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Valproic acid (VPA) is used for epilepsy and bipolar disorder. It has near-complete bioavailability and is primarily metabolized by glucuronosyltransferases and mitochondrial oxidation. This case highlights a 79-year-old male with bipolar disorder on VPA therapy that started with flucloxacillin for Staphylococcus aureus bacteraemia and exhibited significantly reduced VPA serum levels. During hospitalization, flucloxacillin treatment correlated with a sharp decline of 75% in VPA total serum levels, a novel drug-drug interaction not previously reported. Nonadherence and absorption issues of VPA were ruled out, confirming flucloxacillin's role in reducing VPA levels. Because free-fraction serum levels of VPA remained within therapeutic range (5-25 mg/L) and our patient's bipolar disorder remained stable at 1000 mg twice daily, a dose increase was not necessary. Previous reports described cytochrome P450 enzyme induction as the mechanism of flucloxacillin lowering serum levels of immunosuppressants and antimycotics. Because only 10% of VPA is metabolized by cytochrome P450 enzymes, this is not plausible for this case. The proposed mechanism for the VPA-flucloxacillin drug-drug interaction is flucloxacillin as inducer of glucuronosyltransferase enzymes via the pregnane X receptor pathway, accelerating VPA metabolism. Because this case showed that free-fraction serum levels remained within therapeutic range, it underscores the need for free-fraction VPA monitoring in bipolar disorder and flucloxacillin therapy. When VPA is used for epilepsy, it is advised to consider alternative antibiotics to avoid this interaction., (© 2024 British Pharmacological Society.)

Brivaracetam (BRV) is a new third-generation antiseizure medication for the treatment of focal epileptic seizures. Its use has been increasing among epileptic populations in recent years, but pharmacokinetic (PK) behavior may change in hepatic impairment and the elderly populations. Due to ethical constraints, clinical trials are difficult to conduct and data are limited. This study used PK-Sim® to develop a physiologically based pharmacokinetic (PBPK) model for adults and extrapolate it to hepatic impairment and the elderly populations. The model was evaluated with clinical PK data, and dosage explorations were conducted. For the adult population with mild hepatic impairment, the dose is recommended to be adjusted to 70 % of the recommended dose, and to 60 % for moderate and severe hepatic impairment. For the elderly population with mild hepatic impairment under 80 years old, it is recommended that the dose be adjusted to 60 % of the recommended dose and to 50 % for moderate and severe conditions. The elderly population with hepatic impairment over 80 years old is adjusted to 50 % of the recommended dose for all stages. Healthy elderly do not need to adjust. The BRV PBPK model was successfully developed, studying exposure in hepatic impairment and elderly populations and optimizing dosing regimens., Competing Interests: Declaration of interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.)

Purpose: This study aims to assess the predictive performance of published valproic acid (VPA) population pharmacokinetic (PPK) models using an external data set in Chinese adults with epilepsy or after neurosurgery., Methods: A total of 384 concentrations from 290 Chinese adults with epilepsy or after neurosurgery were used for external validation. Data on published VPA PPK models were extracted from the literature. Prediction-based diagnostics (such as F20 and F30), simulation-based diagnostics, and Bayesian forecasting were used to evaluate the predictability of models., Results: The results of prediction-based diagnostics of all models were unsatisfactory. Models B, F, and H showed the best prediction performance in simulation-based diagnostics and Bayesian forecasting, demonstrating superior precision and accuracy. Bayesian forecasting demonstrated significant improvements in the model predictability., Conclusion: The published PPK models showed extensive variation in predictive performance for extrapolation among Chinese adults with epilepsy or after neurosurgery patients. Fixed parameters of Vd and Ka in the PPK modeling of VPA might be the reason for the unsatisfied predictive performance. Bayesian forecasting significantly improved model predictability and may help to individualize VPA dosing., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The number of available antiseizure medications with demonstrated efficacy in cats is limited. As such, there is a need to evaluate the pharmacokinetics of newer medications so that proper dosing regimens can be made. Brivaracetam (BRV) is a more potent analogue of levetiracetam, and is Food and Drug Administration approved for use in people. The goal of this study was to describe the pharmacokinetics of intravenous and oral doses of BRV in healthy cats. A cross-over study involving eight healthy cats, that were administered 10 mg of BRV intravenously as a bolus and orally in the fasted state. Blood samples were collected over 24 h. Analysis was performed using liquid chromatography-mass spectrometry. Data were subjected to non-compartmental analysis. Median (min-max) of maximal concentration, time to maximal concentration, area under the curve, elimination half-life and oral absolute bioavailability were 902 (682-1036) ng/mL, 0.6 (0.5-2.0) h, 6.4 (5.2-7.2) h, 8145 (6669-9351) ng × h/mL and 100% (85-110) respectively. BRV appeared to be well tolerated by all cats. A single dose of BRV is well tolerated both orally and intravenously. Maximal concentrations are produced rapidly and within the human reference interval considered to be therapeutic., (© 2024 John Wiley & Sons Ltd.)

Background: Monitoring free valproate concentrations, as with other highly protein-bound anticonvulsants, is essential in clinical situations where protein binding may be disrupted. Conversion of measured total concentrations to approximate free concentrations offers a cost-effective alternative. This study evaluated the relationship between total and free valproate concentrations for discordance and the impact of key determinants. A novel formula was devised that incorporates significant variables., Methods: A multicentre, cross-sectional observational analytical study included 101 subjects 18 years and older using valproate for 6 months or longer. Participants were recruited from private and public sector healthcare settings from primary to tertiary level in, South Africa, during 2017-2019., Results: Free valproate concentrations could be measured for 84 subjects. Discordance for concomitant total and free valproate concentrations was 79.1%. Among 19 participants with elevated free concentrations, 15 (78.9%) had total valproate concentrations within the recommended reference range. Calculations based on the study-derived formula were more accurate in predicting free valproate concentration than previously proposed methods., Conclusion: This study proposes that the novel formula for calculating free valproate enables more accurate prediction., (© 2024. The Author(s).)

Our goal is to create a population pharmacokinetic (PK) model and identify the best loading dose (LD) of intravenous valproic acid for hospitalized Thai patients. Data from patients who received intravenous valproic acid and underwent measurement of serum valproic acid concentrations during hospitalization were collected retrospectively. A nonlinear mixed-effects modeling approach was conducted to estimate the PK parameters of valproic acid. Covariates affecting the PK parameters of valproic acid were examined and ranked based on their impact on the model's performance. Monte Carlo simulations of 1000 patients were conducted to estimate the optimal LD of valproic acid. A total of 120 hospitalized patients (51.7% male) with 167 valproic acid concentrations were included in the study. A linear one-compartment model with constant residual error was the best base model. An age-covariate model was the best predictor of valproic acid clearance (CL). The typical values of CL and volume of distribution for valproic acid were 0.77 L/h and 14.56 L, respectively. The LD of 1000-1200 mg intravenous was identified as the pragmatic option as an empirical regimen for hospitalized Thai patients. The recommended time to initiate maintenance dose (MD) is 4-8 h following the LD. The population PK model and optimal LD of valproic acid in hospitalized Thai patients has been established, and it may be advisable to initiate the MD at a later time for the elderly., (© 2024, The American College of Clinical Pharmacology.)

Epilepsy is a highly prevalent neurological disease and valproic acid (VPA) is used as a first-line chronic treatment. However, this drug has poor oral bioavailability, which requires the administration of high doses, resulting in adverse effects. Alternative routes of VPA administration have therefore been investigated, such as the nose-to-brain route, which allows the drug to be transported directly from the nasal cavity to the brain. Here, the use of nanostructured lipid carriers (NLC) to encapsulate drugs administered in the nasal cavity has proved advantageous. The aim of this work was to optimise a mucoadhesive formulation of VPA-loaded NLC for intranasal administration to improve the treatment of epilepsy. The Design of Experiment (DoE) was used to optimise the formulation, starting with component optimisation using Mixture Design (MD), followed by optimisation of the manufacturing process parameters using Central Composite Design (CCD). The optimised VPA-loaded NLC had a particle size of 76.1 ± 2.8 nm, a polydispersity index of 0.190 ± 0.027, a zeta potential of 28.1 ± 2.0 mV and an encapsulation efficiency of 85.4 ± 0.8%. The in vitro release study showed VPA release from the NLC of 50 % after 6 h and 100 % after 24 h. The in vitro biocompatibility experiments in various cell lines have shown that the optimised VPA-loaded NLC formulation is safe up to 75 µg/mL, in neuronal (SH-SY5Y), nasal (RPMI 2650) and hepatic (HepG2) cells. Finally, the interaction of the optimised VPA-loaded NLC formulation with nasal mucus was investigated and mucoadhesive properties were observed. The results of this study suggest that the use of intranasal VPA-loaded NLC may be a promising alternative to promote VPA targeting to the brain, thereby improving bioavailability and minimising adverse effects., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Objective: In this study, we aimed to assess main factors influencing the Valproic Acid (V.Acid) plasma trough levels (C0) and to determine their degree of influence on V.Acid C0 in children with epilepsy who had Therapeutic Drug Monitoring (TDM)., Methods: We conducted an observational study in the Department of Clinical Pharmacology including patients with generalized seizures' epilepsy aged between two and 18 years. Only the children that had benefited from at least two V.Acid C0 determinations were included. First, we assessed daily dose optimization, performed by the practitioners. Then we divided our population into two groups: group A with a final V.Acid C0 in the therapeutic range (TR) and group B with a final V. Acid C0 outside the TR to find out factors influencing V.Acid C0 journey., Results: We included 805 patients (2537 V.Acid C0). The median age was 6.24 years and the sex ratio (M/F) was 1.45. The median V.Acid normalized daily dose was 27.27mg/kg/day and the median V.Acid C0 was 57µg/mL. The children's first V.Acid C0 was in the TR in 59.4% and V.Acid daily dose optimization was performed by the practitioners in 72.3%. Comparing GroupA and B, we found that age and the number of V.Acid C0 determinations increases the chance to reach the TR by respectively 3.79% and 7.39%., Conclusion: Older children who benefit from higher number of performed V.Acid C0 were more likely to reach the TR. In children who beneficiate from a TDM of V.Acid, close follow-up is mandatory to reach and maintain therapeutic V.Acid C0.

Background and Objective: Valproic acid (VPA) demonstrates nonlinear pharmacokinetics (PK) due to a capacity-limited protein binding, which has potential implications on its total and unbound plasma concentrations, especially during hypoalbuminemia. A physiologically based pharmacokinetic (PBPK) model was developed to assess the nonlinear dose-exposure relationship of VPA with special emphasis on pediatric patients with hypoalbuminemia., Methods: A PBPK model was first developed and evaluated in adults using PK-Sim ® and MoBi ® (v.11) and the scaled to children 1 year and older. The capacity-limited protein binding was characterized by second-order kinetics between VPA and albumin with a 2:1 molar ratio. All drug-specific parameters were informed by literature and optimized using published PK data of VPA. PK simulations were performed in virtual populations with normal and low albumin levels., Results: The reported concentration-time profiles of total and unbound VPA were adequately predicted by the PBPK model across the age and dose range (3-120 mg/kg). The model was able to characterize the nonlinear PK, as the concentration-dependent fraction unbound (f u ) and the related dose-dependent clearance values were well predicted. Simulated steady-state trough concentrations of total VPA were less than dose-proportional and were within the therapeutic drug monitoring range of 50-100 mg/L for doses between 30 and 45 mg/kg per day in children with normal albumin concentrations. However, virtual children with hypoalbuminemia largely failed to achieve the target exposure., Conclusion: The PBPK model helped assess the nonlinear dose-exposure relationship of VPA and the impact of albumin concentrations on the achievement of target exposure., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Objective: The current standard of care for Dravet syndrome (DS) includes polytherapy after inadequate seizure control with one or more monotherapy approaches. Treatment guidelines are often based on expert opinions, and finding an optimal balance between seizure control and adverse drug effects can be challenging. This study utilizes the efficacy and pharmacokinetic assessment of a second-line treatment regimen that combines clobazam and sodium valproate with an add-on drug as a proof-of-principle approach to establish an effective therapeutic regimen in a DS mouse model., Methods: We evaluated the efficacy of add-on therapies stiripentol, cannabidiol, lorcaserin, or fenfluramine added to clobazam and sodium valproate against hyperthermia-induced seizures in Scn1a A1783V/WT mice. Clobazam, N-desmethyl clobazam (an active metabolite of clobazam), sodium valproate, stiripentol, and cannabidiol concentrations were quantified in plasma and brain using liquid chromatography-tandem mass spectrometry for the combinations deemed effective against hyperthermia-induced seizures. The concentration data were used to calculate pharmacokinetic parameters via noncompartmental analysis in Phoenix WinNonLin., Results: Higher doses of stiripentol or cannabidiol, in combination with clobazam and sodium valproate, were effective against hyperthermia-induced seizures in Scn1a A1783V/WT mice. In Scn1a WT/WT mice, brain clobazam and N-desmethyl clobazam concentrations were higher in the triple-drug combinations than in the clobazam monotherapy. Stiripentol and cannabidiol brain concentrations were greater in the triple-drug therapy than when given alone., Significance: A polypharmacy strategy may be a practical preclinical approach to identifying efficacious compounds for DS. The drug-drug interactions between compounds used in this study may explain the potentiated efficacy of some polytherapies., (© 2024 The Author(s). Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Background: Lamotrigine is a new antiepileptic drug with substantial interindividual variability in its pharmacokinetics and therapeutic responses. This study aimed to develop population pharmacokinetic (PPK) models of lamotrigine and its N2-glucuronide metabolites for model-informed individualized therapy., Methods: A total of 353 plasma concentrations from Chinese patients with epilepsy receiving oral lamotrigine were used to develop a population PPK model using a nonlinear mixed effects modeling method. One- and two-compartment models were applied to the nonmetabolite and metabolite model, respectively. Forward addition and backward elimination were used to establish the final model. Model validation was performed using standard goodness-of-fit, bootstrap, visual predictive checks, and normalized prediction distribution errors. Finally, simulations were performed to propose lamotrigine dosages in different situations to achieve trough concentrations within the reference interval (2.5-15 mg/L)., Results: For both final population PPK models, coadministration with valproic acid (VPA) or enzyme inducer, and body weight significantly affected lamotrigine clearance. The final models for lamotrigine clearance were and for nonmetabolite and metabolite models, respectively. The precision of the PPK parameters was acceptable, and the models exhibited good predictability. Monte Carlo simulations revealed that the lamotrigine dosage administered to patients combined with an enzyme inducer must be tripled that administered with VPA to reach the target trough concentration., Conclusions: Variability in the pharmacokinetics of lamotrigine is large. Coadministration of VPA or an enzyme inducer and body weight are the most important factors in lamotrigine clearance in Chinese patients with epilepsy. The developed population PPK models might support further optimization of lamotrigine dosing regimens., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Carbamazepine (CBZ) is the recommended alternative to rifampicin as a CYP3A4 inducer in drug-drug interaction studies. However, the traditional CBZ dosing paradigm can lead to several adverse events (AEs). This study tested a shorter CBZ dosing regimen using the CYP3A4-sensitive index substrate midazolam (MDZ). This was a fixed-sequence arm of an open-label, phase I study (NCT04840888). Healthy participants (n = 15) aged 18-63 years received oral doses of 1.2 mg MDZ alone (Day 1), CBZ b.i.d. alone (100 mg Days 2-4; 200 mg Days 5-7; 300 mg Days 8-10 and 12-13), and 300 mg CBZ b.i.d. plus 1.2 mg MDZ (Days 11 and 14). One participant (6.7%) experienced constipation due to treatment with CBZ plus MDZ on Day 11. One participant (6.7%) experienced urticaria (Days 12-13), and two participants (13.3%) experienced somnolence (Days 8-10) due to treatment with 300 mg CBZ b.i.d. alone. All AEs were mild. For MDZ, the geometric mean (90% CI) ratio (vs. Day 1) of the area under the curve (AUC 0-∞) was 0.28 (0.24-0.31) on Day 11 and 0.26 (0.23-0.29) on Day 14. The AUC (0-12 hours) of CBZ was 114,000 ng∙h/mL on Day 11 and 105,000 ng∙h/mL on Day 14. Steady-state concentrations of CBZ and induction of CYP3A4 were achieved on Day 11. The data are consistent with predictions of physiologically-based pharmacokinetic models in Simcyp. The 9-day dosing regimen for CBZ induction was well-tolerated by healthy participants, supporting the use of a shorter CBZ regimen for CYP3A4 induction studies., (© 2024 The Author(s). Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Background: This study comprehensively examined the demographic and clinical characteristics of patients undergoing valproic acid therapy and explored their potential impact on plasma valproic acid concentrations. All enrolled patients were administered the extended-release formulation. An in-depth investigation of factors, including dose, age, sex, body mass index, co-administered medications, and laboratory test findings, was conducted to evaluate their potential influence on study outcomes., Methods: In total, 164 patients met the inclusion criteria and were included in the analysis. The patient age ranged from 13 to 60 years, with a median age of 25.71 years. Most patients (89%) received a daily dose of 1 g valproic acid. Co-administered psychiatric medications included aripiprazole, quetiapine, and lorazepam. Laboratory test results, such as hemoglobin and transaminase levels, were also collected as part of the study., Results: The average plasma valproic acid plasma concentration was 79.8 mg/L. The dose significantly affected valproic acid concentrations, as a higher percentage of measurements exceeded the therapeutic range at a daily dose of 1 g. Furthermore, females exhibited significantly higher valproic acid concentrations compared with males at the same dose ( P < 0.05). However, different age groups showed no statistically significant differences in valproic acid concentrations ( P > 0.05). The co-administered antipsychotic and antidepressant medications significantly affected valproate concentrations, as reflected in the multiple regression model ( P < 0.01)., Conclusions: This study offers valuable insights into the demographic and clinical characteristics of patients undergoing valproic acid therapy. It highlights the influence of dose, sex, and concomitant medications on plasma valproic acid concentrations. Overall, these findings can help guide dose adjustments and implement personalized treatment strategies in valproic acid therapy., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: There is limited evidence to support the currently suggested lamotrigine (LTG) therapeutic reference range of 2.5-15 mg/L for the treatment of seizures. The objective of this study was to evaluate the association of LTG plasma concentrations with the efficacy and toxicity of the treatment in patients with epilepsy., Methods: Patients whose LTG plasma concentration was measured between January 2013 and February 2022 were included. Efficacy was defined as seizure freedom for at least 6 months around the time of measured LTG concentration. Toxicity was defined as any LTG-related adverse drug effect documented in each patient's health record or when the reason for measuring the LTG concentration was toxicity. In addition, the dose-concentration relationship of LTG was assessed., Results: In total, 549 concentrations from 259 patients with epilepsy were included. The most common reasons for therapeutic drug monitoring were suspected inefficacy (39%) and pregnancy (21%). The LTG plasma concentration was not associated with efficacy (adjusted odds ratio = 0.94; 95% confidence interval, 0.85-1.04). The LTG plasma concentration was positively associated with the incidence of toxicity after adjusting for age, sex, and number of antiepileptic drugs (odds ratio = 1.11; 95% confidence interval, 1.04-1.19). The daily dose had a significant linear correlation with the LTG plasma concentration ( P < 0.001)., Conclusions: The LTG plasma concentration was associated with toxicity, whereas no association with efficacy was found. A reference range of 2.5-10 mg/L may be considered to decrease the risk of toxicity while maintaining similar efficacy. Therapeutic drug monitoring may be useful when LTG-related toxicity is suspected and in cases of pharmacokinetic changes (eg, pregnancy and concomitant use of interacting drugs) that can influence the LTG plasma concentration., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Rufinamide and stiripentol, orphan drugs used in Lennox-Gastaut and Dravet syndromes, respectively, are antiseizure medications (ASMs), often administered to children; however, pharmacokinetic studies are lacking. The authors compared the pharmacokinetic variability of these drugs with respect to the dose, serum concentrations, comedication, age, and duration of treatment., Methods: Children and adolescents (<18 years) whose serum concentrations were measured were retrospectively identified from the therapeutic drug monitoring (TDM) databases at 2 national epilepsy centers in Norway and Denmark (2012-2021)., Results: Data from 165 patients (56% boys/44% girls) treated with rufinamide and 52 patients (50% boys/50% girls) treated with stiripentol were included. For rufinamide, the median age was 10 (range 2-17) years, dose 23 (3-73) mg/d, and serum concentration 34 (3-227) µmol/L [8.1 mg/L (0.71-54.0 mg/L)]. For stiripentol, the median age was 8.5 (range 1-17) years, dose 37 (18-76) mg/d, and serum concentration 33 (4-113) µmol/L [7.7 mg/L (0.93-26.3 mg/L)]. The concomitant use of 1-9 other ASMs during the data collection was noted. Pharmacokinetic variability, calculated as the concentration/(dose/kg) ratio, ranged from 0.26 to 11.31 (µmol/L)/(mg/kg) for rufinamide and 0.17-1.52 (µmol/L)/(mg/kg) for stiripentol. The intraindividual coefficients of variation ranged widely, from 5% to 110% for rufinamide and 11%-117% for stiripentol. The treatment period was at least 5 years in 50% of patients. No statistically significant effects of age, sex, or ASM comedication were observed, possibly due to the small sample size and heterogeneous groups with variable seizure situations, comorbidities, and changes in comedication and physiology., Conclusions: This study demonstrates considerable pharmacokinetic variability in and between patients for both drugs and similar use in terms of age, burden of comedication and retention rates. TDM may be useful in the clinical setting to monitor and optimize treatment in this vulnerable patient group., Competing Interests: C. Johannessen Landmark has received speaker honoraria from Angelini, Eisai, Jazz, and UCB Pharma Nordic, and M. Nikanorova received speaker honoraria from UCB Pharma Nordic. The other authors declare no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Valproic acid (VPA) is a commonly used broad-spectrum antiepileptic drug. For elderly epileptic patients, VPA plasma concentrations have a considerable variation. We aim to establish a prediction model via a combination of machine learning and population pharmacokinetics (PPK) for VPA plasma concentration., Methods: A retrospective study was performed incorporating 43 variables, including PPK parameters. Recursive Feature Elimination with Cross-Validation was used for feature selection. Multiple algorithms were employed for ensemble model, and the model was interpreted by Shapley Additive exPlanations., Results: The inclusion of PPK parameters significantly enhances the performance of individual algorithm model. The composition of categorical boosting, light gradient boosting machine, and random forest (7:2:1) with the highest R 2 (0.74) was determined as the ensemble model. The model included 11 variables after feature selection, of which the predictive performance was comparable to the model that incorporated all variables., Conclusions: Our model was specifically tailored for elderly epileptic patients, providing an efficient and cost-effective approach to predict VPA plasma concentration. The model combined classical PPK with machine learning, and underwent optimization through feature selection and algorithm integration. Our model can serve as a fundamental tool for clinicians in determining VPA plasma concentration and individualized dosing regimens accordingly., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2024. Published by Elsevier B.V.)

Objective: This study was undertaken to assess the effectiveness/tolerability of adjunctive cenobamate, variations in the load of concomitant antiseizure medications (ASMs) and predictors of clinical response in people with focal epilepsy., Methods: This was a retrospective study at 21 centers participating in the Italian Expanded Access Program. Effectiveness outcomes included retention and responder rates (≥50% and 100% reduction in baseline seizure frequency). Tolerability/safety outcomes included the rate of treatment discontinuation due to adverse events (AEs) and their incidence. Total drug load was quantified as the number of concomitant ASMs and total defined daily dose (DDD). Concomitant ASMs were also classified according to their mechanism of action and pharmacokinetic interactions to perform explorative subgroup analyses., Results: A total of 236 subjects with a median age of 38 (Q 1 -Q 3 = 27-49) years were included. At 12 months, cenobamate retention rate was 78.8% and responders were 57.5%. The seizure freedom rates during the preceding 3 months were 9.8%, 12.2%, 16.3%, and 14.0% at 3, 6, 9, and 12 months. A higher percentage of responders was observed among subjects treated with clobazam, although the difference was not statistically significant. A total of 223 AEs were recorded in 133 of 236 participants, leading to cenobamate discontinuation in 8.5% cases. At 12 months, a reduction of one or two concomitant ASMs occurred in 42.6% and 4.3% of the subjects. The median total DDD of all concomitant ASMs decreased from 3.34 (Q 1 -Q 3  = 2.50-4.47) at baseline to 2.50 (Q 1 -Q 3  = 1.67-3.50) at 12 months (p < .001, median percentage reduction = 22.2%). The highest rates of cotreatment withdrawal and reductions in the DDD were observed for sodium channel blockers and γ-aminobutyric acidergic modulators (above all for those linked to pharmacokinetic interactions), and perampanel., Significance: Adjunctive cenobamate was associated with a reduction in seizure frequency and in the burden of concomitant ASMs in adults with difficult-to-treat focal epilepsy. The type of ASM associated did not influence effectiveness except for a favorable trend with clobazam., (© 2024 The Author(s). Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Lamotrigine is a phenyltriazine anticonvulsant that is primarily metabolized by phase II UDP-glucuronosyltransferases (UGT) to a quaternary N2-glucuronide, which accounts for ~ 90% of the excreted dose in humans. While there is consensus that UGT1A4 plays a predominant role in the formation of the N2-glucuronide, there is compelling evidence in the literature to suggest that the metabolism of lamotrigine is catalyzed by another UGT isoform. However, the exact identity of the UGT isoform that contribute to the formation of this glucuronide remains uncertain. In this study, we harnessed a robust reaction phenotyping strategy to delineate the identities and its associated fraction metabolized (f m ) of the UGTs involved in lamotrigine N2-glucuronidation. Foremost, human recombinant UGT mapping experiments revealed that the N2-glucuronide is catalyzed by multiple UGT isoforms. (i.e., UGT1A1, 1A3, 1A4, 1A9, 2B4, 2B7, and 2B10). Thereafter, scaling the apparent intrinsic clearances obtained from the enzyme kinetic experiments with our in-house liver-derived relative expression factors (REF) and relative activity factors (RAF) revealed that, in addition to UGT1A4, UGT2B10 was involved in the N2-glucuronidation of lamotrigine. This was further confirmed via chemical inhibition in human liver microsomes with the UGT1A4-selective inhibitor hecogenin and the UGT2B10-selective inhibitor desloratadine. By integrating various orthogonal approaches (i.e., REF- and RAF-scaling, and chemical inhibition), we quantitatively determined that the f m for UGT1A4 and UGT2B10 ranged from 0.42 - 0.64 and 0.32 - 0.57, respectively. Finally, we also provided nascent evidence that the pharmacokinetic interaction between lamotrigine and valproic acid likely arose from the in vivo inhibition of its UGT2B10-mediated pathway., (© 2024. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.)

Objectives: To confirm that levetiracetam (LEV) demonstrates predictable pharmacokinetics(PK) at higher doses and to study the pharmacodynamics(PD) of LEV., Design: Pharmacokinetic data from the NEOLEV1 and NEOLEV2 trials were analysed using a non-linear mixed effects modelling approach. A post hoc analysis of the effect of LEV on seizure burden was conducted., Setting: Neonatal intensive care unit., Patients: Term neonates with electrographically confirmed seizures., Interventions: In NEOLEV1, neonates with seizures persisting following phenobarbital (PHB) received LEV 20 or 40 mg/kg bolus followed by 5 or 10 mg/kg maintenance dose(MD) daily. In NEOLEV2, patients received a 40 mg/kg intravenous LEV load, followed by 10 mg/kg doses 8 hourly. If seizures persisted, a further 20 mg/kg intravenous load was given. If seizures persisted, PHB was given. PK data were collected from 16 NEOLEV1 patients and 33 NEOLEV2 patients. cEEG data from 48 NEOLEV2 patients were analysed to investigate onset of action and seizure burden reduction., Main Outcome Measures: Clearance (CL) and volume of distribution (V d ) were determined. Covariates that significantly affected LEV disposition were identified., Results: Primary outcome: The median initial LEV level was 57 µg/mL (range 19-107) after the first loading dose and at least 12 µg/mL at 48 hours in all infants. CL and V d were estimated to be 0.0538 L/hour and 0.832 L, respectively. A direct relationship between postnatal age and CL was observed. The final population pharmacokinetic(PopPK) model described the observed data well without significant biases. CL and V d were described as CL (L/hour)=0.0538×(weight in kg/3.34)0.75×(postnatal age in days/5.5) 0.402 and V d (L)=0.832×(weight in kg/3.34).Seizure burden reduced within 30 min of LEV administration. 28% of patients were completely seizure free after LEV. In an additional 25% of patients, seizure burden reduced by 50%., Conclusions: LEV pharmacokinetics remained predictable at higher doses. Very high-dose LEV can now be studied in neonates., Trial Registration Number: NCT01720667., Competing Interests: Competing interests: RHH and CS have done consulting work for Sparc pharmaceuticals who are seeking FDA indication for PHB in the treatment of neonatal seizures., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Encapsulating antiepileptic drugs (AEDs), including ethosuximide (Etho), into nanoparticles shows promise in treating epilepsy. Nanomedicine may be the most significant contributor to addressing this issue. It presents several advantages compared to traditional drug delivery methods and is currently a prominent area of focus in cancer research. Incorporating Etho into bismuth ferrite (BFO) nanoparticles within diverse controlled drug delivery systems is explored to enhance drug efficacy. This approach is primarily desired to aid in targeted drug delivery to the brain's deepest regions while limiting transplacental permeability, reducing fetal exposure, and mitigating associated adverse effects. In this investigation, we explored Etho, an antiepileptic drug commonly employed for treating absence seizures, as the active ingredient in BFO nanoparticles at varying concentrations (10 and 15 mg). Characterization of the drug-containing BFO nanoparticles involved scanning electron microscopy (SEM) and elemental analysis. The thermal properties of the drug-containing BFO nanoparticles were evaluated via differential scanning calorimetry (DSC) analysis. Cytotoxicity evaluations using the MTT assay were conducted on all nanoparticles, and human neuroblastoma cell line cultures (SH-SY5Y) were treated with each particle over multiple time intervals. Cell viability remained at 135% after 7 days when exposed to 15 mg of Etho in BFO nanoparticles. Additionally, in vitro drug release kinetics for Etho revealed sustained release lasting up to 5 hours with a drug concentration of 15 mg., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Guldorum et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Aims: This study aims to investigate the safety, tolerability, efficacy, and pharmacokinetics of Pynegabine as an add-on therapy in the treatment of focal epilepsy., Methodology: This is a protocol phase-IIa, randomized, double-blinded, placebo-controlled, multicenter study in patients with focal epilepsy from multiple centers in China who have been treated with at least 2 ASMs without effective control. The study involves an 8-week run-in period with stable use of previous medications. Patients are then randomized to receive either Pynegabine or a placebo. Sentinel administration is performed initially, and subsequent patients are randomized based on safety assessments. Three dose cohorts (15, 20, and 25 mg/d) are established. Efficacy is assessed through various measures, including seizure frequency, CGI score, PGI score, HAMA score, HAMD score, MoCA scale score, QOLIE-31 scale score, and 12 h-EEG score. Safety evaluations, PK blood samples, concomitant medications, and adverse events are also recorded., Conclusion: Data from the study will be used to evaluate the safety, tolerability, efficacy, and pharmacokinetics of Pynegabine tablets as add-on therapy for focal epilepsy., (© 2024 The Author(s). CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Introduction: Lamotrigine (LTG) is an antiepileptic drug that has been used in pediatric epilepsy as a combination therapy or monotherapy after stabilization in recent years. However, there are significant drug-drug interactions (DDI) between LTG and combined drugs such as carbamazepine (CBZ) and valproic acid (VPA). It is particularly important to consider the risk of DDI in combination therapy for intractable epilepsy in pediatric patients. Therefore, it is necessary to adjust the dosage of LTG accordingly. The aim of this study was to establish and validate a pediatric physiologically based pharmacokinetic (PBPK) model for predicting LTG exposure. The model is designed to explore the potential for quantifying pharmacokinetic (PK) DDI of LTG when administered concurrently with CBZ or VPA in pediatric patients., Method: Adult and pediatric PBPK models for LTG and VPA were developed using PK-Sim® software in combination with physiological information and drug-specific parameters, and a DDI model was developed in combination with the published CBZ model. The models were validated against available PK data., Results: Predictive and observational results in adults, children, and the DDI model were in good agreement. The recommended doses of LTG for preschool children (2-6 years) and school-aged children (6-12 years) in the absence of drug interactions were 1.47 and 1.2 times higher than those for adults, respectively; 3.1 and 2.6 times higher than those for adults in combination with CBZ; and 0.67 and 0.57 times lower than those for adults in combination with VPA. In addition, plasma exposures in adolescents (12-18 years) were similar to those in adults at the same doses., Conclusion: We have successfully developed PBPK models and DDI models for LTG in adults and children, which provide a reference for rational drug use in the pediatric population., (© 2024 Pharmacotherapy Publications, Inc.)

Significant pharmacokinetic (PK) differences exist between different forms of valproic acid (VPA), such as syrup and sustained-release (SR) tablets. This study aimed to develop a population pharmacokinetic (PopPK) model for VPA in children with epilepsy and offer dose adjustment recommendation for switching dosage forms as needed. The study collected 1411 VPA steady-state trough concentrations (C trough ) from 617 children with epilepsy. Using NONMEM software, a PopPK model was developed, employing a stepwise approach to identify possible variables such as demographic information and concomitant medications. The final model underwent internal and external evaluation via graphical and statistical methods. Moreover, Monte Carlo simulations were used to generate a dose tailoring strategy for typical patients weighting 20-50 kg. As a result, the PK characteristics of VPA were described using a one-compartment model with first-order absorption. The absorption rate constant (k a ) was set at 2.64 and 0.46 h -1 for syrup and SR tablets. Body weight and sex were identified as significant factors affecting VPA's pharmacokinetics. The final PopPK model demonstrated acceptable prediction performance and stability during internal and external evaluation. For children taking syrup, a daily dose of 25 mg/kg resulted in the highest probability of achieving the desired target C trough , while a dose of 20 mg/kg/day was appropriate for those taking SR tablets. In conclusion, we established a PopPK model for VPA in children with epilepsy to tailor VPA dosage when switching between syrup and SR tablets, aiming to improve plasma VPA concentrations fluctuations., (© 2024 The Author(s). CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Current recommendations for refractory status epilepticus (SE) unresponsive to benzodiazepines suggest a loading dose of levetiracetam (LEV) of 60 mg/kg to a maximum of 4500 mg. LEV therapeutic drug monitoring can help guide therapy and is garnering increasing attention. The objective of this study is to simulate the probability of target attainment (PTA) of fixed dose and weight-based loading doses of LEV with respect to established therapeutic target concentrations. Meta-regression of the current literature was performed to evaluate the relationship between intravenous LEV loading dose and seizure cessation in refractory SE patients. A previously published pharmacokinetic model was used to simulate the PTA capacity of competing single intravenous dosing schemes (fixed vs weight-based dosing) to achieve maximum (C peak ) and 12-h (C 12h ) plasma concentrations that exceed 12 mg/L. The meta-regression indicated that dosage was not a statistically significant modulator of seizure control at dosages between 20 and 60 mg/kg. Stochastic simulations showed all dosing schemes achieved plasma C peak >12 mg/L, but C 12h levels were <12 mg/L in subjects over 60 kg with a fixed dose ≤2000 mg or in subjects <60 kg with a weight-based dose <30 mg/kg. Dosages of 40 and 60 mg/kg provided ≥90% PTAs across all weights. Using a weight-based loading dose of 40 mg/kg, up to a suggested maximum of 4500 mg, improves the likelihood of achieving a sustained therapeutic drug concentration after the initial LEV dose, whereas fixed <3000 mg may not achieve the desired concentration before maintenance dosing., (© 2024 The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

Therapeutic drug monitoring is used to ensure that medications are prescribed and administered according to safe doseage advice and for the purpose of achieving the desired therapeutic effects in patients. Several methods are used to perform therapeutic drug monitoring. However, there is insufficient evidence to currently support therapeutic drug monitoring of Valproic acid using salivary samples. The aim of this paper is to determine the feasibility of using salivary samples as a substitute for plasma samples for therapeutic drug monitoring of Valproic acid. In this study a total of 23 patients participated, with the mean age of 33.39. Salivary and plasma samples were collected and analysed to determine the peak and trough concentrations of Valproic acid for comparison between the two methods. Calibrated LC- MS/ MS was used to measure Valproic acid levels. Statistical analyses were performed using ANOVA test and ethical approval was obtained prior to sample collection. The results showed that saliva Valproic acid levels were less than that of plasma levels. There was no significant correlation between saliva and plasma level of Valproic acid (P>0.05). However, there was a significant correlation between the area under the curve for both saliva and plasma Valproic acid (P<0.05). Creatinine clearance was significantly correlated with peak plasma levels of Valproic acid (P<0.05). Albumin was significantly correlated with plasma levels of Valproic acid. There was also a significantly positive and moderate relationship between Log Saliva Cmax and Log plasma free Valproic acid concentration (r=0.76, p<0.018). In conclusion, saliva samples can be used as a substitute for plasma samples in the therapeutic drug monitoring of Valproic acid., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Post-traumatic epilepsy (PTE) is a life-long complication of traumatic brain injury (TBI). The development of PTE is associated with neurological morbidity and increases the risk of mortality. An aim of EpiBioS4Rx (Epilepsy Bioinformatics Study for Antiepileptogenic Therapy) was to test potential therapies to prevent the development of PTE in the lateral fluid percussion injury (LFPI) rat model of TBI, in which rats were subjected to injury at the left parietal cortex. Sodium selenate has been reported to be antiepileptogenic post-TBI in rodent models by activating protein phosphatase 2A and reducing phosphorylated tau (p-tau) protein. We aimed to characterize the pharmacokinetics (PK) and brain uptake of sodium selenate using naïve control and LFPI rats. Rats received either a single bolus dose or a single bolus dose followed by a 7-day subcutaneous minipump infusion of sodium selenate. Sodium selenate and selenium concentrations in plasma and brain were analyzed and used for PK estimation and brain exposure assessment. Selenium concentrations rapidly increased after sodium selenate administration, demonstrating biotransformation from sodium selenate to selenium. Sodium selenate and selenium PK parameters were estimated using non-compartmental analysis. Sodium selenate clearance (CL/F) and volume of distribution (V d /F) varied by dose and route of administration, suggesting differences in bioavailability and nonlinear pharmacokinetics at the doses tested. Brain-to-plasma partition coefficients (AUC brain /AUC plasma ) for sodium selenate and selenium were found to be 0.7-1.3 and 0.1-0.3 following single-dose injection, respectively, indicating active transport of sodium selenate across the blood-brain barrier (BBB)., (© 2024 The Author(s). Pharmacology Research & Perspectives published by British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics and John Wiley & Sons Ltd.)

Aims: To investigate the association of CYP2C9 metabolic phenotypes with phenytoin plasma concentration ([PTH]) in neurosurgical patients from the Brazilian Public Health System., Methods: Patients (n = 170) were treated with phenytoin (300 mg/day) perioperatively as prophylaxis for postoperative seizures. Two to 10 days after surgery, a blood sample was collected for quantification of [PTH] and genotyping of CYP2C9*2 and *3 alleles. CYP2C9 metabolic phenotypes, NM (normal), IM (intermediate), and PM (poor) metabolizer, were inferred from CYP2C9 diplotypes. Linear regression modeling was applied to identify predictors of [PTH]., Results: Wide (22-fold) interindividual variation in [PTH] was observed (2.2-47.5 mg/l). [PTH] associated significantly (Kruskal-Wallis P < 0.005) with CYP2C9 phenotypes and there was a significant trend (Jonckheere-Terpstra test, P < 0.0001) for [PTH] increase in the order NM < IM < PM. [PTH] was within the target therapeutic range (10-20 mg/l) in 34.7% of patients, while 39.4% and 25.9% had [PTH] below and above the range, respectively. CYP2C9 phenotypes associated significantly (chi-square P = 0.004) with the distribution of patients in [PHT] therapeutic categories and the Cramér's V test pointed to moderate magnitude of the effect of CYP2C9 phenotypes (V = 0.211)., Conclusion: Diplotype-predicted CYP2C9 metabolic phenotypes are associated significantly with [PTH] in neurosurgical Brazilian patients receiving phenytoin for postsurgery seizure prophylaxis. [PHT] increased progressively in the phenotype order NM < IM < PM, and all PM patients had [PHT] above the target therapeutic range, consistent with the CPIC guideline 'strong' recommendation for phenytoin dosing adjustments in PMs., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

The mTOR-inhibitor everolimus is a precision drug with antiepileptogenic properties approved for treatment of epilepsy in persons with tuberous sclerosis complex (TSC) in combination with other antiseizure medications (ASMs). However, the pharmacokinetic variability of everolimus is scarcely described, and the available information on pharmacokinetic interactions is scarce. The purpose of this study was to investigate pharmacokinetic variability of everolimus in patients with TSC, and the impact of age, sex and comedication. In this retrospective observational study we used anonymized data from medical records of patients with TSC using everolimus in Norway and Denmark, 2012 to 2020. Long-term therapeutic drug monitoring (TDM) identified inter-patient and intra-patient variability. The study included 59 patients, (36 females (61%)), median age 22 (range 3-59 years). Polytherapy was used in 50 patients (85%). The most frequently used ASMs were lamotrigine (n = 21), valproate (n = 17), and levetiracetam (n = 13). Blood concentrations of everolimus were measured in all patients. Pharmacokinetic variability of everolimus between patients was extensive, as demonstrated by a 24-fold variability from minimum-maximum concentration/dose (C/D)-ratios. The coefficient of variation (CV) for intra-patient (n = 59) and inter-patient variability (n = 47, ≥3 measurements) was 40% and 43%, respectively. The C/D-ratio of everolimus was 50% lower in 13 patients (22%) using enzyme-inducing ASMs compared to the 30 patients who did not (0.7 vs 1.4 ng/mL mg, P < .05). Age and sex were not significantly associated with changes in C/D-ratios of everolimus. Long-term TDM identified extensive variability in concentrations over time for everolimus both within and between patients, where comedication with enzyme-inducing ASMs was an important contributing factor. The findings suggest a need for TDM in patients with TSC treated with everolimus., Competing Interests: The other authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Objectives: The antiepileptic phenytoin has a narrow therapeutic window, nonlinear pharmacokinetics, and can cross the placenta causing apathy and jitteriness in postpartum newborns. Further, the sudden decay of phenytoin concentration can cause withdrawal seizures. This work aimed to assess the brain toxic exposure to phenytoin in newborns after transplacental transfer using neonatal saliva-brain correlations., Methods: The phenytoin dose that the newborn receives transplacentally at birth was estimated using verified physiologically based pharmacokinetic (PBPK) model simulations in third-trimester pregnancy (pregnancy T3). Such doses were used as an input to the newborn PBPK model to estimate the neonatal levels of phenytoin and their correlations in brain extracellular fluid (bECF), plasma, and saliva., Results: The PBPK model-estimated neonatal plasma and bECF concentrations of phenytoin were below the necessary thresholds for anticonvulsant and toxic effects. The neonatal salivary thresholds for phenytoin anticonvulsant and toxic effects were estimated to be 1.3 and 2.5 mg/L, respectively using the plasma-saliva-bECF correlations established herein., Conclusions: The salivary TDM of phenytoin can be a more convenient option for avoiding phenytoin brain toxicity in newborns of epileptic mothers. Still, the appropriateness of using the same adult values of phenytoin anticonvulsant and toxic effects for infants needs investigation., (© 2024 Walter de Gruyter GmbH, Berlin/Boston.)

Dysfunction of voltage-gated sodium channel Nav1.2 causes various epileptic disorders, and inhibition of the channel has emerged as an attractive therapeutic strategy. However, currently available Nav1.2 inhibitors exhibit low potency and limited structural diversity. In this study, a novel series of pyrimidine-based derivatives with Nav1.2 inhibitory activity were designed, synthesized, and evaluated. Compounds 14 and 35 exhibited potent activity against Nav1.2, boasting IC 50 values of 120 and 65 nM, respectively. Compound 14 displayed favorable pharmacokinetics ( F = 43%) following intraperitoneal injection and excellent brain penetration potency (B/P = 3.6). Compounds 14 and 35 exhibited robust antiepileptic activities in the maximal electroshock test, with ED 50 values of 3.2 and 11.1 mg/kg, respectively. Compound 35 also demonstrated potent antiepileptic activity in a 6 Hz (32 mA) model, with an ED 50 value of 18.5 mg/kg. Overall, compounds 14 and 35 are promising leads for the development of new small-molecule therapeutics for epilepsy.

Competing Interests: The authors have disclosed that they do not have any potential conflicts of interest.

Abstract: This study evaluated perampanel pharmacokinetics and cytochrome P450 3A4 (CYP3A4) activity, assessed using the level of 4β-hydroxycholesterol (4β-OHC) as an endogenous biomarker of CYP3A4, before, during, and after pregnancy in a woman with epilepsy and compared these measurements with those from a control group of nonpregnant women with epilepsy. A 21-year-old pregnant woman was being treated with perampanel (serum concentration: 1120 ng/mL), lacosamide, and lamotrigine. After the first trimester, the lamotrigine concentration decreased markedly; however, the perampanel concentration remained almost unchanged (range, 1130-1320 ng/mL). Similarly, serum 4β-OHC levels did not change during pregnancy (before pregnancy, 78.2 ng/mL; during pregnancy, 62.2-83.2 ng/mL). To compare these measurements with those in nonpregnant women, we enrolled 27 nonpregnant women with epilepsy (age range, 16-40 years). In the control patients, we found a strong negative correlation between the concentration-to-dose ratio of perampanel and the 4β-OHC level ( r = -0.78, P < 0.001). As there was no significant change in CYP3A4 activity, we concluded that the serum perampanel concentration did not change significantly before, during, or after pregnancy. More patients need to be studied to confirm these early results., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: This study was the first to evaluate the effect of CYP3A5*3 gene polymorphisms on plasma concentration of perampanel (PER) in Chinese pediatric patients with epilepsy., Methods: We enrolled 98 patients for this investigation. Plasma PER concentrations were measured using liquid chromatography-tandem mass spectrometry. Leftover samples from standard therapeutic drug monitoring were allocated for genotyping analysis. The primary measure of efficacy was the rate of seizure reduction with PER treatment at the final checkup., Results: The plasma concentration showed a linear correlation with the daily dose taken ( r  = 0.17; P  < 0.05). The ineffective group showed a significantly lower plasma concentration of PER (490.5 ± 297.1 vs. 633.8 ± 305.5 μg/ml; P  = 0.019). For the mean concentration-to-dose (C/D) ratio, the ineffective group showed a significantly lower C/D ratio of PER (3.2 ± 1.7 vs. 3.8 ± 2.0; P  = 0.040). The CYP3A5*3 CC genotype exhibited the highest average plasma concentration of PER at 562.8 ± 293.9 ng/ml, in contrast to the CT and TT genotypes at 421.1 ± 165.6 ng/ml and 260.0 ± 36.1 ng/ml. The mean plasma PER concentration was significantly higher in the adverse events group (540.8 ± 285.6 vs. 433.0 ± 227.2 ng/ml; P  = 0.042)., Conclusion: The CYP3A5*3 gene's genetic polymorphisms influence plasma concentrations of PER in Chinese pediatric patients with epilepsy. Given that both efficacy and potential toxicity are closely tied to plasma PER levels, the CYP3A5*3 genetic genotype should be factored in when prescribing PER to patients with epilepsy., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Cenobamate is approved for the treatment of focal seizures in adults and is currently available as an oral tablet. Alternative methods of drug administration are needed for patients who are unable to swallow whole intact tablets. This phase 1, open-label, randomized, single-dose, three-way crossover (3-period, 3-treatment, 6-sequence) study (NCT05572255), conducted in healthy volunteers, assessed the relative bioavailability of a crushed 200-mg cenobamate tablet administered orally or via nasogastric (NG) tube compared with an intact 200-mg tablet. Each treatment was separated by a 13-day washout period. Plasma samples for cenobamate concentration analysis were collected pre-dose and at multiple time points up to 264 h post-dose. Standard bioequivalence study criteria were applied to the relative bioavailability assessments. All 90% confidence intervals of test-to-reference geometric mean ratios for cenobamate pharmacokinetic parameters (C max , AUC last , and AUC inf ) were within 85-110% (predefined limit, 80-125%), suggesting no difference in cenobamate exposures following administration of an intact tablet orally or a crushed tablet orally or via NG tube. All treatment-emergent adverse events (TEAEs) were classified as mild and resolved. There were no deaths or other serious AEs (SAEs), and no TEAEs led to discontinuation. Our results indicate that the administration of cenobamate as a crushed tablet taken orally or via an NG tube can provide additional flexibility when patients cannot swallow intact tablets. Based on the results of this study, cenobamate is now approved by FDA to be taken whole or the tablets can be crushed. The crushed tablet can be mixed with water and either administered by mouth as an oral suspension or administered via a nasogastric tube., (© 2024 The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

Perampanel belongs to a novel class of antiseizure medications (ASMs). Studies examining the effect of hemodialysis on perampanel serum levels in clinical settings are lacking. We aimed to evaluate the changes in serum perampanel levels during hemodialysis. We studied patients with seizures who received oral perampanel between April 2020 and March 2023 and whose serum concentration of perampanel was measured before and after hemodialysis. We analyzed the serum concentrations of levetiracetam and lacosamide for comparison. Fourteen patients, with a mean age of 76.1 ± 7.88 years, were included. The dose of perampanel was 2.14 ± 1.27 mg. The hemodialysis clearance rate of perampanel, levetiracetam, and lacosamide was 0 ± 13%, 69 ± 11%, and 59.6 ± 8.2%, respectively. The post-dialysis CD ratio decreased significantly with levetiracetam but not with perampanel. Adverse but acceptable effects of perampanel were observed in two patients. The serum concentrations of several ASMs have been shown to be reduced during hemodialysis. Our study revealed that the serum perampanel concentration does not decrease during hemodialysis. Owing to the low rate of adverse effects and the stability of perampanel serum concentration during hemodialysis, perampanel could be a favorable choice as an ASM for patients with seizures undergoing hemodialysis. PLAIN LANGUAGE SUMMARY: Our study looked at how hemodialysis affects the serum levels of perampanel, a new type of medication for seizures. In 14 patients who started treatment between April 2020 and March 2023, perampanel serum levels did not decrease during hemodialysis, unlike other seizure medications. This shows that perampanel can be a good option for patients with seizures who need hemodialysis, with fewer side effects compared to other medications., (© 2024 The Author(s). Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Aims: Vigabatrin is an antiepileptic drug used to treat some forms of severe epilepsy in children. The main adverse effect is ocular toxicity, which is related to the cumulative dose. The aim of the study is to identify an acceptable exposure range, both through the development of a population pharmacokinetic model of vigabatrin in children enabling us to calculate patient exposure and through the study of therapeutic response., Methods: We performed a retrospective study including children with epilepsy followed at Necker-Enfants Malades hospital who had a vigabatrin assay between January 2019 and January 2022. The population pharmacokinetic study was performed on Monolix2021 using a nonlinear mixed-effects modelling approach. Children treated for epileptic spasms were classified into responder and nonresponder groups according to whether the spasms resolved, in order to identify an effective plasma exposure range., Results: We included 79 patients and analysed 159 samples. The median age was 4.2 years (range 0.3-18). A 2-compartment model with allometry and creatinine clearance on clearance best fit our data. Exposure analysis was performed on 61 patients with epileptic spasms. Of the 22 patients who responded (36%), 95% had an AUC 0-24 between 264 and 549 mg.h.L -1 ., Conclusions: The population pharmacokinetic model allowed us to identify bodyweight and creatinine clearance as the 2 main factors explaining the observed interindividual variability of vigabatrin. An acceptable exposure range was defined in this study. A target concentration intervention approach using this pharmacokinetic model could be used to avoid overexposure in responder patients., (© 2024 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Background: Carbamazepine is one of the most commonly used antiseizure medications. Although carbamazepine pharmacokinetics in epileptic patients is well described, much less is known about these processes in the patients who experienced self-poisoning episode by this drug. Therefore, the aim of our investigation was to perform population toxicokinetics of carbamazepine and its metabolite carbamazepine-10,11-epoxide in adults., Research Design and Methods: Software program NONMEM and the ADVAN2 TRANS2 subroutine were used for establishing a population toxicokinetic model for the estimation of clearance and volume of distribution based on of the sum values of carbamazepine and carbamazepine-10,11-epoxide concentrations., Results: Our results indicated that the adult patients' ability to eliminate carbamazepine and carbamazepine-10,11-epoxide following acute carbamazepine self-poisoning was strongly associated with the high levels of CRP and ASP, as well as by the treatment with sedation., Conclusions: Our study should provide better understanding of the toxicokinetics of carbamazepine taken in overdose and better management of patient population admitted to hospital.

Background: The aim of this study was to investigate the factors affecting plasma valproic acid (VPA) concentration in pediatric patients with epilepsy and the clinical significance of CYP2C9 gene polymorphisms in personalized dosing using therapeutic drug monitoring and pharmacogenetic testing., Methods: The medical records of children with epilepsy who underwent therapeutic drug monitoring at our institution between July 2022 and July 2023 and met the inclusion criteria were reviewed. Statistical analysis was performed to determine whether age, sex, blood ammonia, liver function, kidney function, and other characteristics affected the concentration-to-dose ratio of VPA (CDRV) in these patients. To investigate the effect of CYP2C9 polymorphisms on CDRV, DNA samples were collected from patients and the CYP2C9 genotypes were identified using real-time quantitative PCR., Results: The mean age of 208 pediatric patients with epilepsy was 5.50 ± 3.50 years. Among these patients, 182 had the CYP2C9 *1/*1 genotype, with a mean CDRV (mcg.kg/mL.mg) of 2.64 ± 1.46, 24 had the CYP2C9 *1/*3 genotype, with a mean CDRV of 3.28 ± 1.74, and 2 had the CYP2C9 *3/*3 genotype, with a mean CDRV of 6.46 ± 3.33. There were statistical differences among these 3 genotypes ( P < 0.05). The CDRV in these patients were significantly influenced by age, aspartate aminotransferase, total bilirubin, direct bilirubin, globulin, albumin/globulin ratio, prealbumin, creatinine, and CYP2C9 polymorphisms. In addition, multivariate linear regression analysis identified total bilirubin, direct bilirubin, and CYP2C9 polymorphisms as independent risk factors for high CDRV., Conclusions: Liver problems and mutations in the CYP2C9 gene increase VPA levels. This underscores the importance of considering these factors when prescribing VPA to children with epilepsy, thereby enhancing the safety and efficacy of the therapy., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

We present a novel liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for quantifying fenfluramine (FFA), its active metabolite norfenfluramine (norFFA), and Epidyolex®, a pure cannabidiol (CBD) oral solution in plasma. Recently approved by the EMA for the adjunctive treatment of refractory seizures in patients with Dravet and Lennox-Gastaut syndromes aged above 2 years, FFA and CBD still do not have established therapeutic blood ranges, and thus need careful drug monitoring to manage potential pharmacokinetic and pharmacodynamic interactions. Our method, validated by ICH guidelines M10, utilizes a rapid extraction protocol from 100 µL of human plasma and a reversed-phase C-18 HPLC column, with deuterated internal standards. The Thermofisher Quantiva triple-quadrupole MS coupled with an Ultimate 3000 UHPLC allowed multiple reaction monitoring detection, ensuring precise analyte quantification. The assay exhibited linear responses across a broad spectrum of concentrations: ranging from 1.64 to 1000 ng/mL for both FFA and CBD, and from 0.82 to 500 ng/mL for norFFA. The method proves accurate and reproducible, free from matrix effect. Additionally, FFA stability in plasma at 4 °C and -20 °C for up to 7 days bolsters its clinical applicability. Plasma concentrations detected in patients samples, expressed as mean ± standard deviation, were 0.36 ± 0.09 ng/mL for FFA, 19.67 ± 1.22 ng/mL for norFFA. This method stands as a robust tool for therapeutic drug monitoring (TDM) of FFA and CBD, offering significant utility in assessing drug-drug interactions in co-treated patients, thus contributing to optimized patient care in complex therapeutic scenarios., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Diazepam is a cornerstone immediate-use antiseizure rescue therapy that may extend the duration between seizure clusters in people living with epilepsy. However, our mechanistic understanding of intermittent rescue therapy on disease progression is limited by the lack of suitable preclinical models. Specifically, the pharmacokinetics of diazepam varies widely between humans and laboratory animals. Here, we developed a novel repeat rescue therapy dosing paradigm in rats to maintain prolonged therapeutic concentrations seen in humans. Rats received three diazepam doses separated by 1 h (0.75, 1.5, or 3 mg/kg, intraperitoneal); plasma and brains were collected at 10 min and 1, 3, or 6 h following the last dose. Plasma and brain concentrations followed a dose-dependent increase with peak concentrations following the repeat 3 mg/kg paradigm (180 ng/mL) being equivalent to plasma levels observed in human studies with diazepam nasal spray. Increased brain-to-plasma ratios in this paradigm indicate that diazepam accumulation in the brain may be long-acting at the site of action. Overall, our repeat diazepam dosing paradigm mimics drug concentrations and accumulation seen in humans, offering a preclinical tool to study the impact of benzodiazepine rescue therapy on seizure-cluster biology in rodent models of epilepsy. PLAIN LANGUAGE SUMMARY: There is more to learn about how diazepam works in the brains of people who use it only when they have two or more seizures in 24 h (this is called a seizure cluster). Ethical studies in animals can be used to learn more about medicines in the body. In this study, we showed that three doses of diazepam in rats give about the same amount of the drug as one dose for a person. We can now test rats with epilepsy to see how the drug might work in people who take it when needed for seizure clusters., (© 2024 The Authors. Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Importance: Precise estimation of a patient's drug metabolism capacity is important for antiseizure dose personalization., Objective: To quantify the differences in plasma concentrations for antiseizure drugs associated with variants of genes encoding drug metabolizing enzymes., Data Sources: PubMed, Clinicaltrialsregister.eu, ClinicalTrials.gov, International Clinical Trials Registry Platform, and CENTRAL databases were screened for studies from January 1, 1990, to September 30, 2023, without language restrictions., Study Selection: Two reviewers performed independent study screening and assessed the following inclusion criteria: appropriate genotyping was performed, genotype-based categorization into subgroups was possible, and each subgroup contained at least 3 participants., Data Extraction and Synthesis: The Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines were followed for data extraction and subsequent quality, validity, and risk-of-bias assessments. The results from the included studies were pooled with random-effect meta-analysis., Main Outcomes and Measures: Plasma concentrations of antiseizure drugs were quantified with the dose-normalized area under the concentration-time curve, the dose-normalized steady state concentration, or the concentrations after a single dose at standardized dose and sampling time. The ratio of the means was calculated by dividing the mean drug plasma concentrations of carriers and noncarriers of the pharmacogenetic variant., Results: Data from 98 studies involving 12 543 adult participants treated with phenytoin, valproate, lamotrigine, or carbamazepine were analyzed. Studies were mainly conducted within East Asian (69 studies) or White or European (15 studies) cohorts. Significant increases of plasma concentrations compared with the reference subgroup were observed for phenytoin, by 46% (95% CI, 33%-61%) in CYP2C9 intermediate metabolizers, 20% (95% CI, 17%-30%) in CYP2C19 intermediate metabolizers, and 39% (95% CI, 24%-56%) in CYP2C19 poor metabolizers; for valproate, by 12% (95% CI, 4%-20%) in CYP2C9 intermediate metabolizers, 12% (95% CI, 2%-24%) in CYP2C19 intermediate metabolizers, and 20% (95% CI, 2%-41%) in CYP2C19 poor metabolizers; and for carbamazepine, by 12% (95% CI, 3%-22%) in CYP3A5 poor metabolizers., Conclusions and Relevance: This systematic review and meta-analysis found that CYP2C9 and CYP2C19 genotypes encoding low enzymatic capacity were associated with a clinically relevant increase in phenytoin plasma concentrations, several pharmacogenetic variants were associated with statistically significant but only marginally clinically relevant changes in valproate and carbamazepine plasma concentrations, and numerous pharmacogenetic variants were not associated with statistically significant differences in plasma concentrations of antiseizure drugs.

Objective: This study was the first to evaluate the effect of CYP3A4 gene polymorphisms on the plasma concentration and effectiveness of perampanel (PER) in Chinese pediatric patients with epilepsy., Methods: We enrolled 102 patients for this investigation. The steady-state concentration was determined after patients maintained a consistent PER dosing regimen for at least 21 days. Plasma PER concentrations were measured using liquid chromatography-tandem mass spectrometry. Leftover samples from standard therapeutic drug monitoring were allocated for genotyping analysis. The primary measure of efficacy was the rate of seizure reduction with PER treatment at the final check-up., Results: The CYP3A4×10 GC phenotype exhibited the highest average plasma concentration of PER at 491.1 ± 328.1 ng/mL, in contrast to the CC phenotype at 334.0 ± 161.1 ng/mL. The incidence of adverse events was most prominent in the CYP3A4×1 G TT and CYP3A4×10 GC groups, with rates of 77.8 % (7 of 9 patients) and 50.0 % (46 of 92 patients), respectively. Moreover, the percentage of patients for whom PER was deemed ineffective was least in the CYP3A4×1 G TT and CYP3A4×10 CC groups, recorded at 11.1 % (1 of 9 patients) and 10.0 % (1 of 10 patients), respectively. There was a significant correlation between PER plasma concentration and either exposure or toxicity (both with p < 0.05). We suggest a plasma concentration range of 625-900 ng/mL as a suitable reference for PER in Chinese patients with epilepsy., Conclusion: The CYP3A4×10 gene's genetic polymorphisms influence plasma concentrations of PER in Chinese pediatric patients with epilepsy. Given that both efficacy and potential toxicity are closely tied to plasma PER levels, the CYP3A4 genetic phenotype should be factored in when prescribing PER to patients with epilepsy., Competing Interests: Declaration of competing interest None of the authors have any conflict of interest to disclose. The authors confirm that they have read the Journal's policy on issues involved in ethical publication, and affirm that this study is consistent with those guidelines., (Copyright © 2024. Published by Elsevier Ltd.)

Background: Padsevonil is an antiseizure medication candidate intended to benefit patients with drug-resistant epilepsy. Our investigations aimed at characterizing pharmacokinetics and drug-drug interaction (DDI) profile of padsevonil., Research Design and Methods: An overview of preclinical and clinical pharmacology studies conducted during padsevonil development is provided., Results: In preclinical studies, cytochrome (CYP) 3A4 was identified as the main P450 isoform involved in padsevonil metabolism, with potential minor contribution from CYP2C19. Padsevonil was shown to be a time-dependent CYP2C19-inhibitor, weak CYP3A4-inducer, weak inhibitor of P-gp/OCT1/MATE2-K, and potent OCT2-inhibitor. Initial clinical pharmacology studies in healthy participants showed that padsevonil had (i) good absorption, (ii) clearance mediated mainly by metabolism, and (iii) time-dependent kinetics. A study in genotyped participants confirmed the role of CYP2C19 in clearance and time-dependent kinetics; the major contribution of CYP3A4 was confirmed in DDI studies with CYP3A4-inducers (carbamazepine, oxcarbazepine) and -inhibitor (erythromycin). Padsevonil did not affect pharmacokinetics of valproate/lamotrigine/levetiracetam/oxcarbazepine or oral contraceptives. In a cocktail clinical study, padsevonil showed moderate CYP2C19 inhibition (omeprazole) and weak CYP3A4 induction (oral midazolam). No specific effects on CYP1A2 (caffeine), CYP2C9 (S-warfarin), and CYP2D6 (dextromethorphan) were observed., Conclusions: The studies presented helped in understanding padsevonil disposition and risks of DDIs, which would inform dosing and prescribing., Clinical Trial Registration: https://www.clinicaltrials.gov identifiers are NCT04131517, NCT03480243, NCT03695094, NCT04075409.

Objective: Increasing evidence suggests that the physiological changes of pregnancy may impact pharmacokinetics of antiseizure medications (ASM), and this may affect treatment outcomes. The aim of this study was to quantify the pregnancy impact on the ASM pharmacokinetics., Methods: A systematic literature search was conducted in PubMed/EMBASE in November 2022 and updated in August 2023 for studies comparing levels of ASM in the same individuals during pregnancy and in the preconception/postpartum period. Alteration ratios between the 3rd trimester and baseline were estimated. We also performed a random-effects meta-analysis calculating between-timepoint differences in mean differences (MDs) and 95% confidence intervals (95%CIs) for dose-adjusted plasma concentrations (C/D ratios). Study quality was assessed using the ClinPK guidelines., Results: A total of 65 studies investigating 15 ASMs in 674 pregnancies were included. The largest differences were reported for lamotrigine, oxcarbazepine and levetiracetam (alteration ratio 0.42, range 0.07-2.45, 0.42, range 0.08-0.82 and 0.52, range 0.04-2.77 respectively): accordingly, C/D levels were lower in the 3rd trimester for lamotrigine, levetiracetam and the main oxcarbazepine metabolite monohydroxycarbazepine (MD = -12.33 × 10 -3 , 95%CI = -16.08 to -8.58 × 10 -3 (μg/mL)/(mg/day), p < 0.001, MD = -7.16 (μg/mL)/(mg/day), 95%CI = -9.96 to -4.36, p < 0.001, and MD = -4.87 (μg/mL)/(mg/day), 95%CI = -9.39 to -0.35, p = 0.035, respectively), but not for oxcarbazepine (MD = 1.16 × 10 -3 (μg/mL)/(mg/day), 95%CI = -2.55 to 0.24 × 10 -3 , p = 0.10). The quality of studies was acceptable with an average rating score of 11.5., Conclusions: Data for lamotrigine, oxcarbazepine (and monohydroxycarbazepine) and levetiracetam demonstrate major changes in pharmacokinetics during pregnancy, suggesting the importance of therapeutic drug monitoring to assist clinicians in optimizing treatment outcomes., Competing Interests: Declaration of competing interest Dr. Deligiannidis reported grants from the National Institutes of Health (Grant R01MH120313) during the conduct of study, nonfinancial support and personal fees from Sage Therapeutics Inc. (i.e., travel reimbursement, consulting), and Brii Biosciences (i.e., consulting); Dr. Kittel-Schneider has received speaker's and author's fee from Medice Arzneimittel Pütter GmbH & Co KG and Takeda; Dr. Paulzen has received speaker fees from Neuraxpharm, Langenfeld, Germany, and Lundbeck, Hamburg, Germany; Dr. Schoretsanitis has served as a consultant for Dexcel Pharma, HLS Therapeutics, Saladax and Thermo Fisher and has received speaker fees from HLS Therapeutics and Saladax; All other authors declare no conflicts of interest. The research study did not receive funds or support from any source., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The intranasal route has demonstrated superior systemic bioavailability due to its extensive surface area, the porous nature of the endothelial membrane, substantial blood flow, and circumvention of first-pass metabolism. In traditional medicinal practices, Bacopa monnieri, also known as Brahmi, is known for its benefits in enhancing cognitive functions and potential effects in epilepsy. This study aimed to develop and optimize a thermosensitive in-situ nasal gel for delivering Bacoside A, the principal active compound extracted from Bacopa monnieri. The formulation incorporated Poloxamer 407 as a thermogelling agent and HPMC K4M as the Mucoadhesive polymer. A 3 2 -factorial design approach was employed for Optimization. Among the formulations. F7 exhibited the most efficient Ex-vivo permeation through the nasal mucosa, achieving 94.69 ± 2.54% permeation, and underwent a sol-gel transition at approximately 30.48 °C. The study's factorial design revealed that gelling temperature and mucoadhesive strength were critical factors influencing performance. The potential of in-situ nasal Gel (Optimized Batch-F7) for the treatment of epilepsy was demonstrated in an in-vivo investigation using a PTZ-induced convulsion model. This formulation decreased both the occurrence and intensity of seizures. The optimized formulation F7 showcases significant promise as an effective nasal delivery system for Bacoside A, offering enhanced bioavailability and potentially increased efficacy in epilepsy treatment., (© 2024. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.)

One third of patients with epilepsy will continue to have uncontrolled seizures despite treatment with antiseizure medications (ASMs). There is therefore a need to develop novel ASMs. Brivaracetam (BRV) is an ASM that was developed in a major drug discovery program aimed at identifying selective, high-affinity synaptic vesicle protein 2A (SV2A) ligands, the target molecule of levetiracetam. BRV binds to SV2A with 15- to 30-fold higher affinity and greater selectivity than levetiracetam. BRV has broad-spectrum antiseizure activity in animal models of epilepsy, a favorable pharmacokinetic profile, few clinically relevant drug-drug interactions, and rapid brain penetration. BRV is available in oral and intravenous formulations and can be initiated at target dose without titration. Efficacy and safety of adjunctive BRV (50-200 mg/day) treatment of focal-onset seizures was demonstrated in three pivotal phase III trials (NCT00490035/NCT00464269/NCT01261325), including in patients who had previously failed levetiracetam. Efficacy and safety of adjunctive BRV were also demonstrated in adult Asian patients with focal-onset seizures (NCT03083665). In several open-label trials (NCT00150800/NCT00175916/NCT01339559), long-term safety and tolerability of adjunctive BRV was established, with efficacy maintained for up to 14 years, with high retention rates. Evidence from daily clinical practice highlights BRV effectiveness and tolerability in specific epilepsy patient populations with high unmet needs: the elderly (≥ 65 years of age), children (< 16 years of age), patients with cognitive impairment, patients with psychiatric comorbid conditions, and patients with acquired epilepsy of specific etiologies (post-stroke epilepsy/brain tumor related epilepsy/traumatic brain injury-related epilepsy). Here, we review the preclinical profile and clinical benefits of BRV from pivotal trials and recently published evidence from daily clinical practice., (© 2024. The Author(s).)

JBPOS0101 is a new antiepileptic drug and is a substrate of UDP-glucuronosyltransferases (UGTs) in in vitro test. In vitro experiments showed different results regarding whether JBPOS0101 induces (EC 50 136 μM) or inhibits (IC 50 95.4-386.5 μM) cytochrome P450 (CYP) 3A4. As co-medication of JBPOS0101 and carbamazepine (CBZ) is expected in clinical settings, drug-drug interactions (DDIs) between them should be determined. This study aimed to investigate pharmacokinetic (PK) interactions of JBPOS0101 influenced by CYP3A4 and UGTs using midazolam (MDZ) and CBZ. A two-cohort, open-label, fixed-sequence study was conducted in healthy Koreans. In cohort A, subjects received MDZ IV alone, and then JBPOS0101 were co-administered with MDZ after oral doses of JBPOS0101 for 7 days. In cohort B, multiple doses of JBPOS0101 and CBZ were administered respectively, and subjects received both together for 7 days. Serial blood samples were collected for PK analysis. When MDZ and JBPOS0101 were co-administered, the systemic exposure of MDZ decreased by 30%. Meanwhile, JBPOS0101 did not significantly changed the PK of CBZ. CBZ decreased the systemic exposure of JBPOS0101 at steady state by 40%, respectively. With IV administration of MDZ, JBPOS0101 acted as a weak inducer of hepatic CYP3A4 and decreased systemic exposure of MDZ. The ability of JBPOS0101 to similarly modulate gut CYP3A4 activity will require further evaluation. Co-administration of multiple doses of JBPOS0101 and CBZ did not significantly alter CBZ pharmacokinetics, but the clinical impact of decreased systemic exposure of JBPOS0101 by CBZ should be further considered., (© 2024 The Author(s). Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Background and Objective: Model-based bioequivalence (MBBE) encompasses the use of nonlinear mixed effect models supporting the estimation of pharmacokinetic endpoints to assess the relative bioavailability between multi-source drug products. This application emerges as a valuable alternative to the standard non-compartmental analysis (NCA) in bioequivalence (BE) studies in which dense sampling is not possible. In this work, we aimed to assess the application of MBBE compared to traditional methods in evaluating the relative bioavailability of two formulations with different drug release properties. Additionally, we sought to predict the performance of a modified-release formulation in a multiple-dose scenario, leveraging data from a single-dose study., Methods: MBBE analysis was implemented to estimate the BE endpoints (90% CI for the Test/Reference geometric mean ratio, T/R GMR) in area under the concentration-time curve (AUC) and maximum concentration (Cmax) using data from a single-dose, 2-period, 2-sequence BE study performed in 14 healthy subjects between a locally developed valproic acid extended-release formulation (Test) and the brand-name delayed-release formulation (Reference)., Results: Results were compared with the standard approach, revealing that MBBE analysis achieved higher discrimination between formulations for Cmax, addressing limitations of the experimental sampling design and highlighting an advantage for this model-based analysis even when rich data are available. Additionally, the bioequivalence outcome under the multiple-dose scenario was predicted through a simulation-based study for both total and unbound valproic acid concentrations, considering the impact of valproic acid saturable binding on BE conclusions., Conclusions: The MBBE analysis was superior to the NCA approach in detecting product-related differences, overcoming limitations in the study experimental design. Predictions for the multiple-dose scenario preclude that the extended-release properties of the Test formulation would persist at steady state, resulting in lower peak-to-trough fluctuation and bioequivalent performance in terms of the extent of drug absorption. Overall, these results should discourage unnecessary experimentation in healthy subjects., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background and Objectives: A substantial inter-individual variability has been observed in the pharmacokinetics of lamotrigine. The aim of the study was to investigate the impact of genetic polymorphism of the metabolizing enzymes (UGT2B7, UGT1A4) and transporter (ABCG2) on the pharmacokinetics and therapeutic efficacy of lamotrigine in patients with epilepsy., Methods: The genetic analysis of single-nucleotide polymorphisms was conducted using polymerase chain reaction sequence. High-performance liquid chromatography/tandem mass spectrometry was employed to measure the plasma concentrations of lamotrigine. The efficacy of lamotrigine was assessed by evaluating the reduction rate of epileptic seizure frequency., Results: This study included a cohort of 331 patients who were treated with lamotrigine as monotherapy. A linear correlation was observed between the lamotrigine concentration and daily dose taken (r = 0.58, p < 2.2e -16 ). Statistically significant differences were found in both the median plasma concentration and dose-adjusted concentration (C/D ratio) when comparing the ineffective to the effective group (p < 0.05). Multivariate analysis showed that UGT1A4 rs2011425, ABCG2 rs2231142 polymorphisms and age had a significant relationship with the lamotrigine concentrations (p < 0.05). Age was a predictive factor for C/D ratio (p < 0.001). Lamotrigine concentration and weight were good predictive factors for effective seizure outcomes (odds ratio [OR] = 0.715, 95% CI 0.658-0.776, p < 0.001; OR = 0.926, 95% CI 0.901-0.951, p < 0.001, respectively). The cut-off values of lamotrigine trough concentrations for clinical outcomes in the age-related groups were determined as 2.49 μg/ml (area under the receiver-operating characteristic curve [AUC]: 0.828, 95% CI 0.690-0.966), 2.70 μg/ml (AUC: 0.805, 95% CI 0.745-0.866) and 3.25 μg/ml (AUC: 0.807, 95% CI 0.686-0.928) for the adult group, adolescent group, and toddler and school-age group, respectively., Conclusions: UGT1A4 rs2011425 and ABCG2 rs2231142 were correlated with lamotrigine concentrations. Lower lamotrigine trough concentration was found in the ineffective group and the troughs were associated with seizure outcomes., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)