Targeting Kv7 Potassium Channels for Epilepsy

Voltage-gated Kv7 potassium channels, particularly Kv7.2 and Kv.7.3 channels, play a critical role in modulating susceptibility to seizures, and mutations in genes that encode these channels cause heterogeneous epilepsy phenotypes. On the basis of this evidence, activation of Kv7.2 and Kv.7.3 channels has long been considered an attractive target in the search for novel antiseizure medications. Ezogabine (retigabine), the first Kv7.2/3 activator introduced in 2011 for the treatment of focal seizures, was withdrawn from the market in 2017 due to declining use after discovery of its association with pigmentation changes in the retina, skin, and mucosae. A novel formulation of ezogabine for pediatric use (XEN496) has been recently investigated in children with KCNQ2-related developmental and epileptic encephalopathy, but the trial was terminated prematurely for reasons unrelated to safety. Among novel Kv7.2/3 openers in clinical development, azetukalner has shown dose-dependent efficacy against drug-resistant focal seizures with a good tolerability profile and no evidence of pigmentation-related adverse effects in early clinical studies, and it is now under investigation in phase III trials for the treatment of focal seizures, generalized tonic-clonic seizures, and major depressive disorder. Another Kv7.2/3 activator, BHV-7000, has completed phase I studies in healthy subjects, with excellent tolerability at plasma drug concentrations that exceed the median effective concentrations in a preclinical model of anticonvulsant activity, but no efficacy data in patients with epilepsy are available to date. Among other Kv7.2/3 activators in clinical development as potential antiseizure medications, pynegabine and CB-003 have completed phase I safety and pharmacokinetic studies, but results have not been yet reported. Overall, interest in targeting Kv7 channels for the treatment of epilepsy and for other indications remains strong. Future breakthroughs in this area could come from exploitation of mechanistic differences in the action of Kv7 activators, and from the development of molecules that combine Kv7 activation with other mechanisms of action

Pregabalin for the management of partial epilepsy

Pregabalin is one of the latest antiepileptic drugs introduced for the treatment of partial epilepsy. Its efficacy and safety as adjunctive therapy in refractory partial epilepsy have been established in four double-blind placebo-controlled trials (n = 1396) and 4 long-term open-label studies (n = 1480). In 3 fixed-dose trials, the proportion of patients with a ≥50% reduction in seizure frequency across the effective dose-range (150–600 mg/day) ranged between 14% and 51%, with a clear dose-response relationship. Suppression of seizure activity could be demonstrated as early as day 2. The most frequently reported CNS-related adverse events included dizziness, somnolence, ataxia and fatigue, were usually mild or moderate, and tended to be dose related. In long-term studies, weight gain was reported as an adverse event by 24% of patients. When pregabalin dose was individualized to according to response within the 150 to 600 mg/day dose range, tolerability was considerably improved compared with use of a high-dose, fixed-dose regimen (600 mg/day) without titration. In long-term studies up to 4 years, no evidence of loss efficacy was identified. During the last year on pregabalin, 3.7% of patients were seizure-free. Pregabalin appears to be a useful addition to the therapeutic armamentariun for the management of refractory partial epilepsy

Epilepsy management during difficult times

Major disruption in the delivery of healthcare services can occur in exceptional situations such as natural disasters, conflicts, periods of severe economic hardship, and epidemics. These disruptions typically affect to the greatest extent the most vulnerable segments of the population, including people with epilepsy. Inability to access healthcare services can lead to failure to undergo necessary diagnostic investigations, or to receive needed therapeutic interventions, including epilepsy surgery. Stress and other factors associated with the nature or the cause of the disruption can adversely affect seizure control status, or precipitate the occurrence of psychiatric disorders and other comorbid conditions. Failure to access antiseizure medications is a common occurrence in these situations and can result in loss of seizure control, withdrawal seizures, and status epilepticus. In this article, we provide examples of recent disruptions in healthcare and their implications for people with epilepsy. We discuss the consequences of natural disasters, conflicts, economic sanctions, and focus in greater detail on lessons learnt during the COVID-19 pandemic. We also discuss possible mitigation procedures, focusing in particular on the application of telemedicine to epilepsy care. Finally, we underline the need for governments, healthcare authorities, and international organizations to improve their preparedness to deal with exceptional situations that may arise in the future

Risk of Major Congenital Malformations and Exposure to Antiseizure Medication Monotherapy

Importance: Women with epilepsy (WWE) require treatment with antiseizure medications (ASMs) during pregnancy, which may be associated with an increased risk of major congenital malformations (MCMs) in their offspring. Objective: To investigate the prevalence of MCMs after prenatal exposure to 8 commonly used ASM monotherapies and changes in MCM prevalence over time. Design, Setting, and Participants: This was a prospective, observational, longitudinal cohort study conducted from June 1999 to October 2022. Since 1999, physicians from more than 40 countries enrolled ASM-treated WWE before pregnancy outcome was known and followed up their offspring until 1 year after birth. Participants aged 14 to 55 years who were exposed to 8 of the most frequently used ASMs during pregnancy were included in this study. Data were analyzed from April to September 2023. Exposure: Maternal use of ASMs at conception. Main Outcomes and Measures: MCMs were assessed 1 year after birth by a committee blinded to type of exposure. Teratogenic outcomes across exposures were compared by random-effects logistic regression adjusting for potential confounders and prognostic factors. Results: A total of 10 121 prospective pregnancies exposed to ASM monotherapy met eligibility criteria. Of those, 9840 were exposed to the 8 most frequently used ASMs. The 9840 pregnancies occurred in 8483 women (mean [range] age, 30.1 [14.1-55.2] years). MCMs occurred in 153 of 1549 pregnancies for valproate (9.9%; 95% CI, 8.5%-11.5%), 9 of 142 for phenytoin (6.3%; 95% CI, 3.4%-11.6%), 21 of 338 for phenobarbital (6.2%; 95% CI, 4.1%-9.3%), 121 of 2255 for carbamazepine (5.4%; 95% CI, 4.5%-6.4%), 10 of 204 for topiramate (4.9%; 95% CI, 2.7%-8.8%), 110 of 3584 for lamotrigine (3.1%; 95% CI, 2.5%-3.7%), 13 of 443 for oxcarbazepine (2.9%; 95% CI, 1.7%-5.0%), and 33 of 1325 for levetiracetam (2.5%; 95% CI, 1.8%-3.5%). For valproate, phenobarbital, and carbamazepine, there was a significant increase in the prevalence of MCMs associated with increasing dose of the ASM. Overall prevalence of MCMs decreased from 6.1% (153 of 2505) during the period 1998 to 2004 to 3.7% (76 of 2054) during the period 2015 to 2022. This decrease over time was significant in univariable logistic analysis but not after adjustment for changes in ASM exposure pattern. Conclusions and Relevance: Of all ASMs with meaningful data, the lowest prevalence of MCMs was observed in offspring exposed to levetiracetam, oxcarbazepine, and lamotrigine. Prevalence of MCMs was higher with phenytoin, valproate, carbamazepine, and phenobarbital, and dose dependent for the latter 3 ASMs. The shift in exposure pattern over time with a declining exposure to valproate and carbamazepine and greater use of lamotrigine and levetiracetam was associated with a 39% decline in prevalence of MCMs, a finding that has major public health implications.publishedVersio

Progress report on new antiepileptic drugs: A summary of the Sixteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XVI): II. Drugs in more advanced clinical development.

The Sixteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XVI) was held in Madrid, Spain on May 22-25, 2022 and was attended by 157 delegates from 26 countries representing basic and clinical science, regulatory agencies, and pharmaceutical industries. One day of the conference was dedicated to sessions presenting and discussing investigational compounds under development for the treatment of seizures and epilepsy. The current progress report summarizes recent findings and current knowledge for seven of these compounds in more advanced clinical development for which either novel preclinical or patient data are available. These compounds include bumetanide and its derivatives, darigabat, ganaxolone, lorcaserin, soticlestat, STK-001, and XEN1101. Of these, ganaxolone was approved by the US Food and Drug Administration in March 2022 for the treatment of seizures associated with cyclin-dependent kinase-like 5 deficiency disorder in patients 2 years of age and older

Progress report on new antiepileptic drugs: A summary of the Sixteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XVI): I. Drugs in preclinical and early clinical development.

The Eilat Conferences have provided a forum for discussion of novel treatments of epilepsy among basic and clinical scientists, clinicians, and representatives from regulatory agencies as well as from the pharmaceutical industry for 3 decades. Initially with a focus on pharmacological treatments, the Eilat Conferences now also include sessions dedicated to devices for treatment and monitoring. The Sixteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XVI) was held in Madrid, Spain, on May 22-25, 2022 and was attended by 157 delegates from 26 countries. As in previous Eilat Conferences, the core of EILAT XVI consisted of a sequence of sessions where compounds under development were presented and discussed. This progress report summarizes preclinical and, when available, phase 1 clinical data on five different investigational compounds in preclinical or early clinical development, namely GAO-3-02, GRT-X, NBI-921352 (formerly XEN901), OV329, and XEN496 (a pediatric granular formulation of retigabine/ezogabine). Overall, the data presented in this report illustrate novel strategies for developing antiseizure medications, including an interest in novel molecular targets, and a trend to pursue potential new treatments for rare and previously neglected severe epilepsy syndromes

The Interplay between Liver First-Pass Effect and Lymphatic Absorption of Cannabidiol and its Implications for Cannabidiol Oral Formulations

For highly lipophilic drugs, passage into the intestinal lymphatic system rather than the portal vein following oral administration may represent a major alternative route of delivery into the general circulation. Increasing intestinal lymphatic transport provides an effective strategy to improve oral bioavailability when hepatic first-pass metabolism is a major rate-limiting step hampering access to the systemic circulation after oral dosing. The transfer of orally administered, highly lipid-soluble drugs to the lymphatic system is mediated by their association with chylomicrons, large intestinal lipoproteins that are assembled in the enterocytes in the presence of long-chain triglycerides or long-chain fatty acids. Due to its very high lipophilicity, cannabidiol (CBD) has physicochemical features (e.g. logP = 6.3) consistent with an oral absorption mediated at least in part by transport via the intestinal lymphatic system. CBD also undergoes extensive first-pass hepatic metabolism. Formulation changes favoring diversion of orally absorbed CBD from the portal to the lymphatic circulation pathway can result in reduced first-pass liver metabolism, enhanced oral bioavailability, and reduced intra- and intersubject variability in systemic exposure. In this manuscript, we discuss (1) evidence for CBD undergoing hepatic first-pass liver metabolism and lymphatic absorption to a clinically important extent; (2) the potential interplay between improved oral absorption, diversion of orally absorbed drug to the lymphatic system, and magnitude of presystemic elimination in the liver; and (3) strategies by which innovative chemical and/or pharmaceutical delivery systems of CBD with improved bioavailability could be developed

Relationship between saliva and plasma rufinamideconcentrations in patients with epilepsy

The assay of saliva samples provides a valuable alternative to the use of blood samples for therapeutic drug monitoring (TDM), at least for certain categories of patients. To determine the feasibility of using saliva sampling for the TDM of rufinamide, we compared rufinamide concentrations in paired samples of saliva and plasma collected from 26 patients with epilepsy at steady state. Within-patient relationships between plasma rufinamide concentrations and dose, and the influence of comedication were also investigated. Assay results in the two tested fluids showed a good correlation (r2 = .78, P < .0001), but concentrations in saliva were moderately lower than those in plasma (mean saliva to plasma ratio = 0.7 ± 0.2). In eight patients evaluated at three different dose levels, plasma rufinamide concentrations increased linearly with increasing dose. Patients receiving valproic acid comedication had higher dose-normalized plasma rufinamide levels than patients comedicated with drugs devoid of strong enzyme-inducing or enzyme-inhibiting activity. Overall, these findings indicate that use of saliva represents a feasible option for the application of TDM in patients treated with rufinamide. Because rufinamide concentrations are lower in saliva than in plasma, a correction factor is needed if measurements made in saliva are used as a surrogate for plasma concentrations.F.B. received consultancy fees from Eisai and GW Pharma. V.F. received consultancy fees from GW Pharma. C.A.G. received speaker's or consultancy fees from Bial-Portela & Ca, Eisai, Lusofarmaco, Sandoz-Novartis Farma, Sanofi, and UCB Pharma. E.P. received speaker's or consultancy fees from Amicus Therapeutics, Arvelle, Biogen, Eisai, GW Pharma, Intas Pharmaceuticals, Laboratorios Bagò, Sanofi, Sun Pharma, UCB Pharma, and Xenon Pharma. C.J.L. received speaker's fees from GW Pharma, Eisai, and Labor Krone.publishedVersio