (HR = 5.33, 95% CI = 1.71-16.61), as well as PER-treated patients with unknown epilepsy etiology versus those with structural etiology (HR = 1.74, 95% CI = 1.05-2.88). BRV with prior LEV therapy showed lower odds of efficacy (odds ratio [OR] = .08, 95% CI = .01-.48) versus LCM, whereas a higher efficacy was observed in women treated with BRV and LEV-naïve (OR = 10.32, 95% CI = 1.55-68.78) versus men. PER (OR = 6.93, 95% CI = 3.32-14.44) and BRV in LEV-naïve patients (OR = 6.80, 95% CI = 2.64-17.52) had a higher chance of AEs than LCM. SIGNIFICANCE: Comparative evidence from real-world studies may help clinicians to tailor treatments according to patients' demographic and clinical characteristics.

Value of drug level concentrations of brivaracetam, lacosamide, and perampanel in care of people with epilepsy.

OBJECTIVE: The aim of this study was to determine whether clinical efficacy and reported adverse effects (AEs) of the newer antiseizure medications (ASMs) brivaracetam (BRV), lacosamide (LCM), and perampanel (PER) have been associated with plasma levels of these ASMs. We also investigated whether plasma levels outside the reference range has led to dose adjustments. METHODS: Plasma levels of 300 people with epilepsy (PWE) seen at our tertiary epilepsy center were determined by liquid chromatography-tandem mass spectrometry. PWE received BRV (n = 100), LCM (n = 100), or PER (n = 100), in most cases in polytherapy. Demographic and clinical data were retrospectively analyzed and related to plasma levels. Clinical efficacy of BRV, LCM, or PER was assessed retrospectively by comparing seizure frequency at the time of current blood draw with seizure frequency at the time of first administration. AEs were also recorded and, if reported, compared retrospectively with the time of first administration. RESULTS: No significant associations were found between plasma levels of BRV, LCM, or PER and seizure freedom (BRV, p = 1.000; LCM, p = .243; PER, p = .113) or responder status (BRV, p = .118; LCM, p = .478; PER, p = .069) at presentation. There was also no pattern between plasma levels and the occurrence of AEs. In the majority of cases, drug levels outside the reference ranges have not led to adjustments in the daily doses of BRV (93.5%), LCM (93.9%), or PER (89.1%). SIGNIFICANCE: Plasma levels at a given time point did not allow conclusions to be drawn about seizure control or the occurrence of AEs. Our findings indicate that efficacy and tolerability cannot be predicted based on averaged data from a single plasma measurement due to high interindividual variability. Instead, individual reference values should be established when sufficient clinical data are available, in line with the 2008 International League Against Epilepsy position paper on therapeutic drug monitoring.

The effect of lacosamide in peripheral neuropathic pain: A randomized, double-blind, placebo-controlled, phenotype-stratified trial.

BACKGROUND: Neuropathic pain is common and difficult to treat. The sodium channel blocker lacosamide is efficacious in animal models of pain, but its effect on neuropathic pain in humans is inconclusive. METHODS: In a multicentre, randomized, double-blinded placebo-controlled phenotype stratified trial, we examined if lacosamide produced better pain relief in patients with the irritable nociceptor phenotype compared to those without. The primary outcome was the change in daily average pain from baseline to last week of 12 weeks of treatment. Secondary and tertiary outcomes included pain relief, patient global impression of change and presence of 30% and 50% pain reduction. RESULTS: The study was prematurely closed with 93 patients included and 63 randomized to lacosamide or placebo in a 2:1 ratio, of which 49 fulfilled the per protocol criteria and was used for the primary objective. We did not find a better effect of lacosamide in patients with the irritable nociceptor phenotype, the 95% CI for the primary objective was 0.41 (-1.2 to 2.0). For all patients randomized, lacosamide had no effect on the primary outcome, but significantly more patients were responders to lacosamide than during placebo, with an NNT of 4.0 (95% CI 2.3-16.1) and 5.0 (95% CI 2.8-24.5) for 30% and 50% pain reduction respectively. We did not identify any predictors for response. Lacosamide was generally well tolerated. CONCLUSION: We could not confirm that lacosamide was more efficacious in patients with the irritable nociceptor type, but the study was prematurely closed, so we cannot exclude a small difference. SIGNIFICANCE: Treatment of neuropathic pain is often a trial and error process. Little is known about which patient benefit from which kind of medication. The sodium channel blocker lacosamide shows variable effect on neuropathic pain. Pain sensory phenotype, as defined by quantitative sensory testing, did not predict response to treatment with lacosamide.

Neonatal Cardiac Arrest Following Lacosamide Treatment: A Case Report.

BACKGROUND: Lacosamide is an antiepileptic drug with US Food and Drug Administration approval for the treatment of partial-onset seizures in patients older than one month. Lacosamide works by selective enhancement of proteins that induce preferential slow promotion of sodium channels to the hyperpolarized inactive state. Lacosamide is generally well-tolerated; however, clinical and nonclinical studies have linked its use with cardiac side effects including PR prolongation and atrioventricular (AV) block. RESULTS: We present the case of a three-week-old female neonatal patient born at 25 weeks' gestation who developed second-degree AV heart block and cardiac arrest after initiating lacosamide therapy. The patient was being treated for neonatal seizure complicated by intraventricular hemorrhage (grade II) and electrolyte disturbances with phenobarbital, levetiracetam, and phenytoin. Before addition of lacosamide therapy, the patient had an unremarkable electrocardiogram and no known cardiac risk factors for lacosamide. After medication discontinuation, the patient experienced no reoccurring episodes or other cardiac events. CONCLUSION: Use of lacosamide for neonatal populations is currently under evaluation. This is the first report of adverse cardiac event (AV block) in the setting of neonatal lacosamide use. Risk of future adverse cardiac events should be evaluated when determining the safety and efficacy of lacosamide in the neonatal population.

Trends and Differences in Status Epilepticus Treatment of Children and Adults Over 10 Years: A Comparative Study of Medical Records (2012-2021) from a University Hospital in Germany.

BACKGROUND AND OBJECTIVES: Over the last decade, significant advancements have been made in status epilepticus (SE) management, influenced by landmark trials such as ESETT and RAMPART. The objectives of this study were to explore the evolution of drug treatments for patients with SE, to investigate its association with outcomes and mortality, and to evaluate differences in treatment patterns between adults and children for a potential shift in medication trends due to the above mentioned trials. METHODS: The medical records of patients with SE treated at University Hospital Frankfurt between 2012 and 2021 were evaluated for medication trends and outcomes. Children and adults were analyzed separately and jointly. RESULTS: This study included 1151 SE episodes in 1021 patients (mean age = 53.3 ± 28.3 years; 52.5 % female [n = 533]). The overall percentage of patients with SE treated prehospital was stable over the last decade. More than half (53.6 %) of children were treated prehospital, compared with less than one-third (26.7 %) of adults. Prehospital midazolam use increased over time, while diazepam use decreased. Lorazepam was the most commonly used benzodiazepine in hospitals in 2012-2013, used in 40.8 % of all episodes. However, its use declined to 27.2 % in 2020-2021, while midazolam use increased to 44.0 %. While the use of older antiseizure medications (ASMs) such as phenobarbital (p = 0.02), phenytoin (p < 0.001), and valproate (p < 0.001) decreased, the use of newer ASMs such as levetiracetam and lacosamide significantly increased (p < 0.001). Propofol and continuous midazolam infusion remained the most used third-line therapy drugs. Overall mortality was 16.5 % at discharge and 18.9 % at 30 days. Mortality rates did not change between 2012 and 2021. CONCLUSION: Midazolam has become the preferred benzodiazepine in pre- and in-hospital settings, both in children and adults. The same applies to the increased use of levetiracetam and lacosamide over time in children and adults, while phenobarbital, phenytoin, and valproate use decreased. Continuous midazolam infusion and propofol remain the most frequently used anesthetic drugs. Mortality and outcome remain stable despite changes in medication patterns.

Differential Pharmacokinetic Interplay of Atorvastatin on Lacosamide and Levetiracetam on Experimental Convulsions in Mice.

BACKGROUND: The beneficial effects of statins, other than their hypocholesterolemia role, have been well documented, however, their use as an adjuvant drug with other antiseizure drugs, in the treatment of epilepsy is poorly understood. OBJECTIVE: This study aimed to investigate the symbiotic effect of ATOR along with either lacosamide (LACO) or levetiracetam (LEVE) on experimentally induced epilepsy (Maximal electro-shock-MES or pentylenetetrazol- PTZ) in mice models. METHODS: Conventional elevated-maze (EPM) and rotarod methods were performed to observe the behavioral effects. RESULTS: In both the animal models, we found that co-administration of ATOR along with LACO showed a significant reduction in hind-limb extension (HLE) and clonic convulsion (CC) responses, respectively, but not in the ATOR+LEVE treated group. Intriguingly, comparable Straub tail response and myoclonic convulsion as the diazepam (DIA) group were observed only in the ATOR+LACO treated group. Moreover, a significant muscle-grip strength was observed in both groups. Also, pharmacokinetic analysis has indicated that the mean plasma concentration of ATOR peaked at 2nd hr in the presence of LACO but marginally peaked in the presence of LEVE. An Insilico study has revealed that ATOR has a higher binding affinity toward neuronal sodium channels. CONCLUSION: This study has demonstrated that the plasma concentration of ATOR was potentiated in the presence of LACO, but not in the presence of LEVE and it has provided significant protection against both the electro and chemo-convulsive models in mice. This could be due to the symbiotic pharmacokinetic interplay of ATOR with LACO, and possibly, this interplay may interfere with sodium channel conductance.