Pharmacogenetics to prevent hypersensitivity reactions to antiepileptic drugs: is testing performed when indicated?

Extensive scientific evidence consistently demonstrates the clinical validity and utility of HLA-B*15:02 pre-screening in averting severe cutaneous adverse reactions (SCARs), namely Stevens-Johnson syndrome and toxic epidermal necrolysis, associated with carbamazepine or oxcarbazepine usage. Current practice guidelines and drug labeling actively advocate for pharmacogenetic pre-screening before initiating these antiepileptic drugs (AED), with particular emphasis on patients of Asian descent. However, there is a potential need to strengthen compliance with these recommendations. This retrospective study aimed to describe the pharmacogenetic pre-screening, documentation, and SCARs incidence for patients of Asian ancestry initiated on carbamazepine or oxcarbazepine at a large Northeastern USA healthcare system. Between 1 July 2016 and August 1, 2021, 27 patients with documented Asian heritage in the electronic health record (EHR) were included. The overall rate of HLA-B*15:02 pre-screening before carbamazepine or oxcarbazepine initiation was 4%. None who underwent pharmacogenetic pre-screening carried the associated HLA-B risk allele, and no SCARs were reported. Notably, pharmacogenetic results were not discretely entered into the EHR, and the results were only found as attached documents in the miscellaneous section of the EHR. There remains a significant opportunity for improving HLA-B*15:02 pre-screening for patients starting carbamazepine and oxcarbazepine to prevent SCARs in the USA.

Comparative Safety of Antiseizure Medication Monotherapy for Major Malformations.

OBJECTIVE: This study was undertaken to examine the comparative safety of antiseizure medication (ASM) monotherapy in pregnancy with respect to risk of major congenital malformations (MCMs), overall and by MCM subtype. METHODS: We conducted a population-based cohort study using national health register data from Denmark, Finland, Iceland, Norway, and Sweden (1996-2020). We compared pregnancies with first trimester exposure to lamotrigine monotherapy to ASM-unexposed, carbamazepine, valproate, oxcarbazepine, levetiracetam, and topiramate to lamotrigine monotherapy, and stratified monotherapy groups by dose. The outcome was nongenetic MCM and specific subtypes. We estimated adjusted risk ratios (aRRs) and 95% confidence intervals (CIs) with log-binomial regression and propensity score weights. RESULTS: There was a higher crude risk of any MCM in pregnancies exposed to lamotrigine monotherapy (n = 8,339) compared to ASM-unexposed pregnancies (n = 4,866,362), but not after confounder adjustment (aRR = 0.97, 95% CI = 0.87-1.08). Compared to lamotrigine, there was an increased risk of malformations associated with valproate (n = 2,031, aRR = 2.05, 95% CI = 1.70-2.46) and topiramate (n = 509, aRR = 1.81, 95% CI = 1.26-2.60), which increased in a dose-dependent manner. We found no differences in malformation risk for carbamazepine (n = 2,674, aRR = 0.91, 95% CI = 0.72-1.15), oxcarbazepine (n = 1,313, aRR = 1.09, 95% CI = 0.83-1.44), or levetiracetam (n = 1,040, aRR = 0.78, 95% CI = 0.53-1.13). Valproate was associated with several malformation subtypes, including nervous system, cardiac, oral clefts, clubfoot, and hypospadias, whereas lamotrigine and carbamazepine were not. INTERPRETATION: Topiramate is associated with an increased risk of MCM similar to that associated with valproate, but lower doses may mitigate the risks for both drugs. Conversely, we found no increased risks for lamotrigine, carbamazepine, oxcarbazepine, or levetiracetam, which is reassuring. ANN NEUROL 2023;93:551-562.

Efficacy of oral sodium chloride in reducing the incidence of hyponatremia in children with epilepsy receiving oxcarbazepine monotherapy: A randomized controlled trial (SCHO Trial).

INTRODUCTION: Hyponatremia is a well-documented adverse effect of oxcarbazepine treatment, but no clinical trial has yet been conducted to explore any intervention for reducing the incidence of hyponatremia. MATERIALS AND METHODS: This open-label trial evaluated the efficacy of add-on daily oral sodium chloride supplementation of 1-2 g/day for 12 weeks in reducing the incidence of hyponatremia in children receiving oxcarbazepine monotherapy aged 1-18 years. Apart from comparing the incidence of symptomatic and severe hyponatremia, serum and urine sodium levels, serum and urine osmolality, changes in behavior and cognition, and the number of participants with recurrence of seizures and requiring additional antiseizure medication (ASM) were also compared. RESULTS: A total of 120 children (60 in each group) were enrolled. The serum sodium level at 12 weeks in the intervention group was higher than that of the control group (136.5 ± 2.6 vs 135.4 ± 2.5 mEq/L, p = 0.01). The number of patients with hyponatremia was significantly lower in the intervention group (4/60vs14/60, p = 0.01). However, the incidence of symptomatic and severe hyponatremia (0/60vs1/60, p = 0.67 for both), changes in social quotient and child behavior checklist total score (0.6 ± 0.8 vs 0.7 ± 0.5, p = 0.41 and 0.9 ± 1.2 vs 1.1 ± 0.9, p = 0.30 respectively), the number of patients with breakthrough seizures (9/60vs10/60, p = 0.89), and the number of patients requiring additional ASMs (8/60vs10/60, p = 0.79) were comparable in both groups. CONCLUSIONS: Daily oral sodium chloride supplementation is safe and efficacious in reducing the incidence of hyponatremia in children with epilepsy receiving oxcarbazepine monotherapy. However, sodium chloride supplementation does not significantly reduce more clinically meaningful outcome measures like symptomatic and severe hyponatremia. Trial registry No. CTRI/2021/12/038388.

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.

Clinical study of the effect of 5 kinds of antiepileptic drugs on the postictal state.

OBJECTIVE: To compare the effects of levetiracetam（LEV）, lamotrigine(LTG), oxcarbazepine(OXC), topiramate(TPM) and valproate (VPA) on postictal state (PIS). METHODS: A total of 187 epilepsy patients undergoing monotherapy were enrolled in a long-term follow-up study at the Affiliated Hospital of Yangzhou College. This included 30 patients on levetiracetam, 41 on valproate, 30 on oxcarbazepine, 28 on topiramate, and 31 on lamotrigine. A control group of 28 newly diagnosed or previously untreated epilepsy patients was also included. The Liverpool Seizure Severity Scale 2.0 (LSSS2.0) and the Seizure Severity Questionnaire (SSQ) were utilized to evaluate the patients' condition, with comparison based on the results of the postictal status items. EEG during PIS termination was assessed using the Grand Total EEG score (GTE) as an objective tool to measure the impact of Antiseizure medications (ASMs) on the post-seizure state. RESULTS: The LSSS2.0 score indicated a statistically significant difference in post-seizure status score among the 5 groups (p < 0.05). The difference between the 5 groups and the control group was statistically significant (p < 0.05). Results of the SSQ demonstrated that all 5 drugs significantly reduced the post-seizure status score compared to the control group (p < 0.05). The GTE score revealed that, in the later stage of the seizure, the GTE score of the levetiracetam group, valproate group, oxcarbazepine group, and lamotrigine group significantly decreased compared to the control group (P < 0.05). There was no significant decrease in the GTE score in the topiramate group (P < 0.05). CONCLUSION: Levetiracetam, lamotrigine, oxcarbazepine, topiramate, and valproate demonstrate favorable efficacy in ameliorating the severity of post-seizure condition. Further investigations are warranted to assess the potential of other widely employed anti-seizure medications in enhancing post-seizure status.

Comparative analysis of adverse drug reactions associated with new antiseizure medications from the Korea Adverse Event Reporting System database.

OBJECTIVE: This study aimed to compare and characterize the safety profiles of new antiseizure medications (ASMs) using a nationwide pharmacovigilance database from a long-term perspective in Korea. METHODS: We reviewed adverse event reports from the Korea Adverse Event Reporting System database between January 2013 and December 2022 for descriptive analysis of six new ASMs (lacosamide, levetiracetam, lamotrigine, oxcarbazepine, topiramate, and zonisamide). We investigated the frequency and characteristics of adverse drug reactions (ADRs) based on the MedDRA terminology, system organ classes, and modified WHO classification. RESULTS: We identified 5,733 reported cases of ADRs. The commonly reported ADRs associated with total ASMs were rash/urticaria (1,822, 31.8 %), dizziness (409, 7.1 %), somnolence/drowsiness (311, 5.4 %), and hepatotoxic effects (273, 4.8 %). Type B (idiosyncratic) effects (2,932; 51.1 %) were more commonly reported than Type A (related to known drug mechanisms) effects (2,613; 45.6 %). Skin and subcutaneous tissue disorders and type B effects were most commonly reported for lamotrigine and oxcarbazepine, whereas nervous system disorders and type A effects were most commonly reported for lacosamide, topiramate, and zonisamide. The pediatric group (<18 years) exhibited skin and subcutaneous tissue disorders and type B effects relatively more frequently than the adult and older adult groups. CONCLUSION: Hypersensitivity skin reactions and type B effects remained significant ADRs in the new ASMs; however, type A effects were more commonly reported in some ASMs. The pediatric group showed a higher rate of type B effects. Overall, new ASMs should also be used with caution.

Intravenous Lidocaine Response as a Predictor for Oral Oxcarbazepine Efficacy in Neuropathic Pain Syndrome: A Prospective Cohort Study.

BACKGROUND Providing pain relief for patients with neuropathic pain syndrome (NPS) is difficult, as sodium-channel blockers pose serious adverse events (AEs). Intravenous (i.v.) lidocaine infusion responses may identify patients likely to benefit from oral sodium channel blockers. We evaluated i.v. lidocaine responses to predict oral oxcarbazepine (OXC) efficacy in patients with NPS. MATERIAL AND METHODS This prospective cohort study administered one-time 3 mg/kg i.v. lidocaine infusion to patients with NPS. Numeric rating scale (NRS) pain scores and AEs were observed. Next, OXC 150 mg was prescribed; dosages were increased by 150 mg every 3 days until ≥50% pain reduction or the maximum tolerable dose or 1800 mg/day was reached. NRS, rescue drug requirements, and AEs were evaluated by phone at 1, 3, and 5 weeks and clinic visits at 2, 4, and 6 weeks. Depression, Anxiety & Stress Scales 21 (DASS-21), and EuroQol-Five Dimensions-Five Levels (EQ-5D-5L) questionnaires were assessed at baseline and in week 6. RESULTS Of 46 patients, 14 discontinued due to intolerable AEs, and 32 were in the final analysis. Average post-intervention NRS significantly decreased from 6.8±1.7 (baseline) to 3.8±2.0 (lidocaine) and 4.1±2.3 (OXC); P<0.001. Negative and positive predictive values for OXC efficacy were 76.2% (95% CI: 61.6-86.5%) and 54.5% (95% CI: 32-75.4%), respectively. Six weeks after OXC treatment, 20 and 11 patients achieved ≥30% pain reduction and ≥50% pain relief, respectively. EQ-5D-5L (P=0.018) and DASS-21 stress dimension (P<0.001) significantly improved. CONCLUSIONS Negative responses to i.v. lidocaine predicted a lack of oral OXC response. AEs of OXC may have obscured an analgesic effect.

Chronic Treatment with Oxcarbazepine Attenuates Its Anticonvulsant Effect in the Maximal Electroshock Model in Mice.

The objective of this study was to assess the impact of acute and chronic treatment with oxcarbazepine on its anticonvulsant activity, neurological adverse effects, and protective index in mice. Oxcarbazepine was administered in four protocols: once or twice daily for one week (7 × 1 or 7 × 2) and once or twice daily for two weeks (14 × 1 or 14 × 2). A single dose of the drug was employed as a control. The anticonvulsant effect was evaluated in the maximal electroshock test in mice. Motor and long-term memory impairment were assessed using the chimney test and the passive avoidance task, respectively. The concentrations of oxcarbazepine in the brain and plasma were determined via high-performance liquid chromatography. Two weeks of oxcarbazepine treatment resulted in a significant reduction in the anticonvulsant (in the 14 × 1; 14 × 2 protocols) and neurotoxic (in the 14 × 2 schedule) effects of this drug. In contrast, the protective index for oxcarbazepine in the 14 × 2 protocol was found to be lower than that calculated for the control. No significant deficits in memory or motor coordination were observed following repeated administration of oxcarbazepine. The plasma and brain concentrations of this anticonvulsant were found to be significantly higher in the one-week protocols. Chronic treatment with oxcarbazepine may result in the development of tolerance to its anticonvulsant and neurotoxic effects, which appears to be dependent on pharmacodynamic mechanisms.

Polymorphism and Pharmacological Assessment of Carbamazepine.

This work provides insight into carbamazepine polymorphs (Forms I, II, III, IV, and V), with reports on the cytoprotective, exploratory, motor, CNS-depressant, and anticonvulsant properties of carbamazepine (CBZ), carbamazepine formulation (CBZ-F), topiramate (TOP), oxcarbazepine (OXC), and diazepam (DZP) in mice. Structural analysis highlighted the significant difference in molecular conformations, which directly influence the physicochemical properties; and density functional theory description provided indications about CBZ reactivity and stability. In addition to neuron viability assessment in vitro, animals were treated orally with vehicle 10 mL/kg, as well as CBZ, CBZ-F, TOP, OXC, and DZP at the dose of 5 mg/kg and exposed to open-field, rotarod, barbiturate sleep induction and pentylenetetrazol (PTZ 70 mg/kg)-induced seizure. The involvement of GABAergic mechanisms in the activity of these drugs was evaluated with the intraperitoneal pretreatment of flumazenil (2 mg/kg). The CBZ, CBZ-F, and TOP mildly preserved neuronal viability. The CBZ-F and the reference AEDs potentiated barbiturate sleep, altered motor activities, and attenuated PTZ-induced convulsion. However, flumazenil pretreatment blocked these effects. Additional preclinical assessments could further establish the promising utility of CBZ-F in clinical settings while expanding the scope of AED formulations and designs.

SCN1A gain-of-function mutation causing an early onset epileptic encephalopathy.

OBJECTIVE: Loss-of-function variants in SCN1A cause Dravet syndrome, the most common genetic developmental and epileptic encephalopathy (DEE). However, emerging evidence suggests separate entities of SCN1A-related disorders due to gain-of-function variants. Here, we aim to refine the clinical, genetic, and functional electrophysiological features of a recurrent p.R1636Q gain-of-function variant, identified in four individuals at a single center. METHODS: Individuals carrying the recurrent SCN1A p.R1636Q variant were identified through diagnostic testing. Whole cell voltage-clamp electrophysiological recording in HEK-293 T cells was performed to compare the properties of sodium channels containing wild-type Nav 1.1 or Nav 1.1-R1636Q along with both Nav ß1 and Nav ß2 subunits, including response to oxcarbazepine. To delineate differences from other SCN1A-related epilepsies, we analyzed electronic medical records. RESULTS: All four individuals had an early onset DEE characterized by focal tonic seizures and additional seizure types starting in the first few weeks of life. Electrophysiological analysis showed a mixed gain-of-function effect with normal current density, a leftward (hyperpolarized) shift of steady-state inactivation, and slower inactivation kinetics leading to a prominent late sodium current. The observed functional changes closely paralleled effects of pathogenic variants in SCN3A and SCN8A at corresponding positions. Both wild type and variant exhibited sensitivity to block by oxcarbazepine, partially correcting electrophysiological abnormalities of the SCN1A p.R1636Q variant. Clinically, a single individual responded to treatment with oxcarbazepine. Across 51 individuals with SCN1A-related epilepsies, those with the recurrent p.R1636Q variants had the earliest ages at onset. SIGNIFICANCE: The recurrent SCN1A p.R1636Q variant causes a clinical entity with a wider clinical spectrum than previously reported, characterized by neonatal onset epilepsy and absence of prominent movement disorder. Functional consequences of this variant lead to mixed loss and gain of function that is partially corrected by oxcarbazepine. The recurrent p.R1636Q variant represents one of the most common causes of early onset SCN1A-related epilepsies with separate treatment and prognosis implications.

Patterns of antiseizure medication utilization in the Human Epilepsy Project.

OBJECTIVE: This study was undertaken to ascertain the natural history and patterns of antiseizure medication (ASM) use in newly diagnosed focal epilepsy patients who were initially started on monotherapy. METHODS: The data were derived from the Human Epilepsy Project. Differences between the durations of the most commonly first prescribed ASM monotherapies were assessed using a Cox proportional hazards model. Subjects were classified into three groups: monotherapy, sequential monotherapy, and polytherapy. RESULTS: A total of 443 patients were included in the analysis, with a median age of 32 years (interquartile range [IQR] = 20-44) and median follow-up time of 3.2 years (IQR = 2.4-4.2); 161 (36.3%) patients remained on monotherapy with their initially prescribed ASM at the time of their last follow-up. The mean (SEM) and median (IQR) duration that patients stayed on monotherapy with their initial ASM was 2.1 (2.0-2.2) and 1.9 (.3-3.5) years, respectively. The most commonly prescribed initial ASM was levetiracetam (254, 57.3%), followed by lamotrigine (77, 17.4%), oxcarbazepine (38, 8.6%), and carbamazepine (24, 5.4%). Among those who did not remain on the initial monotherapy, 167 (59.2%) transitioned to another ASM as monotherapy (sequential monotherapy) and 115 (40.8%) ended up on polytherapy. Patients remained significantly longer on lamotrigine (mean = 2.8 years, median = 3.1 years) compared to levetiracetam (mean = 2.0 years, median = 1.5 years) as a first prescribed medication (hazard ratio = 1.5, 95% confidence interval = 1.0-2.2). As the study progressed, the proportion of patients on lamotrigine, carbamazepine, and oxcarbazepine as well as other sodium channel agents increased from a little more than one third (154, 34.8%) of patients to more than two thirds (303, 68.4%) of patients. SIGNIFICANCE: Slightly more than one third of focal epilepsy patients remain on monotherapy with their first prescribed ASM. Approximately three in five patients transition to monotherapy with another ASM, whereas approximately two in five end up on polytherapy. Patients remain on lamotrigine for a longer duration compared to levetiracetam when it is prescribed as the initial monotherapy.

Thermoresponsive Gel-loaded Oxcarbazepine Nanosystems for Nose- To-Brain Delivery: Enhanced Antiepileptic Activity in Rats.

BACKGROUND: Oxcarbazepine (OXC) is a frequently prescribed antiepileptic drug for managing focal and generalized seizures. Its therapeutic benefits are limited by its dose-dependent side effects. Nose-to-brain delivery is a novel route for improving the efficacy of antiepileptics. Drug encapsulation in mucoadhesive nanoparticles offers even more advantages for the nasal route. OBJECTIVE: The study aimed to develop oxcarbazepine-loaded chitosan nanoparticles (OXC-NP) added to a mucoadhesive thermo-reversible gel for intranasal delivery and enhancement of antiepileptic activity. METHODS: The formulation was optimized based on entrapment efficiency, polydispersity index, particle size, zeta potential, and in vitro release analysis. The therapeutic efficacy of OXC-NP was assessed in an epileptic rat model and compared to intranasal OXC and oral OXC. RESULTS: The optimized OXC-NPs with chitosan exhibited particle size, zeta potential, and entrapment efficiency of 189 nm, + 31.4 mV ± 2.5 and 97.6% ± 0.14, respectively. The release of OXC was prolonged, reaching 47.1% after 6 h and 55% after 24 h. Enhanced antiepileptic activity of OXC-NP was manifested as decreased seizure score and prolonged survival. Halting of hippocampal TNF-α and IL-6 together with upregulated IL-10 could explain its anti-inflammatory mechanisms. CONCLUSIONS: Intranasal OXC-NP-loaded in situ gel represents a promising formulation for enhanced antiepileptic potential achieved at low drug concentrations.

Trends in antiseizure medications utilization among women of childbearing age with epilepsy in Poland between 2015 and 2019.

PURPOSE: To determine trends in the use of antiseizure medications (ASMs) among women of childbearing age (WOCA) and girls aged 12-14 years with epilepsy between 2015 and 2019 in Poland. METHODS: The study used data from the Pex database, which captures information on prescriptions dispensed from 85% of community pharmacies in Poland. The prescriptions issued by neurologists who provide epilepsy care in Poland were studied. Six of the most commonly prescribed ASMs were analyzed: carbamazepine, lamotrigine, levetiracetam, oxcarbazepine, topiramate, and valproate. RESULTS: The use of valproate and carbamazepine decreased in all age groups. Among the newer ASMs, the use of lamotrigine, levetiracetam, and topiramate increased and oxcarbazepine decreased significantly in WOCA. The only subgroup with statistically significant changes in all ASMs prescriptions were women aged 19-34 years. For girls aged 12-14 years, significant changes were found only for valproate and carbamazepine. In the last year of observation (2019) valproate and lamotrigine accounted for two-thirds of ASMs units prescribed to WOCA. Valproate accounted for half of the prescribed drug units in girls aged 12-14 years. The lowest rates of VPA prescriptions were found in women aged 19-34 years. CONCLUSIONS: There is a change in prescribing habits in WOCA with epilepsy in Poland with trends toward using less teratogenic ASMs. However, many WOCAs are treated with valproate and topiramate despite their known teratogenicity risk. Valproate is still the most commonly prescribed ASM in WOCA and girls aged 12-14 years. Educational interventions for healthcare professionals are needed to improve prescribing practices in WOCA with epilepsy in Poland.

Population pharmacokinetics of topiramate in Chinese children with epilepsy.

OBJECTIVE: Topiramate, a broad-spectrum antiepileptic drug, exhibits substantial inter-individual variability in both its pharmacokinetics and therapeutic response. The aim of this study was to investigate the influence of patient characteristics and genetic variants on topiramate clearance using population pharmacokinetic (PPK) models in a cohort of Chinese pediatric patients with epilepsy. METHOD: The PPK model was constructed using a nonlinear mixed-effects modeling approach, utilizing a dataset comprising 236 plasma concentrations of topiramate obtained from 181 pediatric patients with epilepsy. A one-compartment model combined with a proportional residual model was employed to characterize the pharmacokinetics of topiramate. Covariate analysis was performed using forward addition and backward elimination to assess the influence of covariates on the model parameters. The model was thoroughly evaluated through goodness-of-fit analysis, bootstrap, visual predictive checks, and normalized prediction distribution errors. Monte Carlo simulations were utilized to devise topiramate dosing strategies. RESULT: In the final PPK models of topiramate, body weight, co-administration with oxcarbazepine, and a combined genotype of GKIR1-UGT (GRIK1 rs2832407, UGT2B7 rs7439366, and UGT1A1 rs4148324) were identified as significant covariates affecting the clearance (CL). The clearance was estimated using the formulas CL (L/h) = 0.44 × (BW/11.7)0.82 × eOXC for the model without genetic variants and CL (L/h) = 0.49 × (BW/11.7)0.81 × eOXC × eGRIK1-UGT for the model incorporating genetic variants. The volume of distribution (Vd) was estimated using the formulas Vd (L) = 6.6 × (BW/11.7). The precision of all estimated parameters was acceptable. Furthermore, the model demonstrated good predictability, exhibiting stability and effectiveness in describing the pharmacokinetics of topiramate. CONCLUSION: The clearance of topiramate in pediatric patients with epilepsy may be subject to the influence of factors such as body weight, co-administration with oxcarbazepine, and genetic polymorphism. In this study, PPK models were developed to better understand and account for these factors, thereby improving the precision and individualization of topiramate therapy in children with epilepsy.

Population pharmacokinetics of oxcarbazepine active metabolite in Chinese children with epilepsy.

Oxcarbazepine (OXC) is an antiepileptic drug whose efficacy is largely attributed to its monohydroxy derivative metabolite (MHD). Nevertheless, there exists significant inter-individual variability in both the pharmacokinetics and therapeutic response of this drug. The objective of this study is to explore the impact of patients' characteristics and genetic variants on MHD clearance in a population pharmacokinetic (PPK) model of Chinese pediatric patients with epilepsy. The PPK model was developed using a nonlinear mixed effects modeling method based on 231 MHD plasma concentrations obtained from 185 children with epilepsy. The one-compartment model and combined residual model were established to describe the pharmacokinetics of MHD. Forward addition and backward elimination were employed to evaluate the impact of covariates on the model parameters. The model was evaluated using goodness-of-fit, bootstrap, visual predictive checks, and normalized prediction distribution errors. In the two final PPK models, age, estimated glomerular filtration rate (eGFR), and a combined genotype of six variants (rs1045642, rs2032582, rs7668282, rs2396185, rs2304016, rs1128503) were found to significantly reduce inter-individual variability for MHD clearance. The inter-individual clearance equals to 1.38 × (Age/4.74)0.29 × (eGFR/128.66)0.25 × eθABCB-UGT-SCN-INSR for genetic variants included model and 1.30 × (Age/4.74)0.30 × (eGFR/128.66)0.23 for model without genetic variants. The precision of all parameters was deemed acceptable, and the model exhibited good predictability while remaining stable and effective.    Conclusion: Age, eGFR, and genotype may play a significant role in MHD clearance in children with epilepsy. The developed PPK models hold potential utility in facilitating oxcarbazepine dose adjustment in pediatric patients. What is Known: • The adjustment of the oxcarbazepine regimen remains difficult due to the considerable inter- and intra-individual variability of oxcarbazepine pharmacokinetics. • Body weight and co-administration with enzyme-inducing antiepileptic drugs emerge as the most influential factors contributing to the pharmacokinetics of MHD. What is New: • A positive correlation was observed between eGFR and the clearance of MHD in pediatric patients with epilepsy. • We explored the influence of genetic polymorphisms on MHD clearance and identified a combined genotype (ABCB-UGT-SCN-INSR) that exhibited a significant association with MHD concentration.

Validity of Serum Zinc/Copper Ratio as a Potential Novel Biomarker in Childhood Epilepsy.

BACKGROUND: Alterations in zinc and copper homeostasis may contribute to seizure susceptibility, development, termination, and response to antiepileptic medications. The current study examined the profile of zinc, copper, and their ratio in childhood epilepsy and its pharmacological variants (pharmacoresistant and pharmacoresponsive). METHODS: The study included 100 epileptic children (50 pharmacoresistant and 50 pharmacoresponsive) and 50 healthy, age- and gender-matched controls. History, clinical examination, and assays of serum zinc and copper were performed. Zinc/copper ratio was calculated. RESULTS: Serum zinc and the zinc/copper ratio were significantly lower in epileptic children than in controls (p < 0.001). Significantly lower zinc and zinc/copper ratio and higher copper levels were found in children treated with levetiracetam/sodium valproate/oxcarbazepine than those treated with levetiracetam alone or combined with sodium valproate (p < 0.05 for all). Epileptic children, particularly pharmacoresistant, exhibited significant negative correlations between the serum levels of zinc and copper (r = -0.279, p = 0.005, and r = -0.363 and p = 0.010, respectively). At cutoff value of zinc/copper ratio < 1.118 in diagnosing children with epilepsy, it gives a sensitivity of 64% and a specificity of 85% with the AUC = 0.8092. At cutoff value of zinc/copper ratio ≤ 0.7826 in distinguishing pharmacoresistant epilepsy, it produced 52% sensitivity, 64% specificity with AUC = 0.576 Conclusions: Low zinc and high copper levels were associated with childhood epilepsy especially those with pharmacoresistant type and treated with Oxcarbazepine. Zinc/copper ratio might be a potential biomarker in diagnosing childhood epilepsy and to some extent in predicting pharmacoresistant type.

Levetiracetam may be an unsuitable choice for patients with PRRT2-associated self-limited infantile epilepsy.

INTRODUCTION: Self-limited infantile epilepsy (SeLIE) is a benign epilepsy. Previous studies have shown that monotherapy with most antiseizure medications can effectively relieve seizures in patients with SeLIE, but the efficacy of levetiracetam has not been investigated. OBJECTIVE: This study aimed to investigate the efficacy of levetiracetam in the treatment of SeLIE patients with PRRT2 mutations. METHODS: The clinical data of 39 SeLIE patients (21 males and 18 females, aged 4.79 ± 1.60 months) with pathogenic variants in PRRT2 or 16p11.2 microdeletion were retrospectively analyzed. Based on the use of initial antiseizure medication (ASM), the patients were classified into two groups: Levetiracetam group (LEG) and Other ASMs group (OAG). The difference of efficacy between the two groups was compared. RESULTS: Among the 39 SeLIE patients, 16 were LEG (10 males and 6 females, aged 5.25 ± 2.07 months), with whom two obtained a seizure-free status (12.50%) and 14 ineffective or even deteriorated (87.50%). Among the 14 ineffective or deteriorated cases, 13 were seizure-controlled after replacing levetiracetam with other ASMs including topiramate, oxcarbazepine, lamotrigine, and valproate, and the remaining one finally achieved remission at age 3. Of the 39 patients, 23 were OAG (11 males and 12 females; aged 4.48 ± 1.12 months), of whom 22 achieved seizure remission, except for one patient who was ineffective with topiramate initially and relieved by oxcarbazepine instead. Although there were no significant differences in gender and age of onset between the two groups, the effective rate was significantly different (12.50% in LEG vs. 95.65% in OAG) (P < 0.01). CONCLUSION: The findings showed that patients with SeLIE caused by the PRRT2 mutations did not benefit from the use of levetiracetam, but could benefit from other ASMs.

Caffeine and Its Interactions with Antiseizure Medications-Is There a Correlation between Preclinical and Clinical Data?

Experimental studies reveal that caffeine (trimethylxanthine) at subconvulsive doses, distinctly reduced the anticonvulsant activity of numerous antiseizure medications (ASMs) in rodents, oxcarbazepine, tiagabine and lamotrigine being the exceptions. Clinical data based on low numbers of patients support the experimental results by showing that caffeine (ingested in high quantities) may sharply increase seizure frequency, considerably reducing the quality of patients' lives. In contrast, this obviously negative activity of caffeine was not found in clinical studies involving much higher numbers of patients. ASMs vulnerable to caffeine in experimental models of seizures encompass carbamazepine, phenobarbital, phenytoin, valproate, gabapentin, levetiracetam, pregabalin and topiramate. An inhibition of R-calcium channels by lamotrigine and oxcarbazepine may account for their resistance to the trimethylxanthine. This assumption, however, is complicated by the fact that topiramate also seems to be a blocker of R-calcium channels. A question arises why large clinical studies failed to confirm the results of experimental and case-report studies. A possibility exists that the proportion of patients taking ASMs resistant to caffeine may be significant and such patients may be sufficiently protected against the negative activity of caffeine.

Simple HPLC-UV Method for Therapeutic Drug Monitoring of 12 Antiepileptic Drugs and Their Main Metabolites in Human Plasma.

The objective of the present report was to develop and validate a simple, selective, and reproducible high-performance liquid chromatography method with UV detection suitable for routine therapeutic drug monitoring of the most commonly used antiepileptic drugs and some of their metabolites. Simple precipitation of plasma proteins with acetonitrile was used for sample preparation. 10,11-dihydrocarbamazepine was used as an internal standard. Chromatographic separation of the analytes was achieved by gradient elution on a Phenyl-Hexyl column at 40 °C, using methanol and potassium phosphate buffer (25 mM; pH 5.1) as a mobile phase. The method was validated according to the FDA guidelines for bioanalytical method validation. It showed to be selective, accurate, precise, and linear over the concentration ranges of 1-50 mg/L for phenobarbital, phenytoin, levetiracetam, rufinamide, zonisamide, and lacosamide; 0.5-50 mg/L for lamotrigine, primidone, carbamazepine and 10-monohydroxycarbazepine; 0.2-10 mg/L for carbamazepine metabolites: 10,11-trans-dihydroxy-10,11-dihydrocarbamazepine and carbamazepine-10,11-epoxide; 0.1-10 mg/L for oxcarbazepine; 2-100 mg/L for felbamate and 3-150 mg/L for ethosuximide. The suitability of the validated method for routine therapeutic drug monitoring was confirmed by quantification of the analytes in plasma samples from patients with epilepsy on combination antiepileptic therapy.

Theoretical insights into the degradation mechanisms, kinetics and eco-toxicity of oxcarbazepine initiated by OH radicals in aqueous environments.

As an anticonvulsant, oxcarbazepine (OXC) has attracted considerable attention for its potential threat to aquatic organisms. Density functional theory has been used to study the mechanisms and kinetics of OXC degradation initiated by OH radicals in aqueous environment. A total of fourteen OH-addition pathways were investigated, and the addition to the C8 position of the right benzene ring was the most vulnerable pathway, resulting in the intermediate IM8. The H-abstraction reactions initiated by OH radicals were also explored, where the extraction site of the methylene group (C14) on the seven-member carbon heterocyclic ring was found to be the optimal path. The calculations show that the total rate constant of OXC with OH radicals is 9.47 × 109 (mol/L)-1sec-1, and the half-life time is 7.32 s at 298 K with the [·OH] of 10-11 mol/L. Moreover, the branch ratio values revealed that OH-addition (89.58%) shows more advantageous than H-abstraction (10.42%). To further understand the potential eco-toxicity of OXC and its transformation products to aquatic organisms, acute toxicity and chronic toxicity were evaluated using ECOSAR software. The toxicity assessment revealed that most degradation products such as OXC-2OH, OXC-4OH, OXC-1O-1OOH, and OXC-1OH' are innoxious to fish and daphnia. Conversely, green algae are more sensitive to these compounds. This study can provide an extensive investigation into the degradation of OXC by OH radicals and enrich the understanding of the aquatic oxidation processes of pharmaceuticals and personal care products (PPCPs).