The aim of the present review is to discuss the potential value of therapeutic drug monitoring (TDM) of the newer antiepileptic drugs (AEDs) felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, tiagabine, topiramate, vigabatrin, and zonisamide. Studies of the relationship between serum concentrations and clinical efficacy of these drugs are reviewed, and the potential value of TDM of the drugs is discussed based on their pharmacokinetic properties and mode of action. Analytical methods for the determination of the serum concentrations of these drugs are also briefly described. There are only some prospective data on the serum concentration–effect relationships, and few studies have been designed primarily to study these relationships. As TDM is not widely practiced for the newer AEDs, there are no generally accepted target ranges for any of these drugs, and for most a wide range in serum concentration is associated with clinical efficacy. Furthermore, a considerable overlap in drug concentrations related to toxicity and nonresponse is reported. Nevertheless, the current tentative target ranges for felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine (10-hydroxy-carbazepine metabolite), tiagabine, topiramate, vigabatrin, and zonisamide are 125 to 250 μmol/L, 70 to 120 μmol/L, 10 to 60 μmol/L, 35 to 120 μmol/L, 50 to 140 μmol/L, 50 to 250 nmol/L, 15 to 60 μmol/L, 6 to 278 μmol/L, and 45 to 180 μmol/L, respectively. Further systematic studies designed specifically to evaluate concentration–effect relationships of the new AEDs are urgently needed. Although routine monitoring in general cannot be recommended at present, measurements of some of the drugs is undoubtedly of help with individualization of treatment in selected cases in a particular clinical setting.
Objectives Mood stabilizers administered for bipolar disorder during pregnancy, such as valproic acid, can increase the risk of congenital anomalies in offspring. Valnoctamide is a valproic acid derivative associated with a decreased risk for congenital abnormalities in animals. The present study evaluated the efficacy and safety of valnoctamide monotherapy, compared to placebo, in the treatment of patients in an acute manic episode. Methods A 3‐week, double‐blind, randomized, placebo‐ and risperidone‐controlled, parallel group trial was conducted on 173 patients in an acute manic episode. Patients were randomized to receive valnoctamide 1500 mg/d (n=71), risperidone 6 mg/d (n=32), or matching placebo (n=70). The primary outcome measure was the change in Young Mania Rating Scale (YMRS) scores. Results Valnoctamide did not differ significantly from placebo on any of the study endpoints ( YMRS , Positive and Negative Syndrome Scale , and the Clinical Global Impression Scale for Bipolar Disorder [CGI ‐BP] scales; all P >.60). Mixed models for repeated measures showed that risperidone produced significantly more improvement than placebo in the overall bipolar disorder CGI‐BP severity scale ( P =.036), and the CGI‐BP severity scale for mania ( P =.021). The Kaplan‐Meier survival curve revealed higher all‐cause discontinuation rates (mainly due to lack of efficacy) in the valnoctamide group compared to the other study groups ( P =.026). Patients with higher valnoctamide plasma levels had a numerically higher YMRS response, but this was not statistically significant. Conclusions Valnoctamide was well tolerated at 1500 mg/d but lacked efficacy in the treatment of symptoms in patients with acute mania. Possible differences between the biological mechanisms of action of valproic acid and valnoctamide are discussed.
Abstract Since 1992, the Eilat Conferences have provided a forum for all stakeholders in the epilepsy community to appraise the latest data on new antiepileptic drugs and emergency seizure treatments, including, in recent years, updates on progress with the development of novel monitoring and therapeutic devices. Because of the COVID‐19 pandemic, the Fifteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XV) was held as a fully virtual conference on July 27‐30, 2020 for the sessions on drugs and on August 3, 2020 for the sessions on devices, and was attended during the 5 days by >500 participants from 63 countries. This progress report summarizes key preclinical and initial (phase 1) clinical data on eight investigational treatments that are currently in early development, including 2‐deoxy‐D‐glucose, GAO‐3‐02, JNJ‐40411813, NBI‐921352, NTX‐001, sec ‐butylpropylacetamide, XEN1101, and XEN496. This report provides an overview of current scenarios in the area of treatment discovery and development. The information presented illustrates a variety of innovative strategies, including exploration of compounds with novel mechanisms of action, transplantation of interneurons into epileptogenic brain regions, and the targeting of rare, previously neglected syndromes.
Summary: Purpose: Concern persists that the criteria used to establish bioequivalence of generic drugs may not adequately guarantee the interchangeability of antiepileptic medications (AEDs), particularly controlled‐release (CR) formulations. We examined the utilization of several new parameters, in addition to AUC, peak plasma concentration (C max ), and time to reach C max (t max ), for the assessment of bioequivalence and in vivo performance of CBZ and other CR products. These new parameters may offer additional information for evaluation of CR products that yield a prominent plateau in the plasma time‐concentration curve. They include mean residence time (MRT), C max /AUC, plateau time or POT (the time span associated with the concentrations within 25% of C max ), t apical , and C apical , (the arithmetic mean of the POT times and concentrations within 25% of C max respectively). Additional parameters for multiple‐dose studies include the percentage fluctuation and the flatness of the steady state‐concentration curve. Methods: These proposed parameters were used in two recent (single and multiple dose) two‐way crossover studies of a new CR product of CBZ (Teril 400 CR) in comparison with Tegretol CR Divitab. Results: Teril 400 CR was found to be bioequivalent to Tegretol CR Divitab, by using both the classic and the additional proposed parameters. Both CBZ CR products have similar rates of absorption and similar flatness of their plasma time‐concentration curves as assessed by visual inspection and the proposed parameters. Conclusions: The additional parameters examined may supplement the traditional single‐point parameters, C max and t max for assessment of rate of absorption and the flatness of the concentration curve. Their potential benefit and practical utility was confirmed in these two studies. Absorption‐rate assessment is important in light of concentration‐related side effects associated with CBZ therapy and the impact of fluctuations and the flatness of the CBZ plasma concentration curve on the drug efficacy and tolerability.
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