Enzyme-inducing Antiepileptic Drugs Research Articles

Bevacizumab Alone and in Combination With Irinotecan in Recurrent Glioblastoma.

We evaluated the efficacy of bevacizumab, alone and in combination with irinotecan, in patients with recurrent glioblastoma in a phase II, multicenter, open-label, noncomparative trial. One hundred sixty-seven patients were randomly assigned to receive bevacizumab 10 mg/kg alone or in combination with irinotecan 340 mg/m2 or 125 mg/m2 (with or without concomitant enzyme-inducing antiepileptic drugs, respectively) once every 2 weeks. Primary end points were 6-month progression-free survival and objective response rate, as determined by independent radiology review. Secondary end points included safety and overall survival. In the bevacizumab-alone and the bevacizumab-plus-irinotecan groups, estimated 6-month progression-free survival rates were 42.6% and 50.3%, respectively; objective response rates were 28.2% and 37.8%, respectively; and median overall survival times were 9.2 months and 8.7 months, respectively. There was a trend for patients who were taking corticosteroids at baseline to take stable or decreasing doses over time. Of the patients treated with bevacizumab alone or bevacizumab plus irinotecan, 46.4% and 65.8%, respectively, experienced grade ≥ 3 adverse events, the most common of which were hypertension (8.3%) and convulsion (6.0%) in the bevacizumab-alone group and convulsion (13.9%), neutropenia (8.9%), and fatigue (8.9%) in the bevacizumab-plus-irinotecan group. Intracranial hemorrhage was noted in two patients (2.4%) in the bevacizumab-alone group (grade 1) and in three patients (3.8%) patients in the bevacizumab-plus-irinotecan group (grades 1, 2, and 4, respectively). Bevacizumab, alone or in combination with irinotecan, was well tolerated and active in recurrent glioblastoma.

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.

Population Pharmacokinetic Analysis of Perampanel in Portuguese Patients Diagnosed with Refractory Epilepsy.

Perampanel is a promising antiepileptic drug (AED) for refractory epilepsy treatment due to its innovative mechanism of action. This study aimed to develop a population pharmacokinetic (PopPK) model to be further used in initial dose optimization of perampanel in patients diagnosed with refractory epilepsy. A total of seventy-two plasma concentrations of perampanel obtained from forty-four patients were analyzed through a population pharmacokinetic approach by means of nonlinear mixed effects modeling (NONMEM). A one-compartment model with first-order elimination best described the pharmacokinetic profiles of perampanel. Interpatient variability (IPV) was entered on clearance (CL), while the residual error (RE) was modeled as proportional. The presence of enzyme-inducing AEDs (EIAEDs) and body mass index (BMI) were found as significant covariates for CL and volume of distribution (V), respectively. The mean (relative standard error) estimates for CL and V of the final model were 0.419 L/h (5.56%) and 29.50 (6.41%), respectively. IPV was 30.84% and the proportional RE was 6.44%. Internal validation demonstrated an acceptable predictive performance of the final model. A reliable population pharmacokinetic model was successfully developed, and it is the first enrolling real-life adults diagnosed with refractory epilepsy.

THU-210 - Coadministration of hepatitis C direct-acting antivirals and enzyme-inducing antiepileptic drugs: real-world experience from a multi-centre case series

THU-210 - Coadministration of hepatitis C direct-acting antivirals and enzyme-inducing antiepileptic drugs: real-world experience from a multi-centre case series

Therapeutic Drug Monitoring for Rufinamide in Japanese Patients With Epilepsy: Focus on Drug Interactions, Tolerability, and Clinical Effectiveness.

The purposes of this study were to assess drug interactions between rufinamide and concomitant antiepileptic drugs (AEDs) and to identify the therapeutic window for rufinamide. Serum samples (n = 1531) were obtained from 178 patients (aged 2-57 years), and clinical records were retrospectively reviewed to evaluate the safety and efficacy of rufinamide (mean observation time, 1073 ± 846 days). Rufinamide exhibited linear pharmacokinetics at doses of up to 60 mg/kg (range, 50-3200 mg/d). Concomitant use of the enzyme-inducing AEDs such as phenytoin, carbamazepine, and phenobarbital reduced rufinamide concentrations by 43.4%, 13.2%, and 30.3%, respectively. By contrast, concomitant use of valproate significantly elevated rufinamide concentrations. Clinical response was seen in 41 patients (23.0%), with a median therapeutic concentration (interquartile range) of 20.6 mcg/mL (13.3-27.0). There was no difference in the therapeutic concentrations between seizure types, but patients with tonic/atonic seizures tended to have higher rufinamide concentrations. During the study period, adverse events were reported in 64 patients (35.8%), including somnolence, gastrointestinal disorders, dizziness, and irritability/behavior disorders. Conditional logistic regression analysis showed that patients administered a concentration greater than 20 mcg/mL had an 8.6-fold higher incidence of adverse events. Therapeutic drug monitoring for rufinamide is clinically useful for predicting drug interactions between rufinamide and concomitant AEDs. When a patient has tonic/atonic seizures, careful titration is required for concentrations greater than 20 mcg/mL.

Effects of enzyme-inducing antiepileptic drugs on lipid and bone metabolism in pediatric patients

Effects of enzyme-inducing antiepileptic drugs on lipid and bone metabolism in pediatric patients

Physiologically-based pharmacokinetic modeling of oxcarbazepine and levetiracetam during adjunctive antiepileptic therapy in children and adolescents.

Oxcarbazepine (OXZ) and levetiracetam (LEV) are two new generation anti‐epileptic drugs, often co‐administered in children with enzyme‐inducing antiepileptic drugs (EIAEDs). The anti‐epileptic effect of OXZ and LEV are linked to the exposure of OXZ’s active metabolite 10‐monohydroxy derivative (MHD) and (the parent) LEV, respectively. However, little is known about the confounding effect of age and EIAEDs on the pharmacokinetics (PKs) of MHD and LEV. To address this knowledge gap, physiologically‐based pharmacokinetic (PBPK) modeling was performed in the PK‐Sim software using literature data from children greater than or equal to 2 years of age. Age‐related changes in clearance (CL) of MHD and LEV were characterized, both in the presence (group 1) and absence (group 2) of concomitant EIAEDs. The drug‐drug interaction effect of EIAEDs was estimated as the difference in CL estimates between groups 1 and 2. PBPK modeling suggests that bodyweight normalized CL (ml/min/kg) is higher in younger children than their older counterparts (i.e., due to an influence of age). Concomitant EIAEDs further increase MHD’s CL to a fixed extent of 25% at any age, but EIAEDs’ effect on LEV’s CL increases with age from 20% (at 2 years) to 30% (at adolescence). Simulations with the maximum recommended doses (MRDs) revealed that children between 2 and 4 years and greater than 4 years, who are not on EIAEDs, are at risk of exceeding the reference exposure range for OXZ and LEV, respectively. This analysis demonstrates the use of PBPK modeling in understanding the confounding effect of age and comedications on PKs in children and adolescents.

Associations between osteoporosis and drug exposure: A post-marketing study of the World Health Organization pharmacovigilance database (VigiBase®).

Bone remodeling is a complex process, and many conditions (including drug exposure) lead to osteoporosis. Here, we sought to detect new disproportionality signals for drugs associated with osteoporosis. We performed a disproportionality analysis of the World Health Organization's VigiBase® pharmacovigilance database through April 12, 2020. The frequency of reports on osteoporosis for all identified drug classes was compared with that for all other drugs and quoted as the reporting odds ratio (ROR) [95% confidence interval (CI)]. Of the 7,594,968 cases spontaneously recorded to VigiBase®, 4758 concerned osteoporosis. New disproportionality signals with a pharmacologically plausible mechanism were found for drugs used in neurology (levodopa (ROR [95%CI]: 10.18 [4.33-25.10]), selective serotonin agonists (4.22 [2.34-7.00]) and memantine (4.10 [1.56-8.93])), hematology (romiplostim (4.93 [1.15-21.10])), pulmonology (macitentan (3.02 [1.84-4.90])), ophthalmology (ranibizumab (3.31 [1.00-10.51])) and rheumatology (tofacitinib (3.65 [3.00-4.40])). The robustness of these new results is supported by the significant RORs for the vast majority of drugs already known to induce osteoporosis and/or increase the fracture risk, namely glucocorticoids, gonadotropin-releasing hormone analogs, anti-aromatases, androgen receptor blockers, thyroid hormones, proton pump inhibitors, thiazolidinediones, vitamin K antagonists, loop diuretics, protease inhibitors, nucleoside and nucleotide reverse transcriptase inhibitors, and enzyme-inducing antiepileptics including barbiturates and derivatives, hydantoin derivatives, carboxamide derivatives and fatty acid derivatives. We established up a comprehensive list of drugs potentially associated with osteoporosis and highlighted those with pharmacologically plausible mechanisms leading to bone fragility. Our results might pave the way for additional exploration of these mechanisms.

Comparing prevalence of statin prescription between enzyme inducing antiepileptic drugs versus non-enzyme inducing antiepileptic drugs in adult people with epilepsy: A preliminary study

There are many cross-sectional studies that people with epilepsy (PWE) taking enzyme-inducing antiepileptic drugs (EIAEDs) may have higher cholesterol levels. There is also a report that PWE taking EIAEDs have more chance to have statin prescription compared to PWE taking NEIAEDs. The aim of this study is to compare statin prescription prevalence between EIAEDs versus NEIAEDs among PWE in South Korea.

Diversity and Inclusion in Drug Development: Rethinking Intrinsic and Extrinsic Factors with Patient Centricity.

Diversity and Inclusion in Drug Development: Rethinking Intrinsic and Extrinsic Factors with Patient Centricity.

POSTER ABSTRACTS: P58 THE EFFECT OF TOPIRAMATE ON ETONOGESTREL CONCENTRATIONS IN CONTRACEPTIVE IMPLANT USERS

Objectives: Topiramate, commonly used for the treatment of migraines and seizures, is categorized as an enzyme-inducing anti-epileptic drug (EIAED) like carbamazepine and phenobarbital. Limited data suggest topiramate is a mild inducer and may not affect contraceptive efficacy. We evaluated topiramate and etonogestrel (ENG) pharmacokinetic interactions in contraceptive implant users.

Investigation of the effect of anti-epileptic drugs on bone metabolism using osteoprotegerin and bone-specific alkaline phosphatase: The direct effects of antiepileptic drugs on bone metabolism

Background/Aim: Anti-epileptic drugs are long-term medications; thus, side-effects are frequently seen. An important but insufficiently known side-effect is the emergence of metabolic bone diseases. The mechanism of this entity is not clearly known, but it is usually seen with the use of cytochrome P450 enzyme-inducing anti-epileptics. However, recent studies demonstrated that non-enzyme-inducing molecules also cause bone mineral impairment. The aim of this study was to shed light on the pathogenesis of anti-epileptic metabolic bone disease using bone turnover markers. Methods: This comparative, prospective case-control study included 37 patients followed-up in our outpatient clinic and 39 healthy control subjects. All the patients were female, aged over 18 years and in the premenopausal period, and had received the same anti-epileptic treatment for at least 3 months. Male patients, females who were <18 years old, pregnant, in the postmenopausal period, those with osteoporosis, gastrointestinal malabsorption, physical impairment that may prevent normal ambulation, endocrine and metabolic disease, musculoskeletal and joint disease or a history of medication use were excluded from the study. A healthy control group was formed of age-matched premenopausal women, with no disorders causing gastrointestinal malabsorption, no physical impairment preventing normal ambulation, no endocrine or metabolic disorder, or history of medication use that may affect bone turnover. The levels of serum calcium, alkaline phosphatase, 25-hydroxyvitamin D, osteoprotegerin and bone-specific alkaline phosphatase were assessed, and the results were recorded. Results: Evaluation was made of 37 female epilepsy patients with a mean age of 30.8 (8.1) years and a healthy control group of 39 age- and body mass index-matched females (P=0.69, P=0.85, respectively). The mean duration of AED use was 6.1 (5.5) years. The calcium (P=0.09), phosphate (P=0.906) and alkaline phosphatase (P=0.22) levels were similar in both groups. The levels of 25-hydroxyvitamin D (P=0.049), osteoprotegerin (P=0.025), and bone- specific alkaline phosphatase (P=0.037) were significantly lo3wer in the epilepsy group. Conclusion: Our study showed that serum levels of osteoprotegerin and bone-specific alkaline phosphatase, which are markers of increased bone formation, were lower in epilepsy patients. Probably many factors cause the bone mineral disorder seen in epilepsy patients. Antiepileptic use is one of them. These results suggest that antiepileptics may not only affect enzyme induction but also bone turnover. Neurologists should be aware of this issue and monitor patients regularly with respect to bone mineralization to enable early treatment when necessary.

Levetiracetam Therapeutic Drug Monitoring in a Large Cohort of Korean Epileptic Patients.

Levetiracetam is a new antiepileptic drug (AED) used for treating and preventing partial or generalized seizures. The usefulness of levetiracetam therapeutic drug monitoring (TDM) is related to inter- or intra-individual pharmacokinetic variability, drug interactions, and patient noncompliance. We aimed to investigate the levetiracetam TDM status in Korean epilepsy patients. Serum trough levetiracetam concentrations were measured using liquid chromatography–tandem mass spectrometry in 710 samples from 550 patients. The median (range) daily and weight-adjusted levetiracetam doses were 1500 (20–5000) mg and 25.5 (3.03–133.0) mg/kg, respectively. Patients on levetiracetam monotherapy constituted only 19.5% of the population, while 30.1% were on co-medication with valproate and 56.0% with enzyme-inducing AEDs (EIAEDs). Observed levetiracetam concentrations were widely distributed, ranging 0.8–95 mg/L, with a median of 17.3 mg/L. Levetiracetam concentrations were therapeutic, supra-therapeutic, and sub-therapeutic in 58.5% (n = 393), 11.6% (n = 78), and 29.9% (n = 201) of samples, respectively. There was a strong correlation between weight-adjusted levetiracetam dosage and concentrations (ρ = 0.6896, p < 0.0001). In this large-scale clinical study, a large inter-individual difference in levetiracetam pharmacokinetics was observed, and levetiracetam concentrations were influenced by EIAEDs. For individual dose adjustments and monitoring compliance, routine levetiracetam TDM is needed in epilepsy patients.

Perampanel dosage in plasma samples: development and validation of a novel HPLC method with combined UV-Fluorescence detection

Therapeutic drug monitoring (TDM) is a recognized method to improve the quality of use of antiepileptic drugs, such as perampanel (PRP). It is the first compound in the class of selective non-competitive antagonists of AMPA receptors approved in 2012 in Europe and United States for adjunctive therapy of partial seizures. Although several studies have recently underlined that a general reference range for PRP plasmatic concentration might be difficult to propose, TDM of this drug is important in specific clinical situations, as hepatic or renal impairment or co-administration with enzyme-inducing antiepileptics. Several methods have been described in literature for the determination of PRP in different biological matrices, which include the use of liquid chromatography methods coupled with ultraviolet, fluorescence, mass or tandem-mass spectrometry detection. Here we describe the development and validation of a novel method for the measurement of PRP in plasma samples, based on a HPLC-UV/FL double detection approach and using ketoprofen as internal standard. PRP concentration in a small subset of plasma samples of treated patients was evaluated using both our approach and a commercially available CE-IVD LC–MS/MS method. The results obtained were compared, and confirmed the possibility to use our method as an alternative to LC–MS/MS in clinical routine.

Epilepsy, antiepileptic drugs, and the risk of major cardiovascular events.

This study was undertaken to determine whether epilepsy and antiepileptic drugs (including enzyme-inducing and non-enzyme-inducing drugs) are associated with major cardiovascular events using population-level, routinely collected data. Using anonymized, routinely collected, health care data in Wales, UK, we performed a retrospective matched cohort study (2003-2017) of adults with epilepsy prescribed an antiepileptic drug. Controls were matched with replacement on age, gender, deprivation quintile, and year of entry into the study. Participants were followed to the end of the study for the occurrence of a major cardiovascular event, and survival models were constructed to compare the time to a major cardiovascular event (cardiac arrest, myocardial infarction, stroke, ischemic heart disease, clinically significant arrhythmia, thromboembolism, onset of heart failure, or a cardiovascular death) for individuals in the case group versus the control group. There were 10241 cases (mean age = 49.6years, 52.2% male, mean follow-up = 6.1years) matched to 35145 controls. A total of 3180 (31.1%) cases received enzyme-inducing antiepileptic drugs, and 7061 (68.9%) received non-enzyme-inducing antiepileptic drugs. Cases had an increased risk of experiencing a major cardiovascular event compared to controls (adjusted hazard ratio = 1.58, 95% confidence interval [CI] = 1.51-1.63, p<.001). There was no notable difference in major cardiovascular events between those treated with enzyme-inducing antiepileptic drugs and those treated with non-enzyme-inducing antiepileptic drugs (adjusted hazard ratio = .95, 95% CI = .86-1.05, p = .300). Individuals with epilepsy prescribed antiepileptic drugs are at an increased risk of major cardiovascular events compared with population controls. Being prescribed an enzyme-inducing antiepileptic drug is not associated with a greater risk of a major cardiovascular event compared to treatment with other antiepileptic drugs. Our data emphasize the importance of cardiovascular risk management in the clinical care of people with epilepsy.

A multivariable prediction model of a major treatment response for focal-onset seizures: A post-hoc analysis of Phase III trials of perampanel

ObjectiveAlthough 50 % reduction in seizure frequency is a common efficacy endpoint in clinical trials of antiepileptic drugs (AEDs), 75 % or greater reductions may be required to improve patients’ health-related quality of life. Identification of clinical factors that are associated with high responder rates may help to inform clinicians on which patients may optimally benefit from treatment. We evaluated potential predictive factors for achieving major treatment responses (≥75 % reduction in seizure frequency per 28 days from study baseline) in patients with drug-resistant focal-onset seizures, with/without focal to bilateral tonic-clonic (FBTC) seizures in perampanel trials designed for regulatory approval. MethodsUnivariate analyses using logistic regression were performed using data from three double-blind, placebo-controlled Phase III studies of adjunctive perampanel (Studies 304 [NCT00699972], 305 [NCT00699582], 306 [NCT00700310]), and their open-label extension study (OLEx; Study 307 [NCT00735397]). For the double-blind studies, baseline seizure frequency, number of baseline AEDs, baseline seizure type, baseline concomitant enzyme-inducing AEDs (EIAEDs), baseline carbamazepine, lamotrigine, or valproic acid, age at diagnosis, time since diagnosis, etiology, and perampanel plasma concentration were included individually with study treatment. The same factors were included for the OLEx analysis except for plasma concentration and treatment. Variables found to be significant predictors for a major treatment response in univariate analyses were subsequently included in multivariable analyses using backwards and forwards selection. ResultsIn the double-blind studies, 175/1374 patients had a major response to placebo (n = 25) or perampanel (n = 150). The best predictors of a major treatment response in multivariable models with forwards and backwards selection were: the presence of FBTC seizures during baseline (P = 0.0002), higher perampanel plasma concentration (P < 0.0001), older age at diagnosis (P = 0.0024 and 0.0045, respectively), and lower baseline seizure frequency (P = 0.0364 and 0.0127, respectively). In the OLEx, 217/1090 patients had a major treatment response. The best predictors of a major treatment response in the final multivariable model, regardless of backwards or forwards selection, were a lower baseline seizure frequency (P = 0.0022), the absence of focal impaired awareness seizures during baseline (P = 0.0011), the presence of FBTC seizures during baseline (P = 0.0164), lower number(s) of baseline AEDs (P = 0.0002), the absence of EIAEDs during baseline (P = 0.0059), an older age at diagnosis (P = 0.0054), and absence of structural etiologies (P = 0.0138). SignificanceThese analyses of placebo-controlled and long-term extension trial data identified a number of potential predictive factors for patients with focal-onset seizures achieving a major treatment response. These factors may help guide clinicians when predicting a patient’s response to treatment and optimizing individual treatment regimens.

Health-related quality of life in pediatric patients with partial onset seizures or primary generalized tonic-clonic seizures receiving adjunctive perampanel

RationaleStudy 311 (E2007-G000-311; NCT02849626) was a Phase 3, multicenter, open-label single-arm study of adjunctive perampanel oral suspension in pediatric patients (aged 4 to <12 years) with partial-onset seizures (POS) (with/without secondarily generalized tonic-clonic seizures [SGTCS]) or primary generalized tonic-clonic seizures (PGTCS). Health-related quality of life (HRQoL) was an exploratory endpoint initially analyzed through simple descriptive summaries. The aim of this post hoc analysis was to provide a more thorough assessment of HRQoL. MethodsThis analysis focused on EQ-5D-Y data collected at Baseline, Week 23, and Week 52. Individual dimensions, visual analog scale (VAS) and summed misery index (MI) were evaluated at all visits and compared by seizure type (POS versus SGTCS versus PGTCS), age (4 to <7 versus 7 to <12), and use of concomitant enzyme-inducing antiepileptic drugs (EIAEDs) (yes versus no). Paretian Classification of Health Change (PCHC) analysis summarized the proportion of patients who showed improvement or deterioration in HRQoL. Waterfall plots assessed changes in EQ-5D-Y scores by treatment-emergent adverse events (TEAEs) and by reduction in seizure frequency. Health state utility values associated with differing seizure frequency states were estimated using a linear mixed model. ResultsOne hundred and fifteen patients completed EQ-5D-Y at relevant study visits (Seizure type: POS n = 84 [of which 21 had SGTCS], PGTCS n = 31; Age: 4 to <7 years n = 30, 7 to <12 years n = 85; Concomitant EIAEDs: Yes n = 35, No n = 80). Completion rates out of those expected to complete EQ-5D-Y were high at both timepoints (84.4% at Week 23 and 97.2% at Week 52). Overall, VAS/MI remained stable over time (did not exceed minimal important difference); this was similar according to seizure type, age, and EIAED usage. In patients with ‘no problems’ on any EQ-5D-Y dimension at Baseline, nearly all retained their full health at Week 23 (94.7%), and all retained it at Week 52 (100.0%). PCHC analysis showed fewer patients with POS experienced deterioration in EQ-5D-Y than patients with PGTCS at Week 23 (24.1% versus 42.1%). Not experiencing a TEAE, or remaining seizure-free, was associated with improvements in VAS score at Week 23 compared to those experiencing TEAEs or seizures, respectively. Health state utility values (HSUVs) were estimated as follows: seizure free (LS Mean 0.914 [95% CIs 0.587, 1.240]), ≥1 seizure per year (0.620 [0.506, 0.734]), ≥1 seizure per month (0.596 [0.338, 0.855]), ≥1 seizure per week (0.284 [−0.014, 0.582]). ConclusionsAn in-depth analysis of EQ-5D-Y data allowed for a more nuanced exploration of HRQoL than previous descriptive summaries. Our findings provide evidence that perampanel as adjunctive therapy did not result in deterioration of patient HRQoL. The association between TEAEs or remaining seizure-free and HRQoL warrants further exploration. Increasing seizure frequency was associated with decreasing HSUVs; these can inform cost-effectiveness modeling of perampanel and other therapies aiming to reduce seizure frequency in pediatric patients.

Vitamin D deficiency in a Portuguese epilepsy cohort: who is at risk and how to treat.

The epilepsy-related risk factors for vitamin D deficiency, particularly the use of enzyme-inducing antiepileptic drugs (EIAEDs), and how to treat vitamin D deficiency in patients with epilepsy remain unclear. Our aims were to explore risk factors and the influence of EAIEDs in vitamin D status and to determine the efficacy of a daily dose of oral cholecalciferol (vitamin D3) in epileptic patients with vitamin D deficiency. Clinical data were collected and 25-hydroxyvitamin D (25(OH)D) serum levels were measured. All patients with vitamin D deficiency (25(OH)D ≤20ng/mL) or insufficiency (25(OH)D from 21-29 ng/mL) were treated with 6,670IU/day cholecalciferol for eight weeks and 25(OH)D was then remeasured. Descriptive and inferential statistics were employed. A total of 92 patients (44.6% males), with mean age of 41.0±14.8 years, were included. Measurements of 25(OH)D revealed that 79.3% patients had abnormal levels: 56.5% were vitamin D deficient and 22.8% were vitamin D insufficient. The statistically significant risk factors for vitamin D deficiency identified were: number of AEDs, treatment with EIAEDs, low sun exposure, high body mass index (BMI) and a high frequency of epileptic seizures. After treatment, 25(OH)D mean level increased by 98.99% (regardless of EIAED use or being overweight). In our sample, more than half of the adults with epilepsy showed 25(OH)D deficiency. Patients on EIAEDs had lower 25(OH)D levels. A daily dose of 6,670IU cholecalciferol successfully led to the correction of 25(OH)D levels. A higher dose in obese patients or in patients taking EIAEDs may not be warranted and this should be considered in future guidelines for routine vitamin D deficiency treatment.

Therapeutic monitoring of carbamazepine and its active metabolite during the 1st postnatal month: Influence of drug interactions

ObjectiveTo receive information about carbamazepine and its active metabolite 10,11-epoxide transport into mature milk and suckling infants. MethodsIn this cohort study, maternal serum, mature milk, and infant serum carbamazepine and epoxide levels were measured between the 6th and 29th postnatal day (carbamazepine in 1990–2017, epoxide in 1997–2017). Paired maternal serum, infant serum and milk levels were used for the assessment of ratios of this levels. The influence of combined treatment with enzyme-inducing antiepileptic drugs and valproic acid was assessed. Relationship between maternal serum, infant serum, and milk levels was also evaluated. ResultsMaternal carbamazepine levels were 1.4–10.4 mg/L, milk 0.5–6.7 mg/L and infant 0.5–2.6 mg/L. Maternal 10,11-epoxide levels were 0.3–5.4 mg/L, milk 0.3–3.7 mg/L and infant 0.3–0.6 mg/L. Highly significant correlations were observed exclusively between milk and maternal serum levels of both carbamazepine and 10,11-epoxide. Concomitant administration of enzyme-inducing antiepileptic drugs significantly increased the maternal apparent oral clearance of carbamazepine by approximately 130%. Carbamazepine combined with valproic acid significantly increased epoxide levels in milk and maternal serum but not in breastfed infants. ConclusionsIn breastfed infants, carbamazepine levels did not reach the lower limit of the therapeutic range used for the general epileptic population, and the majority of epoxide levels were less than the lower limit of quantification. Routine monitoring of carbamazepine in these infants is not compulsory. However, observation of breastfed infants is desirable. If signs of potential adverse reactions are evident, infant serum concentrations should be monitor.

Prevalence and Risk Factors for Vitamin D Insufficiency among Adults with Epilepsy at University Hospital in Jeddah, Saudi Arabia: A Cross Sectional Study

Background: Vitamin D is essential for bone physical condition, and vitamin D insufficiency may add to further autoimmune diseases, infections or even cancer. Enzyme-inducing antiepileptic drugs have been predominantly linked with osteoporosis hazard proved their impacts on vitamin D. The study aim was to determine the prevalence of vitamin D insufficiency and deficiency and the covariates associated with it among the adult epileptic patients attending King Fahd neurology outpatient clinics.&#x0D; Subjects and Methods: 297 adult epilepsy patients joined this cross-sectional study at King Fahd Hospital in 2017. Vitamin D level was considered as deficiency (&lt;10ng/ml), insufficiency (&lt;30ng/ml), or normal (≥30ng/ml). Antiepileptic drugs were sorted out according to their enzyme inducing criteria.&#x0D; Results: 87.88% adult epileptic patients were between 18 – 50 years of age, more than half were females, married, and with higher degree of education, less than half received monthly income of less than 5,000 SR, nearly two third were either smokers or ex-smokers. Multiple linear regression model for predictors of vitamin D insufficiency and deficiency declared that; enzyme induced antiepileptic drugs, polytherapy, and smoking were significantly correlated with vitamin deficiency and insufficiency (p &lt; 0.05).&#x0D; Conclusion: Vitamin D insufficiency and deficiency is widespread among adult epileptic patients. Screening of vitamin D level should be taken into consideration as part of the regular follow up of epileptic patients.