Meir Bialer

Dicloxacillin is a penicillinase‐resistant beta‐lactam antibiotic and potent activator of the Pregnane X receptor (PXR), known to induce CYP2C9, CYP2C19, and CYP3A4 activity. Clinical data suggest it reduces anticoagulation in warfarin‐treated patients and increases the risk of thromboembolic events. This open‐label, sequential drug–drug interaction study quantitatively evaluated the effect of dicloxacillin on the pharmacokinetics of warfarin and phenytoin, two prototype CYP2C9 substrates with narrow therapeutic indices, and possible impact of CYP2C9 polymorphisms on the extent of this interaction. Twenty‐eight healthy non‐smoker subjects, 15 carriers of CYP2C9*1/*1, and 13 carriers of a single CYP2C9*2 or CYP2C9*3 allele, received single doses of warfarin (20 mg) and 1 week later, phenytoin (300 mg) before and during a 21‐day course of dicloxacillin 500 mg four times daily. Plasma concentration of warfarin enantiomers and phenytoin and urine concentration of p‐HPPH were measured using validated HPLC methods. Warfarin pharmacodynamics was monitored via serial INR measurements for up to 120 hours. Dicloxacillin increased oral clearance of ( S )‐warfarin and ( R )‐warfarin by 53.2% and 63.2%, respectively ( P < 0.001). The area under the INR‐time curve decreased by 15.5% ( P < 0.001). Phenytoin oral clearance and p‐HPPH formation clearance increased by 42.4% and 40.5%, respectively ( P < 0.001). CYP2C9 induction was significantly greater in carriers of CYP2C9*1/*1 genotype and INR reduction was more pronounced among VKORC1 AA haplotype carriers. Dicloxacillin substantially induces the metabolism of warfarin and phenytoin. Whenever dicloxacillin is initiated, the dose of CYP2C9 substrates characterized by a narrow therapeutic window should be increased and drug levels and/or pharmacodynamic response should be closely monitored.

Objective: Based on the evidence that fenfluramine‐induced anorexia, weight loss, and cardiovascular toxicity are primarily mediated by the d ‐enantiomers of fenfluramine and its metabolite norfenfluramine, we investigated pharmacokinetic/pharmacodynamic correlations for the active enantiomers of fenfluramine and norfenfluramine in the rat maximal electroshock seizure (MES) test. This is part of a series of studies aimed at optimizing selection of an enantiomerically pure compound for development as a safer alternative to racemic fenfluramine. Methods: Median effective concentrations (EC ₅₀ ) in the MES model and median neurotoxic concentrations (TC ₅₀ ) of each enantiomer in plasma and brain were estimated after intraperitoneal administration of d ‐fenfluramine, l ‐fenfluramine, and l ‐norfenfluramine as well as racemates, and compared with the respective median effective (ED ₅₀ ) and neurotoxic (TD ₅₀ ) doses. A newly developed enantioselective assay allowed differentiation of concentrations of each enantiomer after administration of racemates. Protective indexes (PIs) were estimated based on dose (TD ₅₀ /ED ₅₀ ) and concentration (TC ₅₀ /EC ₅₀ ) in plasma and brain. Results: Based on ED ₅₀ , all enantiomers tested had comparable potency, but l ‐norfenfluramine had a lower PI than the other enantiomers. Based on EC ₅₀ in plasma and brain, l ‐norfenfluramine and d ‐fenfluramine had the highest potency, but l ‐norfenfluramine was consistently more toxic than the other enantiomers. The PIs of d ‐fenfluramine, l ‐fenfluramine, and l ‐norfenfluramine were 2.7, 2.4, and 1.2, respectively, based on plasma concentrations, and 4.1, 2.8, and 1.2, respectively, based on brain concentrations. Potency estimates for each enantiomer after dosing with racemic fenfluramine and norfenfluramine were consistently lower than after dosing with the pure enantiomers, indicating that both enantiomers contributed to antiseizure activity. Significance: Based on these results, l ‐fenfluramine has more favorable properties than l ‐norfenfluramine for potential development as an enantiomerically pure medication. Although our findings are consistent with those previously reported for the MES test in mice and the scn1Lab ^−/− mutant zebrafish, they differ from those reported for the audiogenic seizures mouse model. Further studies, preferably in disease‐specific models, would be desirable.

Over the last 34 years, the Eilat Conference on New Antiepileptic Drugs and Devices has provided an interactive forum for stakeholders to discuss investigational and recently licensed treatments for seizures and epilepsy. The Eighteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XVIII) took place in Madrid, Spain, on May 3–6, 2026. This article provides summaries of eight treatments in preclinical and early clinical development that were presented at EILAT XVIII. These include AUT00206, a positive allosteric modulator of Kv3.1 and Kv3.2 voltage‐gated potassium channels in development for the treatment of rare epilepsy syndromes as well as neurodevelopmental and neuropsychiatric disorders; ION283, an antisense oligonucleotide designed to suppress the expression of glycogen synthase 1, under investigation for the treatment of Lafora disease; MSCA‐7136, a selective allosteric RAS/mitogen‐activated protein kinase—extracellular signal regulated kinase (MEK) inhibitor being developed for the treatment of focal seizures associated with mesial temporal lobe epilepsy and seizures associated with tuberous sclerosis complex; OV329, a selective inhibitor of γ‐aminobutyric acid (GABA) aminotransferase, in development for the treatment of drug‐resistant focal seizures; PTI5803 (probenecid), an uricosuric agent and a blocker of pannexin 1 channels, repurposed as a treatment for seizures associated with focal cortical dysplasia; simufilam, a filamin A modulator under investigation for the treatment of tuberous sclerosis complex‐related epilepsy; SN‐2000, a selective allosteric phosphodiesterase 4B inhibitor, in development for the treatment of focal seizures; and sodium selenate, a promoter of the dephosphorylation of pathological hyperphosphorylated tau in the brain, under investigation as a disease‐modifying agent in mesial temporal lobe epilepsy. Treatments in more advanced clinical development are discussed in an accompanying article.

This article summarizes data for 13 investigational treatments for which at least preliminary seizure outcome data in patients with epilepsy were reported at the Eighteenth Eilat Conference on New Antiepileptic Drugs and Devices held in Madrid, Spain, on May 3–6, 2026. The treatments reviewed include bexicaserin, a selective 5‐hydroxytryptamine (5‐HT, serotonin) type 2C (5‐HT _2C ) receptor superagonist investigated as a treatment for developmental and epileptic encephalopathies (DEEs); BMB‐101, a selective 5‐HT _2C receptor agonist investigated for the treatment of absence seizures and DEEs; elsunersen, an antisense oligonucleotide designed for the treatment of early‐onset SCN2A ‐DEE; EPX‐100 (clemizole hydrochloride), an antihistamine endowed with agonist activity at 5‐HT _2A and 5‐HT _2B receptors, repurposed as a treatment for DEEs; ES‐481, an antagonist of α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) receptors containing the transmembrane AMPA receptor regulatory protein γ8 (TARP‐γ8), under investigation for the treatment of drug‐resistant epilepsy; ETX‐101, a gene therapy in development for the treatment of SCN1A ‐positive Dravet syndrome; PrevEp‐006 (intranasal seletracetam), a synaptic vesicle glycoprotein 2A (SV2A) ligand under investigation as an acute seizure rescue therapy; radiprodil, a negative allosteric modulator that binds to the GluN2B subunit of the N ‐methyl‐ D ‐aspartate (NMDA) receptor, in development for the treatment of seizures and other symptoms associated with GRIN‐related neurodevelopmental disorder, tuberous sclerosis complex, and focal cortical dysplasia type II; RAP‐219, a selective negative allosteric modulator of TARP‐γ8, in development for drug‐resistant focal epilepsy; relutrigine, a selective disease‐state sodium channel modulator investigated as a treatment for SCN2A ‐ and SCN8A ‐DEE; Staccato Alprazolam, a breath‐actuated device that delivers alprazolam to the lungs for rapid seizure termination; vormatrigine, a functionally selective sodium channel modulator in development for the treatment of focal seizures; and zorevunersen, an antisense oligonucleotide engineered to restore endogenous Nav1.1 protein expression, investigated for the treatment of Dravet syndrome. Overall, the evidence reviewed justifies expectations for improved health outcomes for the millions of children and adults with epilepsy who do not fully benefit from existing therapies.

The EILAT Conferences on New Antiepileptic Drugs (AEDs), which have taken place biennially since 1992, have traditionally offered a forum for stakeholders from industry and academia to present updates on potential antiseizure medications (ASMs) in development. We reviewed publicly accessible data on compounds that were presented at EILAT conferences over this period but failed to reach the ASM market. The overarching aim was to determine the most likely reason(s) for terminating development and to provide potentially useful clues to improve the efficiency of ASM development in the future. We restricted our analysis to investigational compounds in clinical development that targeted common epilepsies. Of 56 such compounds, 15 reached the ASM market, 11 are still in development, and 30 had their development for epilepsy indications terminated. Compounds whose development was terminated include atimepazole, beprodone, cannabidivarin, carabersat, conantokin-G, dezinamide, elpetrigine, flunarizine, fluorofelbamate, ICA-105665, isovaleramide, JNJ-40411813, losigamone, naluzotan, padsevonil, pitolisant, ralitoline, remacemide, safinamide, soretolide, talampanel, tonabersat, T2000, T2007, valnoctamide, valrocemide, VX-765, zandatrigine, zuranolone, and 534U87. For most of these compounds, termination of development occurred during phase 1 or phase 2. Unfavorable pharmacokinetic properties, such as short half-life or high drug-drug interaction potential, were a common likely cause of early termination. Overall, the most common reason for terminating clinical development was lack of efficacy, possibly related, at least in some cases, to use of suboptimal trial designs. Review of preclinical data suggested that, for many compounds, suboptimal clinical efficacy was unlikely to be primarily explained by their mechanism of action. In some instances, failure to pursue an epilepsy indication could be explained by prioritization of development for other neurological or psychiatric conditions. This may reflect the perception of the drug market for common epilepsies being relatively crowded, and only attractive for compounds with outstanding safety or efficacy advantages over existing medications.

Background and Objective Direct oral anticoagulants have largely replaced vitamin K antagonists, for example, warfarin, because of their favorable safety profile and predictable pharmacokinetics, with apixaban being the most widely used direct oral anticoagulant. Although routine therapeutic drug monitoring is not required, measuring apixaban plasma concentrations may be useful in high-risk clinical scenarios. This aim of this study was to evaluate the impact of a repeat apixaban concentration measurement combined with a pharmacokinetic analysis and dose adjustment on drug concentrations and clinical outcomes. Methods We conducted a retrospective observational cohort study at Hadassah Mount Scopus Hospital, including elderly patients hospitalized between January 2020 and September 2024 with prescriptions for apixaban. Patients with two appropriately timed, maximum apixaban plasma concentrations within 90 days were analyzed. Results A total of 127 patients were included (median age 79 years, maximum age 97 years; 51% female). At baseline, 16% had subtherapeutic apixaban plasma concentrations and 20% had supratherapeutic concentrations. Female sex was associated with subtherapeutic concentrations while a standard dose (10 mg/day) of apixaban was associated with supratherapeutic plasma concentrations. Dose adjustment was more common in patients with standard dose therapy and in patients with an out-of-range baseline apixaban measurement with adjusted odds ratio of 6.1 and 95% confidence interval of 2.2–16.9 and 4.9 (95% confidence interval 1.9–12.7), respectively. In patients who had undergone repeated apixaban maximum plasma concentration measurements, we found 24 bleeding events and six thrombotic or embolic events within a 1-year follow-up from the second maximum plasma concentration measurement. Bleeding events were more common in patients whose maximum plasma concentration was out of the therapeutic range (28% vs 15%), Conclusions Dose adjustment based on apixaban plasma concentration monitoring increased the proportion of patients who have apixaban concentrations within the therapeutic range. In high-risk elderly patients, an apixaban concentration measurement coupled with active intervention (e.g., dose adjustment) is likely to be clinically beneficial in avoiding bleeding and thromboembolic events.

Objective: The in vivo effects of fenfluramine result from the combined actions of four active molecular entities ( l‐ fenfluramine, d‐ fenfluramine, and the corresponding enantiomers of the primary metabolite norfenfluramine). Each of these compounds has different properties, with cardiovascular toxicity risk being ascribed primarily to the d ‐enantiomers. To determine whether l ‐fenfluramine or l ‐norfenfluramine is a better candidate for development as an enantiomerically pure antiseizure medication, we investigated dose–response and brain/plasma concentration–response relationships for each of the four individual enantiomers in mice. Methods: Antiseizure activity was evaluated in the maximal electroshock (MES) model at the time of peak effect. Neurotoxicity was assessed by determining minimal motor impairment (MMI) in the rotarod test. Median effective dose (ED ₅₀ ), median toxic dose (TD ₅₀ ), median effective concentration (EC ₅₀ ), and median toxic concentration (TC ₅₀ ) in plasma and brain were estimated from dose– and concentration–response curves after administration of each individual enantiomer. Protective indexes (PIs) were estimated based on dose (TD ₅₀ /ED ₅₀ ) and plasma/brain concentrations (TC ₅₀ /EC ₅₀ ). Results: The four enantiomers differed in antiseizure potency and neurotoxic activity. d‐ Norfenfluramine had the highest potency, but it also had the highest toxicity and the lowest PI. Differences in antiseizure potency and toxicity estimated from plasma and brain concentrations were more prominent than those estimated based on dose. l‐ Fenfluramine had greater potency than d‐ fenfluramine and l‐ norfenfluramine, and was overall the compound with the highest PI (6.3 based on dose, 41.6 based on plasma concentrations, and 39.2 based on brain concentrations). Significance: These findings are relevant in determining which enantiomer is most suitable for clinical development as a stereoselectively pure follow‐up compound to the marketed racemic fenfluramine, and indicate that l ‐fenfluramine has superior antiseizure activity over l ‐norfenfluramine in the MES model. This study also illustrates the limitations of relying solely on dose–response curves, and the added value of assessing concentration–response relationships.

Objective: We have previously shown that valproic acid (VPA) alters the expression of placental carriers of essential nutrients, including folates. Here, we exposed a placental cell line to VPA, its central nervous system‐active amide derivative sec‐butylpropylacetamide (SPD), and its individual stereoisomers to address the question of whether folate carrier expression can predict the teratogenicity of VPA‐related compounds. We additionally conducted a pilot analysis of folate transfer across placental cell monolayers to estimate the translation of altered carrier expression to carrier activity.Methods: BeWo cells were incubated for 2 or 5 days with racemic SPD, its stereoisomers (2S,3S)‐SPD, (2R,3S)‐SPD, and (2R,3R)‐SPD (previously found to be teratogenic at high doses in mice; .5 or 1 mmol·L⁻¹), VPA (1 mmol·L⁻¹ = 144 mg/L), or their vehicle. Expression of FOLR1 (folate receptor alpha), SLC19A1 (reduced folate carrier), and ABCG2 (breast cancer resistance protein) was measured by real‐time polymerase chain reaction. Folate transfer across monolayers of BeWo b30 cells exposed to .5 mmol·L⁻¹ (2R,3R)‐SPD or 1 mmol·L⁻¹ VPA was quantified by liquid chromatography–mass spectrometry analysis.Results: At 1 mmol·L⁻¹, racemic SPD, (2S,3S)‐SPD, and (2R,3S)‐SPD reduced by twofold SLC19A1 expression, similar to VPA (p < .001). SPD and its enantiomers induced FOLR1 expression by up to twofold (p < .05) or did not significantly affect it, and racemic SPD increased ABCG2 expression (p < .01). After 5 days, VPA, but not (2R,3R)‐SPD, enhanced both maternal‐to‐fetal and fetal‐to‐maternal folate transfer (p < .01), resulting in a 15% increase in net transfer in the fetal direction.Significance: Altered expression of the studied carriers could not explain the folate transfer kinetics across placental cell monolayers. Future studies should assess the effects of VPA and other antiseizure medications on transplacental transfer of essential compounds in vivo and the ability to predict it by functional in vitro assays.

The 17th Eilat Conference on New Antiepileptic Drugs and Devices took place in Madrid, Spain on May 5–8, 2024. As usual, the core part of the conference consisted of presentations on investigational drugs at various stages of development for epilepsy‐related indications. Summaries of information on compounds in preclinical or early clinical development are included in an accompanying publication (Part I). In this article, we provide summaries for five compounds in more advanced clinical development, i.e. compounds for which some information on antiseizure activity in individuals with epilepsy is available. These investigational treatments include azetukalner (XEN1101), a potent, K_V7.2/7.3‐specific potassium channel opener in development for the treatment of focal seizures, generalized tonic–clonic seizures, and major depressive disorder; bexicaserin (LP352), a selective 5‐HT_2C receptor superagonist in development for the treatment of seizures associated with developmental and epileptic encephalopathies; radiprodil, a selective negative allosteric modulator of NR2B subunit‐containing N‐methyl‐D‐aspartate glutamate receptors, in development for the treatment of seizures and behavior manifestations associated with disorders caused by gain‐of‐function mutations in the GRIN1, −2A, ‐2B, or ‐2D genes; soticlestat (TAK‐935), a selective inhibitor of cholesterol 24‐hydroxylase in development for the treatment of seizures associated with Dravet syndrome and Lennox–Gastaut syndrome; and STK‐001, an antisense oligonucleotide designed to upregulate Na_v1.1 protein expression and improve outcomes in individuals with Dravet syndrome. The diversity in mechanisms of action of these agents illustrates different approaches being pursued in the discovery of novel treatments for seizures and epilepsy. For two of the compounds discussed in this report (azetukalner and soticlestat), clinical evidence of efficacy has already been obtained in a randomized placebo‐controlled adjunctive‐therapy trial. For the other compounds, adequately powered placebo‐controlled efficacy trials have not been completed to date.