Sodium Channels in Human Pain Disorders: Genetics and Pharmacogenomics.

Acute pain is adaptive, but chronic pain is a global challenge. Many chronic pain syndromes are peripheral in origin and reflect hyperactivity of peripheral pain-signaling neurons. Current treatments are ineffective or only partially effective and in some cases can be addictive, underscoring the need for better therapies. Molecular genetic studies have now linked multiple human pain disorders to voltage-gated sodium channels, including disorders characterized by insensitivity or reduced sensitivity to pain and others characterized by exaggerated pain in response to normally innocuous stimuli. Here, we review recent developments that have enhanced our understanding of pathophysiological mechanisms in human pain and advances in targeting sodium channels in peripheral neurons for the treatment of pain using novel and existing sodium channel blockers.

Unraveling the genetic link: an umbrella review on HLA-B*15:02 and antiepileptic drug-induced Stevens-Johnson syndrome/toxic epidermal necrolysis.

PURPOSE: This umbrella review was conducted to summarize the association between HLA*1502 allele with antiepileptic induced Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). METHODS: Pubmed, Scopus and EMBASE were searched for eligible reviews in May 2023. Two authors independently screened titles and abstracts and assessed full-text reviews for eligibility. The quality of meta-analyses and case-control studies was appraised with Assessing the Methodological Quality of Systematic Reviews 2 and Newcastle-Ottawa Scale, respectively. Narrative summaries of each antiepileptic drug were analyzed. Preestablished protocol was registered on the International Prospective Register of Systematic Reviews Registry(ID: CRD42023403957). RESULTS: Included studies are systematic reviews, meta-analyses and case-control studies evaluating the association of HLA-B*1502 allele with the following antiepileptics. Seven meta-analyses for carbamazepine, three meta-analyses for lamotrigine (LTG), three case-control studies for oxcarbazepine, nine case-control studies for phenytoin and four case-control studies for phenobarbitone were included. The findings of this umbrella review suggest that there is a strong association between HLA-B-1502 with SJS/TEN for carbamazepine and oxcarbazepine and a milder association for lamotrigine and phenytoin. CONCLUSION: In summary, although HLA-B*1502 is less likely to be associated with phenytoin or lamotrigine-induced SJS/TEN compared to carbamazepine-induced SJS/TEN, it is a significant risk factor that if carefully screened, could potentially reduce the development of SJS/TEN. In view of potential morbidity and mortality, HLA-B*1502 testing may be beneficial in patients who are initiating lamotrigine/phenytoin therapy. However, further studies are required to examine the association of other alleles with the development of SJS/TEN and to explore the possibility of genome-wide association studies before initiation of treatment.

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.

Facial dysmorphology in children exposed in pregnancy to anticonvulsant medications correlates with deficits in IQ.

Some children exposed at conception to the antiepileptic drugs (AEDs) phenytoin (PHT), phenobarbital (PB), and carbamazepine (CBZ) have changes in their midface and fingers. It has been suggested that the anticonvulsant-exposed child with these subtle changes in facial features (the "anticonvulsant face") has a greater likelihood of having deficits in IQ in comparison with children exposed to the same anticonvulsants who do not have these features. 115 AED-exposed children (40, PHT; 34, PB; and 41, CBZ) between 6.5 and 16 years of age and 111 unexposed children matched by sex, race, and year in school were evaluated. The evaluations were (WISC-III), physical examination with measurements of facial features and digits and photographs. The AED-exposed children had cephalometric radiographs, but not the unexposed. Each parent had a similar examination of face and hands plus tests of intelligence. These AED-exposed children showed an increased frequency of a short nose and anteverted nares, features of the "anticonvulsant face." Lateral skull radiographs showed a decrease in the angle between the anterior cranial base and nasal bone, which produces anteverted nares. Mean IQs were significantly lower on one or more IQ measures for the children with these facial features. Shortening of the distal phalanges and small fingernails correlated with the presence of a short nose in that child. The findings in 115 children exposed at conception to either phenytoin, phenobarbital, or carbamazepine, as monotherapy, confirmed the hypothesis that those with a short nose and anteverted nares had a lower IQ than exposed children without those features.

Association of antiseizure medications and adverse cardiovascular events: A global health federated network analysis.

OBJECTIVE: A diagnosis of epilepsy has been associated with adverse cardiovascular events (CEs), but the extent to which antiseizure medications (ASMs) may contribute to this is not well understood. The aim of this study was to compare the risk of adverse CEs associated with ASM in patients with epilepsy (PWE). METHODS: A retrospective case-control cohort study was conducted using TriNetX, a global health federated network of anonymized patient records. Patients older than 18 years, with a diagnosis of epilepsy (International Classification of Diseases, 10th Revision code G40) and a medication code of carbamazepine, lamotrigine, or valproate were compared. Patients with cardiovascular disease prior to the diagnosis of epilepsy were excluded. Cohorts were 1:1 propensity score matched (PSM) according to age, sex, ethnicity, hypertension, heart failure, atherosclerotic heart disease, atrial and cardiac arrythmias, diabetes, disorders of lipoprotein metabolism, obesity, schizophrenia and bipolar disorder, medications, and epilepsy classification. The primary outcome was a composite of adverse CEs (ischemic stroke, acute ischemic heart disease, and heart failure) at 10 years. Cox regression analyses were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) following 1:1 PSM. RESULTS: Of 374 950 PWE included; three cohorts were established after PSM: (1) carbamazepine compared to lamotrigine, n = 4722, mean age 37.4 years; (2) valproate compared to lamotrigine, n = 5478, mean age 33.9 years; and (3) valproate compared to carbamazepine, n = 4544, mean age 37.0 years. Carbamazepine and valproate use were associated with significantly higher risk of composite cardiovascular outcome compared to lamotrigine (HR = 1.390, 95% CI = 1.160-1.665 and HR = 1.264, 95% CI = 1.050-1.521, respectively). Valproate was associated with a 10-year higher risk of all-cause death than carbamazepine (HR = 1.226, 95% CI = 1.017-1.478), but risk of other events was not significantly different. SIGNIFICANCE: Carbamazepine and valproate were associated with increased CE risks compared to lamotrigine. Cardiovascular risk factor monitoring and careful follow-up should be considered for these patients.

The extent of cytochrome P450 3A induction by antiseizure medications: A systematic review and network meta-analysis.

OBJECTIVE: Antiseizure medications (ASMs) are commonly categorized as enzyme-inducers and non-enzyme-inducers based on their propensity to enhance the metabolism of concomitantly administered drugs. This systematic review and network meta-analysis aimed to rank ASMs as cytochrome P450 3A (CYP3A)-inducers based on a comparative assessment of ASM-induced reduction in the concentrations of sensitive substrate drugs. METHODS: The protocol was registered with PROSPERO (International Prospective Register of Systematic Reviews; CRD42022335846), and the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) standards were followed. We searched MEDLINE, Embase, and Cochrane until March 14, 2023 without an initial date restriction. Data were additionally obtained via the US Food and Drug Administration database. Studies had to be prospective, with ASM monotherapy for ≥5 days. The primary parameter was the magnitude of change in the area under the concentration-time curve of CYP3A substrates following treatment with the ASM. The standardized mean difference (SMD) was used as the point estimate for the indirect comparisons between ASMs using the pairwise method. Bias risk was assessed using the PKclin tool. RESULTS: We identified 14 open-label, fixed-sequence studies with 370 participants. The effect size of 600 mg/day carbamazepine did not differ from those of 300 mg/day phenytoin (SMD = -.06, 95% confidence interval [CI] = -.18 to .07) and 200 mg/day cenobamate (SMD = -.11, 95% CI = -.26 to .04). Carbamazepine at 600 mg/day was the strongest CYP3A-inducer (P-score = .88), followed by carbamazepine 400 mg/day (.83), phenytoin 300 mg/day (.79), and cenobamate 200 mg/day (.73). Eslicarbazepine (800 mg/day) ranked higher than cenobamate 100 mg/day and oxcarbazepine 900 mg/day (.60, .39, and .37, respectively). SIGNIFICANCE: Despite the limited number of studies, our network meta-analysis emphasizes that the magnitude of ASM effects on CYP3A substrate metabolism is a dose-dependent continuum. When possible, ASM classification as inducers should apply cutoff values tailored to the outcome. Prescribers should monitor plasma concentrations or clinical effects of CYP3A substrates and consider selecting concomitant medications accordingly.

Epilepsy with generalized tonic-clonic seizures alone: Electroclinical features and prognostic patterns.

OBJECTIVE: Epilepsy with generalized tonic-clonic seizures alone (GTCA) is a common but poorly characterized idiopathic generalized epilepsy (IGE) syndrome. Hence, we investigated electroclinical features, seizure outcome, and antiseizure medication (ASM) withdrawal in a large cohort of GTCA patients. METHODS: In this multicenter retrospective study, GTCA patients defined according to the diagnostic criteria of the International League Against Epilepsy (2022) were included. We investigated prognostic patterns, drug resistance at the last visit, and ASM withdrawal, along with their prognostic factors. RESULTS: We included 247 patients with a median (interquartile range [IQR]) age at onset of 17 years (13-22) and a median follow-up duration of 10 years (IQR = 5-20). Drug resistance at the last visit was observed in 40 (16.3%) patients, whereas the median latency to achieve 2-year remission was 24 months (IQR = 24-46.5) with a median number of 1 (IQR = 1-2) ASM. During the long-term follow-up (i.e., 202 patients followed ≥5-years after the first ASM trial), 69 (34.3%) patients displayed an early remission pattern and 36 (17.9%) patients displayed a late remission pattern, whereas 16 (8%) and 73 (36.3%) individuals had no-remission and relapsing-remitting patterns, respectively. Catamenial seizures and morning predominance of generalized tonic-clonic seizures (GTCS) independently predicted drug resistance at the last visit according to multivariable logistic regression. Treatment withdrawal was attempted in 63 (25.5%) patients, with 59 (93.7%) of them having at least a 12-month follow-up after ASM discontinuation. At the last visit, 49 (83%) of those patients had experienced GTCS recurrence. A longer duration of seizure freedom was the only factor predicting a higher chance of successful ASM withdrawal according to multivariable Cox regression. SIGNIFICANCE: GTCA could be considered a relatively easily manageable IGE syndrome, with a low rate of drug resistance and a high prevalence of early response to treatment. Nevertheless, a considerable proportion of patients experience relapsing patterns of seizure control, highlighting the need for appropriate counseling and lifestyle recommendations.

Effects of Polymers on Cocrystal Growth in a Drug-Drug Coamorphous System: Relations between Glass-to-Crystal Growth and Surface-Enhanced Crystal Growth.

Coamorphous and cocrystal drug delivery systems provide attractive crystal engineering strategies for improving the solubilities, dissolution rates, and oral bioavailabilities of poorly water-soluble drugs. Polymeric additives have often been used to inhibit the unwanted crystallization of amorphous drugs. However, the transformation of a coamorphous phase to a cocrystal phase in the presence of polymers has not been fully elucidated. Herein, we investigated the effects of low concentrations of the polymeric excipients poly(ethylene oxide) (PEO) and poly(vinylpyrrolidone) (PVP) on the growth of carbamazepine-celecoxib (CBZ-CEL) cocrystals from the corresponding coamorphous phase. PEO accelerated the growth rate of the cocrystals by increasing the molecular mobility of the coamorphous system, while PVP had the opposite effect. The coamorphous CBZ-CEL system exhibited two anomalously fast crystal growth modes: glass-to-crystal (GC) growth in the bulk and accelerated crystal growth at the free surface. These two fast growth modes both disappeared after doping with PEO (1-3% w/w) but were retained in the presence of PVP, indicating a potential correlation between the two fast crystal growth modes. We propose that the different effects of PEO and PVP on the crystal growth modes arose from weaker effects of the polymers on cocrystallization at the surface than in the bulk. This work provides a deep understanding of the mechanisms by which polymers influence the cocrystallization kinetics of a multicomponent amorphous phase and highlights the importance of polymer selection in stabilizing coamorphous systems or preparing cocrystals via solid-based methods.

Pharmacokinetics of asundexian with combined CYP3A and P-gp inhibitors and an inducer: Target in vitro and in vivo studies.

AIMS: Asundexian is an oral, direct and reversible inhibitor of activated factor XI (FXIa) in development for the treatment of thromboembolic events. This article summarizes results from preclinical and clinical studies, including identification of enzymes involved in asundexian pharmacokinetics, and evaluation of potential target drug-drug interactions. METHODS: In vitro studies investigated the substrate characteristics of asundexian towards several cytochrome P450 (CYP) isoforms, hydrolytic enzymes and drug transporters. Inhibition of the amide hydrolysis of asundexian was investigated in vitro for several relevant drugs. Phase 1 studies in healthy male participants investigated the pharmacokinetics (PK) of asundexian upon co-administration of combined inhibitors or an inducer of P-gp and CYP3A4 (itraconazole, verapamil or carbamazepine, respectively, or the moderate CYP3A4 inhibitor fluconazole). The pharmacodynamic (PD) markers are activated partial thromboplastin time and FXIa inhibition. RESULTS: Asundexian was predominantly metabolized via carboxylesterase 1 and, to a lesser extent, via CYP3A4 and is a substrate of P-gp. The asundexian area under the plasma concentration-time curve (AUC) increased by 103% and 75.6% upon combined inhibition of P-gp and strong or moderate inhibition of CYP3A4, respectively, but was unaffected by moderate CYP3A4 inhibition. Combined P-gp and CYP3A4 induction by carbamazepine decreased asundexian AUC by 44.4%. PD is concentration-dependent, thus no differences in maximum responses and recovery commensurate with PK effect(s) were observed. Adverse events were mild and asundexian was well tolerated. CONCLUSIONS: The presented studies confirmed that CYP3A4 and P-gp contribute to asundexian metabolism and excretion. Observed effects were in line with data from a previous mass balance study.

An Evaluation of Wet Granulation Process Selection for API Prone to Polymorphic Form Conversion in the Presence of Moisture and Heat.

PURPOSE: Wet granulation (WG) is one of the most versatile processes to improve blend properties for processing. However, due to its need for moisture and heat, it is often considered not amenable to active pharmaceutical ingredients (APIs) prone to forming hydrates. Despite this claim, little literature exists evaluating the extent to which polymorphic form conversions occur for such API when processed with WG. This work sets out to explore two common WG methods, high-shear (HSG) and fluid-bed (FBG), and two drying processes, tray-drying (TD) and fluid-bed drying (FBD), and evaluate the risk they pose to hydrate form conversion. METHODS: The progression of anhydrous to hydrate form conversion of two model compounds with vastly different solubilities, fexofenadine hydrochloride and carbamazepine, was monitored throughout the various processes using powder X-ray diffraction. The resultant granules were characterized using thermogravimetric analysis, differential scanning calorimetry, BET adsorption, and sieve analysis. RESULTS: FBG and FBD processing resulted in the preservation of the original form of both APIs, while HSG+TD resulted in the complete conversion of the API. The FBD of fexofenadine and carbamazepine granules prepared with HSG resulted in partial and complete re-conversion back to the original anhydrous forms, respectively. CONCLUSION: The drying process is a critical factor in anhydrous form conservation. FBG and FBD yielded better preservation of the initial anhydrous forms. HSG could be an acceptable granulation method for API susceptible to hydrate formation if the API solubility is low. Selecting an FBG+FBD process minimizes API hydrate formation and preserves the original anhydrous form.

IVIVC Revised.

PURPOSE: To revise the IVIVC considering the physiologically sound Finite Absorption Time (F.A.T.) and Finite Dissolution Time (F.D.T.) concepts. METHODS: The estimates τ and τd for F.A.T. and F.D.T., respectively are constrained by the inequality τd ≤ τ; their relative magnitude is dependent on drug's BCS classification. A modified Levy plot, which includes the time estimates for τ and τd was developed. IVIVC were also considered in the light of τ and τd estimates. The modified Levy plot of theophylline, a class I drug, coupled with the rapid (30 min) and very rapid (15 min) dissolution time limits showed that drug dissolution/absorption of Class I drugs takes place in less than an hour. We reanalyzed a carbamazepine (Tegretol) bioequivalence study using PBFTPK models to reveal its complex absorption kinetics with two or three stages. RESULTS: The modified Levy plot unveiled the short time span (~ 2 h) of the in vitro dissolution data in comparison with the duration of in vivo dissolution/absorption processes (~ 17 h). Similar results were observed with the modified IVIVC plots. Analysis of another set of carbamazepine data, using PBFTPK models, confirmed a three stages absorption process. Analysis of steady-state (Tegretol) data from a paediatric study using PBFTPK models, revealed a single input stage of duration 3.3 h. The corresponding modified Levy and IVIVC plots were found to be nonlinear. CONCLUSIONS: The consideration of Levy plots and IVIVC in the light of the F.A.T. and F.D.T. concepts allows a better physiological insight of the in vitro and in vivo drug dissolution/absorption processes.

Effect of Carbamazepine on Darunavir Trough Concentrations: When the Dose Can Make the Difference-A Case Study.

BACKGROUND: Carbamazepine (CBZ) is an antiseizure medication known to induce the expression of cytochrome P4503A metabolic enzymes. Here, we describe a man living with HIV who underwent several changes in the daily dose of CBZ, which resulted in different induction effects on darunavir trough concentrations. METHODS: A 59-year-old man with HIV, successfully undergoing maintenance antiretroviral treatment with darunavir/cobicistat once daily (combined with raltegravir), was prescribed CBZ for recurrent trigeminal neuralgia. Over subsequent months, the patient underwent various changes in the doses (from 200 to 800 mg/d) and trough concentrations (from 3.6 to 18.0 mg/L) of CBZ, guided by clinical response to trigeminal neuralgia. RESULTS: A highly significant inverse association was observed between darunavir trough concentration and both CBZ dose or trough concentration (coefficient of determination >0.75, P < 0.0001). Ultimately, the darunavir dose was increased to 600 mg twice daily with ritonavir and dolutegravir to ensure optimal antiretroviral coverage, anticipating potential further uptitration of CBZ doses. CONCLUSIONS: The impact of CBZ on boosted darunavir exposure seemed to be dose- and concentration-dependent. The management of such drug-drug interactions in daily practice was facilitated through therapeutic drug monitoring. This case underscores the importance of a multidisciplinary approach that incorporates both antiretroviral and nonantiretroviral comedications contributing to the optimal management of polypharmacy in individuals living with HIV.

An isotope dilution-liquid chromatography-tandem mass spectrometry (ID-LC-MS/MS)-based candidate reference measurement procedure for the quantification of carbamazepine-10,11-epoxide in human serum and plasma.

OBJECTIVES: A reference measurement procedure (RMP) using isotope dilution liquid chromatography-tandem mass spectrometry (ID-LC-MS/MS) was developed and validated with the aim of accurately measuring carbamazepine-10,11-epoxide concentrations in human serum and plasma. METHODS: To establish traceability to SI units, the absolute content of the reference material was determined using quantitative nuclear magnetic resonance (qNMR) spectroscopy. As sample preparation a protein precipitation protocol followed by a high dilution step was established. Chromatographic separation from carbamazepine and potential metabolites was achieved using a C18 stationary phase. Selectivity, specificity, matrix effects, precision and accuracy, inter-laboratory equivalence, and uncertainty of measurement were evaluated based on guidelines from the Clinical and Laboratory Standards Institute, the International Conference on Harmonization, and the Guide to the Expression of Uncertainty in Measurement. RESULTS: The RMP demonstrated very good selectivity and specificity, showing no evidence of a matrix effect. This enabled accurate quantification of carbamazepine-epoxide in the concentration range of 0.0400-12.0 µg/mL. The intermediate precision was found to be less than 2.1 %, and the repeatability coefficient of variation (CV) ranged from 1.2 to 1.8 % across all concentration levels. Regarding accuracy, the relative mean bias varied from 1.4 to 2.5 % for native serum levels and from 1.4 to 3.5 % for Li-heparin plasma levels. The measurement uncertainty for single measurements ranged from 1.6 to 2.1 %. CONCLUSIONS: In this study, we introduce a new LC-MS/MS-based candidate RMP for accurately measuring carbamazepine-10,11-epoxide in human serum and plasma. This novel method offers a traceable and dependable platform, making it suitable for standardizing routine assays and assessing clinically relevant samples.

The association of ABCB1 gene polymorphism with clinical response to carbamazepine monotherapy in patients with epilepsy.

BACKGROUND: Epilepsy is a common neurological disease but around 30% of patients fail to respond to antiepileptic drug (AED) treatment. Genetic variation of the ATP-binding cassette subfamily B, member 1 (ABCB1) gene, a drug efflux transporter may infer treatment resistance by decreasing gastrointestinal absorption and preventing AED entry into the brain. This study examined the impact of ABCB1 genetic variants on carbamazepine responsiveness. MATERIALS AND METHODS: Genomic DNA was extracted from whole blood of 104 epileptic patients. Genotyping of 3 ABCB1 variants (c.C3435T, c.G2677T/A and c.C1236T) was undertaken using validated TaqMan allelic discrimination assays. Plasma carbamazepine levels were measured at 3 and 6 months following the initial dose using high-performance liquid chromatography (HPLC) alongside clinical outcomes evaluation. RESULTS: Nonresponse to carbamazepine (CBZ) was associated significantly with the ABCB1 variants c.C3435T, c.G2677T/A, c.C1236T and TTT, TTC haplotypes (P < 0.05). There was no significant association between variants and plasma CBZ level (P > 0.05). CONCLUSIONS: Our results showed that variant alleles of the ABCB1 gene and TTT, TTC haplotypes were significantly associated with CBZ resistance without affecting the plasma level of carbamazepine. The findings of this study may help to predict patient's response to treatment ultimately it will improve the personalized and evidence based treatment choice of patients with epilepsy.

Distinctive Amplitude-Integrated EEG Ictal Pattern and Targeted Therapy with Carbamazepine in KCNQ2 and KCNQ3 Neonatal Epilepsy: A Case Series.

BACKGROUND: Carbamazepine (CBZ) is effective in treating KCNQ2/3-related seizures, which may present with a distinctive amplitude-integrated electroencephalography (aEEG) pattern. OBJECTIVE: To assess how improved recognition of the distinctive aEEG ictal pattern associated with KCNQ2/3 variants has enabled early and effective targeted therapy with CBZ. METHODS: Retrospective descriptive study of five neonates with KCNQ2/3 pathogenic gene variants admitted at a level 3 neonatal intensive care unit (NICU) over an 8-year period. RESULTS: The distinctive ictal aEEG pattern was recognized in four neonates after an average of 61.5 hours (minimum 12 hours, maximum 120 hours) from the first electroclinical seizure and prompted the use of CBZ that was effective in all. The two most recently diagnosed patients could avoid polytherapy as they received CBZ as the first and second antiseizure medication, respectively. Three out of five patients with continuous normal voltage (CNV), sleep-wake cycling (SWC), and shorter postictal suppression had normal neurodevelopmental outcome. Regarding the remaining two infants, one was not trialed with CBZ and had a high seizure burden, both presented with a prolonged postictal suppression, no SWC, and had moderate-to-severe developmental delay. Genetic results became available after the neonatal period in all but one of the infants, who had a prenatal diagnosis. CONCLUSION: Recognition of the distinctive ictal aEEG pattern in the NICU allowed early and effective targeted therapy with CBZ in four neonates, well before genetic results became available. Furthermore, a CNV background pattern with SWC and short postictal suppression were associated with normal developmental outcomes.

Evaluation of anti-seizure medications and their serum concentration with regard to cardiovascular risk parameters: A cross-sectional study.

OBJECTIVE: Epilepsy is a chronic disease that requires long-term monitoring and treatment. It is suspected that there is a interaction between the use of anti-seizure medications and the risk of cardiovascular disease. The aim of the study is to investigate the association between the intake of phenobarbital, carbamazepine and valproic acid and their serum drug concentrations (SDC) with various cardiovascular risk parameters (homocysteine, folic acid, vitamin B12, total cholesterol (TC), triglycerides, high- and low-density lipoprotein (LDL)). METHODS: This is a cross-sectional study. Data (demographic characteristics and laboratory results) of patients treated for epilepsy in a tertiary care hospital between January 2020 and February 2022 were analyzed retrospectively (n = 2014). Kruskal Wallis, Mann-Whitney U, correlation analysis was used, p < 0.05 was considered statistically significant. RESULTS: The median age of patients was 15 years (IQR:8-31) and 48.3 % were women. The highest homocysteine level was found in patients receiving valproic acid, but it was not statistically significant. Patients receiving phenobarbital had the highest levels of folic acid and B12 and the lowest levels of total cholesterol and low-density lipoprotein cholesterol, which was statistically significant. In patients receiving carbamazepine, a moderately negative significant association was found between serum drug concentration and folic acid levels and a moderately positive significant association was found between TC and LDL levels. CONCLUSION: In our study, the majority of patients were children and adolescents. Regular monitoring of drug serum concentrations and metabolic parameters may be useful to select the safest drug in terms of cardiovascular disease risk. Randomized controlled trials on the long-term effects of anti-seizure treatment are needed.

Cost-effectiveness analysis of HLA-B*15:02 screening before treatment of epilepsy in Indonesia.

INTRODUCTION: Adverse skin reactions due to drugs such as Stevens Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) occur in 3% of people receiving anti epileptic drugs (AED). Although SJS/TEN has a low incidence, the mortality and morbidity rates are high. Indonesia has not adopted HLA-B*1502 screening prior to administration of carbamazepine (CBZ), although previous studies found a relationship between HLA-B*1502 and SJS/TEN. METHODS: A hybrid decision tree and Markov model was developed to evaluate three strategies for treating newly diagnosed focal epilepsy: CBZ direct therapy, levetiracetam (LEV) direct therapy, and therapy based on HLA-B*15:02 test results. From a societal perspective, base case and sensitivity analyses were carried out over a lifetime. RESULTS: Direct administration of CBZ appears to have a slightly lower average cost than the HLA-B*15:02 allele screening strategy. The increase in quality-adjusted life year (QALY) in HLA-B*15:02 screening before treatment related to the cost difference reached 0.519 with an incremental cost-effectiveness ratio (ICER) of around USD 984 per unit of QALY acquisition. Direct treatment of LEV increased treatment costs by almost USD 2000 on average compared to the standard CBZ strategy. The increase in QALY is 0.834 in direct levetiracetam treatment, with an ICER of around USD 2230 for each QALY processing. CONCLUSION: Calculation of the cost-effectiveness of lifetime epilepsy therapy in this study found that the initial screening strategy with the HLA-B*15:02 test was the most cost-effective.

Second antiseizure medication monotherapy in patients with adult-onset epilepsy: A register-based analysis.

OBJECTIVE: Revision of therapy is fundamental in epilepsy care, since only half of patients achieve seizure freedom and tolerate the first antiseizure medication (ASM). We studied the selection and retention of second antiseizure medication monotherapy in adults who discontinued treatment with one of the three most frequently prescribed first ASMs, and the impact of age or brain comorbidities. METHODS: Using Swedish national registers, we conducted a population-based, retrospective cohort study from 2007 to 2019 on patients age ≥ 30 at the epilepsy diagnosis that had switched to a second monotherapy after the three most common initial monotherapies (n = 7369). Retention rates (RR) were estimated via Kaplan-Meier. Discontinuation of the second monotherapy was defined as 12-month prescription gap or initiation of a third ASM. Analyses were stratified by sex, age, and presence of stroke or dementia. RESULTS: The three most commonly prescribed second ASMs were carbamazepine, levetiracetam, and lamotrigine. The 1-year retention rate was 63-76% in all patients. For groups with stroke or dementia, the maximal 1-year RRs were 77% and 87%, respectively. After five years, retention rates ranged from 12% to 39%. There were no major differences between ASMs, apart from in patients discontinuing carbamazepine, where lamotrigine had a superior retention compared to levetiracetam as second monotherapy. SIGNIFICANCE: The three most often prescribed second ASMs seem to be suitable treatment options according to present guidelines. The second ASMs' retention rates were initially high in all studied patient groups but dropped to approximately the expected proportion of second monotherapy responders over the next five years. This suggests that therapy revision could be expedited.

Correlation of drug dose estimated from national prescription registers with mean blood level of antiseizure medication in pregnancy.

PURPOSE: The purpose was to examine the correlation of antiseizure medication drug dose estimated from prescription fill records from prescription registers with blood levels during pregnancy. METHODS: We conducted a Nation-wide study of mothers who gave birth in Denmark between 1 January 2014 and 31 December 2018 using data from Danish Prescription and Laboratory Registers. We identified mothers with blood level measurements of antiseizure medication. The main exposure was estimated antiseizure medication dosage estimated from pregnancy-filled prescriptions in the Danish Prescription Register. The main outcome was the correlation of estimated dose with mean blood level of antiseizure medication in pregnancy. For privacy reasons, the number of blood level measurement and prescription fills were rounded to nearest 10, but proportions reported as exact values. RESULTS: Among 298 560 pregnancies, we identified pregnancies with recorded prescription fill from the prescription register for valproate (N = 90), lamotrigine (N = 1360), levetiracetam (N = 340), topiramate (N = 100), and carbamazepine (N = 60). In these pregnancies, blood level measurements were available in 50 (53%) pregnancies for valproate, 850 (62%) pregnancies for lamotrigine, 320 (93%) pregnancies for levetiracetam, 50 (68%) pregnancies for carbamazepine, and 40 (35%) pregnancies for topiramate. Pearsons's correlation coefficients for the correlation of estimated antiseizure medication dose with mean blood levels were 0.67 (p < 0.0001) for valproate, 0.63 (p < 0.0001) for lamotrigine, 0.63 (p < 0.0001) for levetiracetam, 0.76 (<0.0001) for carbamazepine and 0.89 (<0.0001) for topiramate. CONCLUSIONS: Dose of antiseizure medication estimated from prescription fills was a good proxy for blood levels and thus for biological exposure in pregnancy, suggesting that administrative prescription fill records may be a valuable resource for estimating exposure to antiseizure medication in pregnancy.