Reintroduction of oxcarbazepine after allergic reaction in two pediatric patients with epilepsy.

Allergic reactions are common reasons for withdrawal of oxcarbazepine treatment in patients with epilepsy. However, some patients are not responsive to other antiseizure medications. Herein, two pediatric patients with epilepsy and allergic to oxcarbazepine to whom oxcarbazepine therapy was successfully reintroduced are described. The reintroduction strategy used in this study was simple, feasible, and suitable for the reintroduction of oxcarbazepine in pediatric patients with epilepsy.

Population pharmacokinetics of oxcarbazepine: a systematic review.

INTRODUCTION: Oxcarbazepine is commonly used as first-line treatment for partial and generalized tonic-clonic seizures. Owing to the high pharmacokinetic variability, several population pharmacokinetic models have been developed for oxcarbazepine to explore potential covariates that affect its pharmacokinetic variation. AREAS COVERED: This review summarizes the published population pharmacokinetic studies of oxcarbazepine in children and adults available in PubMed and Embase databases. The quality of the retrieved studies was evaluated, and significant covariates that may have an impact on the dosage regimen of oxcarbazepine were explored. EXPERT OPINION: The pharmacokinetics of oxcarbazepine was founded to be affected by body weight and co-administration with enzyme inducers. Pediatric patients require a higher dose per kilogram than adults because children generally have a higher clearance than adults. Moreover, to maintain the target concentration, patients co-administrate with enzyme inducers need a higher dose than monotherapy due to higher clearance in those patients. Because limited information is available for exposure-response relationship, additional pharmacokinetic/pharmacodynamics investigations of oxcarbazepine need to be conducted to optimize the dosage regimen in clinical practice.

Population pharmacokinetic model development and its relationship with adverse events of oxcarbazepine in adult patients with epilepsy.

This study aimed to develop a pharmacokinetic (PK) model of oxcarbazepine (OXC) and analyse the relationship between monohydroxylated derivative (MHD), an active metabolite of OXC, and the adverse events of OXC. We obtained 711 OXC samples from 618 patients with epilepsy who were enrolled in the Epilepsy Registry Cohort of Seoul National University Hospital from February 2011 to January 2014. The plasma PK model was developed using a nonlinear mixed-effect modelling method with NONMEM (ver 7.3). A one-compartment model with a first-order absorption model and proportional residual error adequately described the MHD concentration-time profiles. The only covariate incorporated for CL/F and V/F was body weight. Of the 447 patients analysed, 28 (6.26%) had dose-related adverse events (DRAEs), which were dizziness, somnolence, headache, and diplopia. For DRAE occurrence, the cut-off values of the MHD trough and AUC were 12.27 mg/L (specificity 0.570, sensitivity 0.643) and 698.5 mg h/L (specificity, sensitivity 0.571), respectively. Multivariate analysis showed the sole dizziness symptom was significantly associated with both the MHD trough and the AUC (p = 0.013, p = 0.038, respectively). We newly developed a population PK model using sparse sampling data from patients with epilepsy, and the model better reflects the actual clinical situation.

Comparison of long-term efficacy, tolerability, and safety of oxcarbazepine, lamotrigine, and levetiracetam in patients with newly diagnosed focal epilepsy: An observational study in the real world.

OBJECTIVE: We performed observational cohort study to compare the long-term efficacy, tolerability, and safety of oxcarbazepine (OXC), lamotrigine (LTG), and levetiracetam (LEV) monotherapy for newly diagnosed focal epilepsy patients. METHODS: Three hundred and eighty eight newly diagnosed focal epilepsy patients aged 1-70 years were enrolled in this study between June 2009 and March 2016. Among the patients, 191 were treated with OXC, 98 were treated with LTG, and 99 were treated with LEV monotherapy. The study was performed in a real-world setting and the primary outcomes were the one-year and three-year seizure-free rates. The secondary outcomes were the one-year and three-year withdrawal rates, the time to treatment withdrawal, the time to the first seizure, and the time to achieve one-year remission. RESULTS: The three-year seizure-free rates with LTG (39.8 %) and LEV (41.4 %) were significantly better than that with OXC (26.2 %) (both P < 0.05). However, no significant difference was observed among the three drugs for the one-year seizure-free rate. The three-year withdrawal rate was 50.8 %, 46.9 %, and 43.4 % for OXC, LTG, and LEV, respectively (all P > 0.05). The one-year withdrawal rate for OXC (31.7 %) was higher than those for LTG (30.6 %) and LEV (26.3 %) (all P > 0.05). LEV [Relative Risk (RR) = 0.69, 95 % CI: 0.49∼0.99] and LTG (RR = 0.63, 95 % CI: 0.44∼0.9) were significantly better than OXC in preventing first seizure. LEV appears to be the superior option with regard to the time to achieve one-year remission. SIGNIFICANCE: The results of the study showed that LEV and LTG are significantly more effective than OXC for the treatment of newly diagnosed focal epilepsy. LEV has milder adverse events than OXC and LTG in clinical practice.

Influence of dose and antiepileptic comedication on brivaracetam serum concentrations in patients with epilepsy.

The aim of this study was to investigate the influence of concomitant antiepileptic drugs (AEDs) on brivaracetam (BRV) trough serum concentrations. A total number of 368 routinely collected blood samples from 148 inpatients from Mara Hospital (Bethel Epilepsy Center) and von Bodelschwingh Foundation Bethel were retrospectively evaluated. Generalized estimation equations (GEEs) were used for statistical analysis. GEE analyses showed that BRV trough serum concentrations were significantly lower in patients with strong enzyme-inducing AEDs (carbamazepine, phenytoin, and/or phenobarbital/primidone, -49%), but were not affected by concomitant intake of oxcarbazepine or eslicarbazepine. Age and gender did not have a significant effect. An alternative GEE model analyzing the BRV level-to-dose ratios yielded comparable results. Our results from routine therapeutic drug monitoring data indicate that the effect of enzyme-inducing AEDs on BRV serum concentrations is stronger than the 20%-30% reduction in BRV exposure previously reported in pharmacokinetics studies. Further research is necessary to evaluate these differences and to elucidate possible clinical consequences.

Post-treatment with oxcarbazepine confers potent neuroprotection against transient global cerebral ischemic injury by activating Nrf2 defense pathway.

Oxcarbazepine (OXC), a voltage-gated sodium channel blocker, is an antiepileptic medication and used for the bipolar disorders treatment. Some voltage-gated sodium channel blockers have been demonstrated to display strong neuroprotective properties in models of cerebral ischemia. However, neuroprotective effects and mechanisms of OXC have not yet been reported. Here, we investigated the protective effect of OXC and its mechanisms in the cornu ammonis 1 subfield (CA1) of gerbils subjected to 5 min of transient global cerebral ischemia (tGCI). tGCI led to death of most pyramidal neurons in CA1 at 5 days after ischemia. OXC (100 and 200 mg/kg) was intraperitoneally administered once at 30 min after tGCI. Treatment with 200 mg/kg, not 100 mg/kg OXC, significantly protected CA1 pyramidal neurons from tGCI-induced injury. OXC treatment significantly decreased superoxide anion production, 4-hydroxy-2-nonenal and 8-hydroxyguanine levels in ischemic CA1 pyramidal neurons. In addition, the treatment restored levels of superoxide dismutases, catalase, and glutathione peroxidase. Furthermore, the treatment distinctly inhibited tGCI-induced microglia activation and significantly reduced levels of pro-inflammatory cytokines (interleukin-1ß and tumor necrosis factor-α). In particular, OXC treatment significantly enhanced expressions of nuclear factor erythroid 2-related factor 2 (Nrf2) and its downstream protein heme oxygenase-1 in ischemic CA1. The neuroprotective effects of OXC were abolished by brusatol (an inhibitor of Nrf2). Taken together, these results indicate that post-treatment of OXC can display neuroprotection against brain injuries following ischemic insults. This neuroprotection may be displayed by attenuation of oxidative stress and neuroinflammation, which can be mediated by activation of Nrf2 pathway.

Complete loss of KCNA1 activity causes neonatal epileptic encephalopathy and dyskinesia.

BACKGROUND: Since 1994, over 50 families affected by the episodic ataxia type 1 disease spectrum have been described with mutations in KCNA1, encoding the voltage-gated K+ channel subunit Kv1.1. All of these mutations are either transmitted in an autosomal-dominant mode or found as de novo events. METHODS: A patient presenting with a severe combination of dyskinesia and neonatal epileptic encephalopathy was sequenced by whole-exome sequencing (WES). A candidate variant was tested using cellular assays and patch-clamp recordings. RESULTS: WES revealed a homozygous variant (p.Val368Leu) in KCNA1, involving a conserved residue in the pore domain, close to the selectivity signature sequence for K+ ions (TVGYG). Functional analysis showed that mutant protein alone failed to produce functional channels in homozygous state, while coexpression with wild-type produced no effects on K+ currents, similar to wild-type protein alone. Treatment with oxcarbazepine, a sodium channel blocker, proved effective in controlling seizures. CONCLUSION: This newly identified variant is the first to be reported to act in a recessive mode of inheritance in KCNA1. These findings serve as a cautionary tale for the diagnosis of channelopathies, in which an unreported phenotypic presentation or mode of inheritance for the variant of interest can hinder the identification of causative variants and adequate treatment choice.

Clinical features of patients with paroxysmal kinesigenic dyskinesia, mutation screening of PRRT2 and the effects of morning draughts of oxcarbazepine.

BACKGROUND: The objective of this study was to summarize clinical features and PRRT2 mutations of paediatric paroxysmal kinesigenic dyskinesia (PKD) patients and observe the tolerability and effects of morning draughts of oxcarbazepine. METHODS: Twenty patients diagnosed with PKD at Children's Hospital of Fudan University between January 2011 and December 2015 were enrolled. These patients' medical records were reviewed. Peripheral venous blood was obtained from all enrolled patients, and polymerase chain reaction (PCR) and Sanger sequencing were used to sequence proline-rich transmembrane protein 2 (PRRT2) gene mutations. Clinical features of PKD patients with and without PRRT2 mutations were compared. All enrolled patients were treated with morning draughts of oxcarbazepine (OXC). The starting dose was 5 mg/kg·d, and the dose was increased by 5 mg/kg·d each week until attacks stopped. Effective doses and adverse effects were recorded. RESULTS: For all enrolled patients, dyskinesia was triggered by sudden movement. Dyskinetic movement usually involved the limbs and was bilateral; the majority of enrolled patients exhibited both dystonia and choreoathetosis. We identified PRRT2 mutations in 5 patients, including 4 familial patients and 1 sporadic patient. All 20 patients took low doses of OXC (5-20 mg/kg·d) as draughts in the morning, and dyskinesia attacks stopped in 19 patients. CONCLUSIONS: Paediatric PKD patients have various phenotypes. PRRT2 mutations are common in familial cases. OXC taken as morning draughts can be a treatment option for paediatric PKD patients.

Novel SCN2A mutation in a family associated with juvenile-onset myoclonus: Case report.

RATIONALE: The phenotypic spectrum caused by SCN2A mutations includes benign neonatal/infantile seizures, Ohtahara syndrome, infantile spasms, West syndrome, and other unclassified epileptic phenotypes. Mutations in SCN2A have been implicated in neonatal seizure cases. Here, we described a Chinese family with 2 members having juvenile-onset myoclonus and identified a novel SCN2A point mutation within this family. PATIENT CONCERNS: The 21-year-old male proband suffered from frequent myoclonus at 11 years old with subsequent progressive ataxia. His elder maternal half-sister also experienced myoclonus. Genomic DNA of the patients was extracted from the peripheral blood cells of the proband, elder maternal half-sister, parents, and uncle of the proband. Targeted next-generation sequencing was used to screen gene mutations in the proband. The potential functional effects of mutations within SCN2A were predicted In silico analyses. DIAGNOSES: Genetic testing revealed a novel SCN2A variant, c.T4820C, which contains a highly conserved amino acid substitution within segment S5 (p.V1607A). This mutation was predicted to produce a dysfunctional Nav1.2 protein by Mutation Taster and Protein Variation Effect Analyzer (PROVEAN). Genotype-phenotype correlation showed an incomplete penetrance of p.V1607A. INTERVENTIONS: The proband was treated by multiple antiepileptic drugs. These included carbamazepine, oxcarbazepine, valproate, and topiramate. OUTCOMES: The duration of follow up was 2 years, and the proband developed drug-resistant epilepsy. LESSONS: The case gives us the lesson that SCN2A mutation can contribute to juvenile-onset myoclonus. Our findings extend the spectrums of SCN2A mutations and the clinical features of patients with SCN2A mutations.

Population pharmacokinetics and dose simulation of oxcarbazepine in Chinese paediatric patients with epilepsy.

WHAT IS KNOWN AND OBJECTIVES: Oxcarbazepine (OXC) is a widely used antiepileptic drug whose effect mainly depends on its active metabolite 10-hydroxycarbazepine (MHD). This study established a population pharmacokinetic (PPK) model of MHD in Chinese children with epilepsy and conducted a dosage simulation in order to provide support for individualized OXC treatment. METHODS: Ninety-one plasma sampling points from 88 paediatric patients were retrospective collected. MHD concentrations were detected, and patients' clinical data were recorded. PPK analysis was performed using a non-linear, mixed-effect modelling approach. The goodness-of-fit (GOF) plots, bootstrap method, prediction-corrected visual predictive check (pcVPC) and normalized prediction distribution errors (NPDE) were performed to evaluate the final model. External model validations by an independent group of paediatric patients (10 patients, 10 blood samples) were conducted. The steady-state trough concentrations of MHD were determined by Monte Carlo simulations for doses ranging from 8 to 60 mg/kg/day. RESULTS: A one-compartment model with first-order elimination successfully described the data. The typical values for MHD clearance (CL/F), distribution volume (V/F) and absorption rate constant (Ka) were 3.25 L/h/70 kg, 151.41 L/70 kg and 0.598 h-1 , respectively. The CL/F and V/F of MHD were related to body weight (WT) via an empirical allometric model. Internal and external validations demonstrated a good predictability of the final model. Monte Carlo simulations revealed that for most paediatric patients, a dosing regimen of 20-30 mg/kg/d bid maybe sufficient to reach MHD therapeutic range. WHAT IS NEW AND CONCLUSION: A PPK model of MHD in Chinese paediatric patients was successfully established. A priori dosing guideline was proposed considering WT and MHD plasma concentrations, providing a basis for OXC dosage calculations and adjustments in Chinese epileptic children.

Oxcarbazepine free or loaded PLGA nanoparticles as effective intranasal approach to control epileptic seizures in rodents.

The brain as a target for drug delivery is a challenge in pharmaceutical research. Among the several proposed strategies, the intranasal route represents a good strategy to deliver drugs to the brain. The goal of this study was to investigate the potential use of oxcarbazepine (OXC) to enhance brain targeting efficiency after intranasal (IN) administration. As well as attempting to use as low a dose as possible to obtain therapeutic effect. Our results showed that, after IN administrations, the dose of OXC that was effective in controlling epileptic seizures was 0.5 mg/kg (1 dose, every 20 min for 1 h) in rodents, confirmed by Cerebral Spinal Fluid (CSF) bioavailability. With the aim of reducing the number of administrations, sustaining drug release and increasing brain targeting, OXC was loaded into poly(lactide-co-glycolide) (PLGA) nanoparticles (NPs). The selected nanoformulation for in vivo studies was obtained re-suspending the freeze-dried and cryo-protected OXC loaded PLGA NPs. The translocation of 1-1'-Dioctadecyl-3,3,3',3'-tetramethylindotricarbocyanine Iodide loaded PLGA NPs, from nose to the brain, was confirmed by Fluorescence Molecular Tomography, which also evidenced an accumulation of NPs in the brain after repeated IN administrations. IN administrations of OXC loaded PLGA NPs reduced the number of administrations to 1 over 24 h compared to the free drug thus controlling seizures in rats. Immunohistochemical evaluations (anti-neurofilament, anti-beta tubulin, and anti-caspase3) demonstrated a neuroprotective effect of OXC PLGA NPs after 16 days of treatment. These encouraging results confirmed the possibility of developing a novel non-invasive nose to brain delivery system of OXC for the treatment of epilepsy.

Comparative effectiveness of add-on therapy with newer-generation antiepileptic drugs in Bulgarian patients with refractory epilepsy.

OBJECTIVES: The objective of this study is to perform an open, prospective study on various aspects of comparative effectiveness of newer-generation antiepileptic drugs as add-on therapy in Bulgarian patients with drug-resistant epilepsy. METHODS: The study was performed with the participation of 1259 patients with epilepsy who attended the Clinic of Neurology at the University Hospital in Plovdiv, Bulgaria for regular visits and completed diaries about seizure frequency, severity, and adverse events. RESULTS: Oxcarbazepine was used in 82 patients, topiramate in 120 patients, lamotrigine in 73 patients, levetiracetam in 135 patients, pregabalin in 47 patients, tiagabine in 43 patients, gabapentin in 18 patients, lacosamide in 12 patients, and retigabine in 6 patients. During the first 24 months of study, improvement of seizure severity and frequency was most frequent in patients on treatment with pregabalin and levetiracetam and rarest in those on treatment with oxcarbazepine. The retention rate of patients on pregabalin and tiagabine was significantly lower compared to the retention rate of patients on most of the other antiepileptic drugs. The frequency of adverse events was higher in patients on treatment with tiagabine and pregabalin. CONCLUSION: Despite some similar characteristics of newer-generation antiepileptic drugs' effectiveness, levetiracetam stands out with better dynamic improvement of seizure severity and frequency and satisfactory tolerability; typical for pregabalin is a very good dynamic improvement of seizure severity and frequency mainly in patients with focal seizures, but a lower tolerability, and the main advantage of oxcarbazepine is a good tolerability, efficacy, however, is less satisfactory.

Sustained viral suppression with co-administration of oxcarbazepine and dolutegravir.

Co-administration of dolutegravir and oxcarbazepine has been reported to reduce levels of dolutegravir and therefore is contraindicated due to insufficient data to make dosing recommendations. We present eight cases in which patients with human immunodeficiency virus (HIV) inadvertently received oxcarbazepine while concurrently receiving 50 mg of dolutegravir daily as part of their antiretroviral therapy. Upon further evaluation, lab results revealed that despite the risk of decreased levels of dolutegravir due to possible oxcarbazepine enzyme induction, patients maintained at or near virologic suppression (viral load <20 copies/ml). Suppression was maintained in patients virally suppressed prior to oxcarbazepine initiation as well as in patients receiving high doses of oxcarbazepine (>1200 mg). All patients self-reported complete adherence to oxcarbazepine and dolutegravir. Furthermore, careful review of additional patient medications suggested no other identifiable drug interactions that could have affected their antiretroviral therapy. This case series suggests that despite the well-documented drug interaction, concomitant administration of oxcarbazepine and dolutegravir in the clinical setting did not adversely affect viral suppression in patients with HIV.