Search

Frank MC Besag,1,2 Philip N Patsalos3,41South Essex Partnership University NHS Foundation Trust (SEPT), Mid Beds Clinic, Bedford, Bedfordshire, UK; 2Institute of Psychiatry, London, UK; 3Pharmacology and Therapeutics Unit, Department of Clinical and Experimental Epilepsy, UCL-Institute of Neurology, London, UK; 4Epilepsy Society, Chalfont Centre for Epilepsy, Chalfont St Peter, Buckinghamshire, UKAbstract: Although most people presenting with partial-onset seizures will achieve control with antiepileptic medication, a considerable minority will have difficult-to-treat epilepsy that is resistant to existing medication. Over the last few years, a large number of new antiepileptic drugs have been developed. Some of these have a novel mode of action. Many of the older antiepileptic drugs act through sodium channels or by enhancement of gamma amino butyric acid (GABA). Lamotrigine has sodium-channel blocking properties but also has other important modes of action, indicated by efficacy in treating not only partial-onset but also generalized seizures. Vigabatrin and tiagabine both increase GABA activity, by inhibiting GABA transaminase and limiting GABA reuptake, respectively. The main mode of action of gabapentin and pregabalin is not via GABA but through a selective inhibitory effect on voltage-gated calcium channels containing the α2δ-1 subunit. Levetiracetam inhibits the recycling of SV2A (synaptic vesicle protein 2A) neurotransmitter vesicles but also has other effects, including inhibition of voltage-dependent calcium channels. Some drugs, eg, felbamate, zonisamide, and topiramate, have multiple modes of action. In many cases, although the main mode of action may have been identified, other modes of action also play a role. Two recently developed antiepileptic drugs appear to have completely novel primary modes of action; retigabine (ezogabine) and perampanel act on the potassium channel and on AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors, respectively. The hope is that antiepileptic drugs with a novel mode of action will be effective where previous drugs have failed and will not have unacceptable adverse effects. However, experience with these medications is too limited to allow any conclusions to be drawn at present.Keywords: partial-onset seizures, difficult-to-treat epilepsy, antiepileptic drugs

1. Antipyrine (AP) clearance, half-life and volume of distribution were determined in 52 patients, taking one or more antiepileptic drug (AED), before and 4 weeks after the complete removal of phenytoin (PHT, n = 20), carbamazepine (CBZ, n = 15) and sodium valproate (VPA, n = 17). 2. PHT removal was associated with a mean 13% fall in AP clearance and a mean 16% increase in AP half-life, in patients who were also taking CBZ with or without barbiturates. There was no significant difference between patients who did, and did not, take barbiturates, in addition to CBZ. 3. CBZ removal was associated with a mean 45% fall in AP clearance and a mean 69% increase in AP half-life, if there was no inducing AED comedication, but had no effect on AP clearance and half- life if PHT and/or barbiturates were also being taken. 4. Removal of VPA had no effect on AP clearance or half-life. 5. The removal of PHT, CBZ and VPA had no significant effect on AP volume of distribution. 6. PHT appears to be a more powerful inducer of hepatic enzyme activity, as measured by the AP test, than is CBZ. [ABSTRACT FROM AUTHOR]

Introduction: Antiseizure medications (ASMs) and antipsychotic drugs are frequently coadministered with the potential for drug-drug interactions. Interactions may either be pharmacokinetic or pharmacodynamic, resulting in a decrease or increase in efficacy and/or an increase or decrease in adverse effects., Areas Covered: The clinical evidence for pharmacokinetic and pharmacodynamic interactions between ASMs and antipsychotics is reviewed based on the results of a literature search in MEDLINE conducted in April 2023., Expert Opinion: There is now extensive published evidence for the clinical importance of interactions between ASMs and antipsychotics. Enzyme-inducing ASMs can decrease blood concentrations of many of the antipsychotics. There is also evidence that enzyme-inhibiting ASMs can increase antipsychotic blood concentrations. Similarly, there is limited evidence showing that antipsychotic drugs may affect the blood concentrations of ASMs through pharmacokinetic interactions. There is less available evidence for pharmacodynamic interactions, but these can also be important, as can displacement from protein binding. The lack of published evidence for an interaction should not be interpreted as meaning that the given interaction does not occur; the evidence is building continually. There is no substitute for careful patient monitoring and sound clinical judgment.

The objective of this study was to identify and quantify barriers to generic substitution of antiseizure medications (ASM). A questionnaire on generic ASM substitution was developed by the International League Against Epilepsy (ILAE) Task Force on Generic Substitution. Questions addressed understanding of bioequivalence, standards for generic products, experiences with substitution, and demographic data. The survey was web-based and distributed to ILAE chapters, their membership, and professional colleagues of task force members. Comparisons in responses were between ILAE regions and country income classification. A total of 800 individuals responded, with 44.2% being from the Asia-Oceania ILAE Region and 38.6% from European Region. The majority of respondents had little or no education in generic substitution or bioequivalence. Many respondents indicated lack of understanding aspects of generic substitution. Common barriers to generic substitution included limited access, poor or inconsistent quality, too expensive, or lack of regulatory control. Increase in seizures was the most common reported adverse outcome of substitution. Of medications on the World Health Organization Essential Medication list, problems with generic products were most frequent with carbamazepine, lamotrigine, and valproic acid. Several barriers with generic substitution of ASM revolved around mistrust of regulatory control and quality of generic ASM. Lack of education on generic substitution is also a concern. Generic ASM products may be the only option in some parts of the world and efforts should address these issues. Efforts to address these barriers should improve access to medications in all parts of the world., (© 2022 The Authors. Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Highly purified cannabidiol (CBD) has demonstrated efficacy with an acceptable safety profile in patients with Lennox-Gastaut syndrome or Dravet syndrome in randomized, double-blind, add-on, controlled phase 3 trials. It is important to consider the possibility of drug-drug interactions (DDIs). Here, we review six trials of CBD (Epidiolex/Epidyolex; 100 mg/mL oral solution) in healthy volunteers or patients with epilepsy, which investigated potential interactions between CBD and enzymes involved in drug metabolism of common antiseizure drugs (ASDs). CBD did not affect CYP3A4 activity. Induction of CYP3A4 and CYP2C19 led to small reductions in exposure to CBD and its major metabolites. Inhibition of CYP3A4 activity did not affect CBD exposure and caused small increases in exposure to CBD metabolites. Inhibition of CYP2C19 activity led to a small increase in exposure to CBD and small decreases in exposure to CBD metabolites. One potentially clinically important DDI was identified: combination of CBD and clobazam (CLB) did not affect CBD or CLB exposure, but increased exposure to major metabolites of both compounds. Reduction of CLB dose may be considered if adverse reactions known to occur with CLB are experienced when it is coadministered with CBD. There was a small increase of exposure to stiripentol (STP) when coadministered with CBD. STP had no effect on CBD exposure but led to minor decreases in exposure to CBD metabolites. Combination of CBD and valproate (VPA) did not cause clinically important changes in the pharmacokinetics of either drug, or 2-propyl-4-pentenoic acid. Concomitant VPA caused small increases in exposure to CBD metabolites. Dose adjustments are not likely to be necessary when CBD is combined with STP or VPA. The safety results from these trials were consistent with the known safety profile of CBD. These trials indicate an overall low potential for DDIs between CBD and other ASDs, except for CLB., (© 2020 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Introduction : Antiepileptic drugs (AEDs) are the cornerstone of treatment of patients with epilepsy, and there are presently 27 licensed AEDs making AEDs among the most common medications for which therapeutic drug monitoring (TDM) is performed. The aim of this review is to provide an overview of the current evidence of the use and implementation of AED TDM in patients with epilepsy and other non-epilepsy conditions. Areas covered : The pharmacokinetic variability of AEDs is extensive, resulting in pronounced variability in serum concentrations between patients. TDM may thus be useful to individualize the treatment of patients with epilepsy and also in non-epilepsy conditions. Indications for TDM include settings where pharmacokinetic variability is anticipated (e.g. in children, the elderly, during pregnancy, and patients prescribed polytherapy resulting in drug interactions) and drug adherence. TDM contributes to provide a quality assurance of the treatment. Patient management is, therefore, best guided by the determination of individual therapeutic concentrations. Expert opinion : Because of pharmacokinetic variability is prevalent among AEDs, TDM allows a bespoke approach to epilepsy care allowing dose adjustments based on measured drug concentrations so as to optimize clinical outcome. Future advances include the use of additional markers of toxicity and genetic variability so as to further aid individualization and optimize AED treatment.

Background: In elderly patients (≥65 years of age) with epilepsy who take medications for comorbid conditions, some antiepileptic drugs (AEDs) may alter the metabolism of other treatments and increase the risk of adverse consequences and healthcare utilisation. This analysis compares healthcare costs associated with enzyme-inducing AEDs (EIAEDs) and non-enzyme active AEDs (nEAAEDs) use in elderly patients with epilepsy., Methods: This retrospective matched cohort study used the Clinical Practice Research Datalink (CPRD) of UK primary care medical records, linked to the Hospital Episode Statistics (HES) database. Selected patients with epilepsy were ≥ 65 years and prescribed an EIAED or nEAAED between 2001 and 2010 (index) after ≥1 year without AEDs (baseline) and followed until the first occurrence of the following: end of HES data coverage, end of GP registration, or death; practice's up-to-standard status or addition of an AED belonging to another cohort or discontinuation of the last AED of that cohort. Propensity score matching reduced confounding factor effects between cohorts. Key outcomes included time to cohort treatment failure, time to index AED treatment failure, and direct healthcare costs in 2014 Pound Sterling (£) values., Results: Overall, 1425 elderly patients were included: 964 with EIAEDs and 461 with nEAAEDs. At baseline, the EIAED cohort was older (mean age, 76.2 vs. 75.1 years) and a higher proportion were male. Baseline direct healthcare costs were similar. After matching (n = 210 each), and over the entire follow-up period, median monthly direct healthcare costs were higher for patients taking EIAEDs than nEAAEDs (£403 vs. £317; p = 0.0150, Mann-Whitney U). Costs were higher for patients remaining in the EIAED cohort after 3 follow-up years. The median time to cohort treatment failure for the EIAED cohort was 1110 days vs. 1175 days for the nEAAED cohort., Conclusion: Newly treated elderly patients with epilepsy were more likely to be prescribed EIAEDs than nEAAEDs. In matched cohorts, elderly patients with epilepsy treated with EIAEDs had higher average total direct and epilepsy-related healthcare costs than nEAAED-treated patients; this difference was greater than previously reported in the overall adult population. Changing treatment practices could improve patient care and reduce costs.

Background: Volumetric absorptive microsampling (VAMS) is a novel sampling technique for the collection of fixed-volume capillary blood. In this study, a new analytical method was developed and used to quantify 14 different antiepileptic drugs (AEDs) and 2 active metabolites in samples collected by VAMS. These data were compared with concentration measurements in plasma., Methods: The authors developed a selective and sensitive liquid chromatography-mass spectrometry (LC-MS/MS) assay to measure the concentrations of several AEDs in whole blood collected by VAMS, which were compared with a commercially available LC-MS/MS kit for AED monitoring in plasma. Drugs and internal standards were extracted from whole blood/plasma samples by a simple protein precipitation., Results: An LC-MS/MS method analyzing VAMS samples was successfully developed and validated for the determination of various AED concentrations in whole blood according to EMA guidelines for bioanalytical method validation. Extraction recovery was between 91% and 110%. No matrix effect was found. The method was linear for all drugs with R ≥0.989 in all cases. Intra-assay and inter-assay reproducibility analyses demonstrated accuracy and precision within acceptance criteria. Carry over and interferences were negligible. No volumetric HCT% bias was found at 3 different HCT values (35%-55%) with recovery being consistently above 87%. Samples are very stable at temperatures ranging from -20°C to 37°C and for a 4-month period. Leftover EDTA samples from 133 patients were tested to determine concentration differences between plasma and whole blood sampled by VAMS. The resulting difference varied less than 15% apart from those drugs with a blood/plasma ratio (R) different from 1., Conclusions: The assay allows for highly sensitive and selective quantification of several AEDs in whole blood samples collected by VAMS. The developed method is accurate and precise and free from matrix effects and volumetric HCT% bias.

Objective: Assessment of the relevance between serum drug concentration to its therapeutic response is a valid monitoring strategy for the clinical efficacy of antiepileptic drugs (AEDs). Levetiracetam (LEV) is a broad spectrum AED with a possible anti-inflammatory effect. We aimed to determine the relationship between LEV concentrations and its therapeutic response, and the effect of LEV on IL1-beta concentrations in patients with epilepsy., Methods: Patients on monotherapy (n = 7) or polytherapy (n = 15) with LEV for their seizures management were included. Blood samples of each patient were collected: just before LEV intake, 1 h, 2 h, 4 h and 8 h following the last dose. Serum LEV concentrations were measured by liquid chromatography mass spectrometry and IL1-beta concentrations by chemiluminescent immunometric assay. Concentration to dose (C/D) ratio values was used for analyses. LEV concentrations were compared between responders (≤1 seizure/month) and non-responders (>1 seizure/month) and patients with or without adverse reactions. IL1-beta concentrations before and at 2 h following LEV ingestion were compared in order to detect the effect of the increase in serum LEV concentration on IL1-beta., Results: Although there was no change in LEV (C/D) ratio or LEV maximum concentration (Cmax)/D ratio of the responders and non-responders, the C/D ratio following 1 h of LEV intake (2.17 ± 0.59 kg.day/L) and Cmax/D ratio (2.25 ± 0.56 kg.day/L) in the patients with adverse effects was significantly higher than for the patients without adverse effects (1.09 ± 0.12 kg.day/L and 1.49 ± 0.14 kg.day/L respectively). A statistically significant decrease was found in the IL1-beta concentration to LEV (C/D) ratio with the increase in LEV concentration in patients on LEV monotherapy., Conclusion: The possible relationship between LEV Cmax and its therapeutic response or IL1-beta concentrations may be an importance indication of LEV antiepileptic efficacy. Consequently, monitoring LEV Cmax values may enhance LEV adherence because patients would be less likely to develop adverse effects., (Copyright © 2018. Published by Elsevier B.V.)

Background: Antiepileptic drugs (AEDs) are the mainstay of epilepsy treatment. Since 1989, 18 new AEDs have been licensed for clinical use and there are now 27 licensed AEDs in total for the treatment of patients with epilepsy. Furthermore, several AEDs are also used for the management of other medical conditions, for example, pain and bipolar disorder. This has led to an increasingly widespread application of therapeutic drug monitoring (TDM) of AEDs, making AEDs among the most common medications for which TDM is performed. The aim of this review is to provide an overview of the indications for AED TDM, to provide key information for each individual AED in terms of the drug's prescribing indications, key pharmacokinetic characteristics, associated drug-drug pharmacokinetic interactions, and the value and the intricacies of TDM for each AED. The concept of the reference range is discussed as well as practical issues such as choice of sample types (total versus free concentrations in blood versus saliva) and sample collection and processing., Methods: The present review is based on published articles and searches in PubMed and Google Scholar, last searched in March 2018, in addition to references from relevant articles., Results: In total, 171 relevant references were identified and used to prepare this review., Conclusions: TDM provides a pragmatic approach to epilepsy care, in that bespoke dose adjustments are undertaken based on drug concentrations so as to optimize clinical outcome. For the older first-generation AEDs (carbamazepine, ethosuximide, phenobarbital, phenytoin, primidone, and valproic acid), much data have accumulated in this regard. However, this is occurring increasingly for the new AEDs (brivaracetam, eslicarbazepine acetate, felbamate, gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, perampanel, piracetam, pregabalin, rufinamide, stiripentol, sulthiame, tiagabine, topiramate, vigabatrin, and zonisamide).

Objective: Given that only the free non-protein-bound concentration of an antiepileptic drug (AED) crosses the blood-brain barrier, entering the brain and producing an antiepileptic effect, knowledge and measurement of the free drug fraction is important. Such data are sparse, particularly for newer AEDs, and have arisen from the use of disparate methodologies and settings over the past six decades. We report on the protein binding of 25 AEDs that are available for clinical use, along with two pharmacologically active metabolites (carbamazepine-epoxide and N-desmethyl clobazam), using standardized methodology and under set conditions., Methods: The protein binding of the various AEDs was undertaken in sera of 278 patients with epilepsy. Separation of the free non-protein-bound component was achieved by using ultracentrifugation (Amicon Centrifree Micropartition System) under set conditions: 500 μl serum volume; centrifugation at 1,000 g for 15 min, and at 25°C. Free and total AED concentrations were measured by use of fully validated liquid chromatography/mass spectroscopy (LC/MS) techniques., Results: Gabapentin and pregabalin are non-protein-bound, whereas highly bound AEDs (≥88%) include clobazam, clonazepam, perampanel, retigabine, stiripentol, tiagabine, and valproic acid as well as the N-desmethyl-clobazam (89%) metabolite. The minimally bound drugs (<22%) include ethosuximide (21.8%), lacosamide (14.0%), levetiracetam (3.4%), topiramate, (19.5%) and vigabatrin (17.1%). Ten of the 25 AEDs exhibit moderate protein binding (mean range 27.7-74.8%)., Significance: These data provide a comprehensive comparison of serum protein binding of all available AEDs including the metabolites, carbamazepine-epoxide and N-desmethyl-clobazam. Knowledge of the free fraction of these AEDs can be used to optimize epilepsy treatment., (Wiley Periodicals, Inc. © 2017 International League Against Epilepsy.)

Purpose: The therapeutic equivalence of generic and brand antiepileptic drugs, based on studies performed on healthy volunteers, has been questioned. We compare, in a routine clinical setting, brand versus generic levetiracetam (LEV) bioequivalence in patients with epilepsy and also the clinical efficacy and tolerability of the substitution., Methods: A prospective, open-label, non-randomized, steady-state, multiple-dose, bioequivalence study was conducted in 12 patients with epilepsy (5 females), with a mean age of 38.4±16.2 years. Patients treated with the brand LEV (Keppra; UCB Pharma) were closely followed for a four-week period and subsequently switched to a generic LEV (Pharmaten) and followed for another four-week period. Blood samples were collected at the end of each 4-week period, during a dose interval for each formulation, for LEV concentration measurements by liquid chromatography mass spectrometry. Steady-state area under the curve (AUC) and peak plasma concentration (Cmax) data were subjected to conventional average bioequivalence analysis. Secondary clinical outcomes, including seizure frequency and adverse events, were recorded., Results: Patients had epilepsy for a mean period of 14.1±10.6years and the mean daily LEV dose was 2583.3±763.7mg. The mean AUC±SD and Cmax±SD was 288.4±86.3(mg/L)h and 37.8±10.4mg/L respectively for brand LEV and 319.2±104.7(mg/L)h and 41.6±12.3mg/L respectively for the generic LEV. Statistic analysis showed no statistical significant difference in bioequivalence. Also, no change in seizures frequency and/or adverse events was recorded., Conclusions: In our clinical setting, generic LEV was determined to be bioequivalent to brand LEV. Furthermore, seizures frequency or/and adverse events were not affected upon switching from brand to generic LEV., (Copyright © 2017 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Background: Perampanel (PMP), a noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor antagonist, is a novel anti-epileptic drug (AED) licensed for the adjunctive treatment of focal and generalized epilepsy. There is limited information on PMP's pharmacokinetics and drug interaction characteristics with concomitant AEDs. We have investigated the effects of PMP dose, age, sex, and coprescribed AEDs on serum PMP concentrations., Methods: We used the database of a therapeutic drug monitoring unit at a tertiary epilepsy referral center to identify patients who had PMP as part of their treatment and extracted clinical information from their medical notes. Sera PMP concentrations were determined using liquid chromatography/mass spectroscopy., Results: In total, 160 sera from 107 patients (66 females) aged 18-70 years and weighing 40-125 kg were identified. They were prescribed a median PMP dose of 6 mg/d (range 2-12 mg/d) and were coprescribed a variety of AEDs, including enzyme-inducing [carbamazepine (CBZ) and oxcarbazepine (OXC)] and enzyme-inhibiting (valproic acid) AEDs. A linear relationship was observed between PMP dose and serum concentrations (r = 0.714, P < 0.0005). Sex and age were found not to influence PMP serum concentration. Enzyme-inducing AEDs dose-dependently decreased PMP concentrations, with CBZ and OXC decreasing mean values by 69% and 37%, respectively. In contrast, although topiramate and phenytoin also decreased mean PMP concentrations by 18% and 13%, respectively, these changes did not achieve statistical significance., Conclusions: PMP exhibits a linear dose-concentration relationship, with serum PMP concentrations being age and sex independent. CBZ and OXC can significantly decrease PMP concentrations, probably through an induction of CYP3A4-mediated metabolism.

The clinical pharmacology profile of a drug critically determines its therapeutics, and this review summarizes the characteristics associated with the antiepileptic drug (AED) perampanel. A PubMed literature search was performed for perampanel. Congress abstract data are included where necessary and Eisai Ltd provided access to unpublished data on file. After oral ingestion, perampanel is rapidly absorbed and peak plasma concentrations occur 0.5-2.5 h later; its bioavailability is ~100%. Although the rate of perampanel absorption is slowed by food co-ingestion, the extent absorbed remains unchanged; therefore, perampanel can be administered without regard to meal times. The pharmacokinetics of perampanel are linear and predictable over the clinically relevant dose range (2-12 mg); perampanel is 95% protein-bound to albumin and α1-acid glycoprotein. Perampanel is extensively metabolized (>90%) in the liver, primarily by cytochrome P450 (CYP) 3A4, to various pharmacologically inactive metabolites. In healthy volunteers, the apparent terminal half-life is ~105 h, whereas the calculated effective half-life is 48 h. These half-life values allow for once-daily dosing, which will aid patient compliance and in the event of a missed dose, will have minimal impact on seizure control. In healthy volunteers prescribed carbamazepine, half-life decreases to 25 h. Clearance values are not significantly different in adolescents (~13.0 ml/min) and the elderly (~10.5 ml/min) compared with adults (10.9 ml/min). Perampanel has minimal propensity to cause pharmacokinetic interactions. However, it is the target of such interactions and CYP3A4-inducing AEDs enhance its clearance; this can be used to advantage because dose titration can be faster and thus optimum therapeutic outcome can be achieved sooner. Perampanel 12 mg, but not 4 or 8 mg, enhances the metabolism of the progesterone component of the oral contraceptive pill, necessitating the need for an additional reliable contraceptive method. Overall, perampanel has a favorable clinical pharmacology profile, which should aid its clinical use., (Wiley Periodicals, Inc. © 2014 International League Against Epilepsy.)

Objective: Lacosamide (LCM), a new antiepileptic drug (AED) approved as adjunctive therapy for the treatment of patients with partial-onset seizures, has limited pharmacokinetic and drug interaction data. The main objectives of the present study were to investigate the effects of dose, age, gender, and hepatic enzyme-inducing AEDs on the pharmacokinetics of LCM as assessed by steady state serum LCM values., Methods: An LCM AED therapeutic drug monitoring database was analyzed with regard to LCM serum concentrations and other relevant patient and AED drug information. One hundred twenty eight sera were identified. These were collected from 68 women and 61 men aged 19-66 years, who were prescribed a median LCM dose of 300 mg (range 50-600 mg)., Results: Serum LCM concentrations were observed in the following main groupings: LCM monotherapy (n = 5), LCM with nonenzyme-inducing AEDs (n = 50), LCM with enzyme-inducing AEDs (n = 49), LCM with valproic acid (n = 20), and LCM with enzyme-inducing AEDs plus valproic acid (n = 4). Analysis of variance showed a correlation of dose with LCM concentrations (r = 0.53, P < 0.001), and women had statistically higher mean LCM concentration than did men, 37.2 ± 23.6 versus 26.8 ± 12.9 μmol/L (P = 0.001). Serum LCM concentrations were significantly lower (P = 0.002) in the enzyme-inducing AED group (carbamazepine and phenytoin) compared with the LCM monotherapy group and the nonenzyme-inducing group, 23.5 ± 11.0, 34.5 ± 7.7, and 32.7 ± 17.9 μmol/L, respectively., Conclusions: Serum LCM concentrations increased dose dependently, were age independent, and were higher in women compared with men. Carbamazepine and phenytoin can significantly decrease serum LCM concentrations, probably via induction of LCM metabolism.

Since antiepileptic drugs (AEDs) are prescribed to treat various non-epilepsy-related disorders in addition to the fact that patients with epilepsy may develop concurrent disorders that will need treatment, the propensity for AEDs to interact with non-AEDs is considerable and indeed can present a difficult clinical problem. The present review details the pharmacokinetic and pharmacodynamic interactions that have been reported to occur with the new AEDs (eslicarbazepine acetate, felbamate, gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, perampanel, pregabalin, retigabine (ezogabine), rufinamide, stiripentol, tiagabine, topiramate, vigabatrin and zonisamide) and drugs used to treat non-epilepsy disorders. Interaction study details are described, as necessary, so as to allow the reader to take a view as to the possible clinical significance of particular interactions. Pharmacokinetic interactions relate to hepatic enzyme induction or inhibition and involved a variety of drugs including psychoactive drugs, cardioactive drugs, oral contraceptives, antituberculous agents, analgesics and antineoplastic drugs. A total of 68 pharmacokinetic interactions have been described, with lamotrigine (n = 22), topiramate (n = 18) and oxcarbazepine (n = 7) being associated with most, whilst lacosamide, pregabalin, stiripentol and vigabatrin are associated with none. Overall, only three pharmacodynamic interactions have been described and occur with oxcarbazepine, perampanel and pregabalin.

Since 1989 there has been an exponential introduction of new antiepileptic drugs (AEDs) into clinical practice and these include eslicarbazepine acetate, felbamate, gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, perampanel, pregabalin, retigabine (ezogabine), rufinamide, stiripentol, tiagabine, topiramate, vigabatrin and zonisamide; 16 in total. Because often the treatment of epilepsy is lifelong, and because patients are commonly prescribed polytherapy with other AEDs, AED interactions are an important consideration in the treatment of epilepsy and indeed can be a major therapeutic challenge. For new AEDs, their propensity to interact is particularly important because inevitably they can only be prescribed, at least in the first instance, as adjunctive polytherapy. The present review details the pharmacokinetic and pharmacodynamic interactions that have been reported to occur with the new AEDs. Interaction study details are described, as necessary, so as to allow the reader to take a view as to the possible clinical significance of particular interactions. The principal pharmacokinetic interaction relates to hepatic enzyme induction or inhibition whilst pharmacodynamic interactions principally entail adverse effect synergism, although examples of anticonvulsant synergism also exist. Overall, the new AEDs are less interacting primarily because many are renally excreted or not hepatically metabolised (e.g. gabapentin, lacosamide, levetiracetam, topiramate, vigabatrin) and most do not (or minimally) induce or inhibit hepatic metabolism. A total of 139 pharmacokinetic interactions between concurrent AEDs have been described. The least pharmacokinetic interactions (n ≤ 5) are associated with gabapentin, lacosamide, tiagabine, vigabatrin and zonisamide, whilst lamotrigine (n = 17), felbamate (n = 15), oxcarbazepine (n = 14) and rufinamide (n = 13) are associated with the most. To date, felbamate, gabapentin, oxcarbazepine, perampanel, pregabalin, retigabine, rufinamide, stiripentol and zonisamide have not been associated with any pharmacodynamic interactions.

Introduction: Current pathways for treatment of partial onset epilepsy are diverse and include 14 new antiepileptic drugs (AEDs) licensed for use as either monotherapy or adjunctive therapy. However, the impact of these new AEDs on the treatment of partial epilepsy has so far been disappointing and there persists a need for additional drugs. Recently, perampanel, a first-in-class AED was licensed as an adjunct for the management of refractory partial onset seizures with or without secondary generalization in patients 12 years and older. This review highlights the current management of partial epilepsy and analyses the published clinical and preclinical data of perampanel to consider its potential role in the treatment of partial epilepsy., Methods: A literature review of Embase, Medline and PubMed was conducted in April 2013 using the search terms 'perampanel' and 'AMPA receptor antagonist/blocker'. Publications were included if they discussed perampanel in the context of preclinical or clinical epilepsy., Results: Perampanel acts on the glutamate pathway. It is a novel highly selective non-competitive alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist. This is a previously untargeted post-synaptic glutamate receptor. It is responsible for mediating rapid trans-synaptic signal transduction and hence believed to play a major role in seizure propagation. The three pivotal placebo-controlled trials of adjunctive perampanel demonstrated that the effective dosing range is 4-12 mg/day. The drug can be prescribed once daily, and its adverse effect profile is minimal with dizziness, fatigue, headache, and somnolence being the most commonly reported., Conclusions: Perampanel is a welcome addition as it represents an alternative approach in the management of epilepsy with potential to have a significant impact on the prognosis of intractable epilepsy. However, it has only recently been licensed for clinical use in Europe, the USA, and Canada, and there are no data directly comparing it with other AEDs; hence, it remains far too early to ascertain its place in the treatment of patients with partial epilepsy.

Epilepsy is, of course, not one disease but rather a huge number of disorders that can present with seizures. In common, they all reflect brain dysfunction. Moreover, they can affect the mind and, of course, behavior. While animals too may suffer from epilepsy, as far as we know, the electrical discharges are less likely to affect the mind and behavior, which is not surprising. While the epileptic seizures themselves are episodic, the mental and behavioral changes continue, in many cases, interictally. The episodic mental and behavioral manifestations are more dramatic, while the interictal ones are easier to study with anatomical and functional studies. The following extended summaries complement those presented in Part 1., (Copyright © 2013. Published by Elsevier Inc.)

Blood (serum/plasma) antiepileptic drug (AED) therapeutic drug monitoring (TDM) has proven to be an invaluable surrogate marker for individualizing and optimizing the drug management of patients with epilepsy. Since 1989, there has been an exponential increase in AEDs with 23 currently licensed for clinical use, and recently, there has been renewed and extensive interest in the use of saliva as an alternative matrix for AED TDM. The advantages of saliva include the fact that for many AEDs it reflects the free (pharmacologically active) concentration in serum; it is readily sampled, can be sampled repetitively, and sampling is noninvasive; does not require the expertise of a phlebotomist; and is preferred by many patients, particularly children and the elderly. For each AED, this review summarizes the key pharmacokinetic characteristics relevant to the practice of TDM, discusses the use of other biological matrices with particular emphasis on saliva and the evidence that saliva concentration reflects those in serum. Also discussed are the indications for salivary AED TDM, the key factors to consider when saliva sampling is to be undertaken, and finally, a practical protocol is described so as to enable AED TDM to be applied optimally and effectively in the clinical setting. Overall, there is compelling evidence that salivary TDM can be usefully applied so as to optimize the treatment of epilepsy with carbamazepine, clobazam, ethosuximide, gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, phenobarbital, phenytoin, primidone, topiramate, and zonisamide. Salivary TDM of valproic acid is probably not helpful, whereas for clonazepam, eslicarbazepine acetate, felbamate, pregabalin, retigabine, rufinamide, stiripentol, tiagabine, and vigabatrin, the data are sparse or nonexistent.

Polytherapy antiepileptic drug (AED) regimens are prevalent in the treatment of epilepsy and the potential for AEDs to interact results in many challenges. Understanding the underlying mechanism of an interaction, along with the magnitude and its time course of presentation can allow a graded and informed therapeutic adjustment so as to minimize the adverse consequences (breakthrough seizures, increased adverse effects) of the interaction. The purpose of the present review is to address the importance of characterizing interactions among AEDs and to emphasize how preclinical studies, both in vitro and in animal models, can help inform the design of clinical studies and the characterization of potential interactions in patients with epilepsy. In addition, we review and discuss methodological issues of how case studies, population pharmacokinetic data and data from therapeutic drug-monitoring databases can provide invaluable signals regarding potential interactions that have yet to be investigated in formal clinical trials.

Introduction: The search for new, more effective antiepileptic drugs (AEDs) continues. The three most recently approved drugs, the so-called third-generation AEDs, include lacosamide, retigabine and eslicarbazepine acetate and are licensed as adjunctive treatment of partial epilepsy in adults., Areas Covered: For the above three AEDs, their mechanisms of action, pharmacokinetic characteristics, drug-drug interactions, pharmacotherapeutics, dose and administration and therapeutic drug monitoring are reviewed in this paper., Expert Opinion: Lacosamide and retigabine act through novel mechanisms, while eslicarbazepine acetate, a pro-drug for eslicarbazepine, acts in a similar manner to several other AEDs. All three AEDs are associated with linear pharmacokinetic and rapid absorption and undergo metabolism. Their drug-drug interaction profile is low (lacosamide and retigabine) to modest (eslicarbazepine) in propensity. At the highest approved doses for the three AEDs, responder rates were similar. The most commonly observed adverse effects compared with placebo were dizziness, headache, diplopia and nausea for lacosamide; dizziness, somnolence and fatigue for retigabine and dizziness and somnolence for eslicarbazepine acetate. The precise role that these new AEDs will have in the treatment of epilepsy and whether they will make a significant impact on the prognosis of intractable epilepsy is not yet known and will have to await further clinical experience.

Purpose: Lacosamide is a new antiepileptic drug that has a novel mechanism of action, linear pharmacokinetics, and proven efficacy in the adjunctive treatment of partial-onset seizures. We ascertained the relationship between serum and saliva lacosamide concentrations so as to determine whether saliva may be a useful alternative to serum for therapeutic drug monitoring., Methods: Blood samples were obtained from 98 people with intractable epilepsy (51 male; mean age 43 ± 12; range 19-76 years) prescribed lacosamide as adjunctive therapy. For 48 patients, concurrent saliva samples were also collected. Lacosamide concentrations in serum (free and total) and in saliva were determined by high performance liquid chromatography (HPLC)., Results: Linear regression analysis showed a good correlation between lacosamide dose and both total (r(2) = 0.825; n = 32) and free (r(2) = 0.815; n = 29) serum concentrations, and lacosamide serum total and free concentrations were linearly related (r(2) = 0.721; n = 97). There was also a good correlation between saliva lacosamide and both total (r(2) = 0.842; n = 49) and free (r(2) = 0.828; n = 47) serum lacosamide concentrations. Based on the saliva data, the protein binding of lacosamide in serum is calculated to be 87 ± 4% and is comparable to the value calculated by direct measurement of the free and total lacosamide concentration in serum (91 ± 4%)., Discussion: These data support the use of saliva as a viable alternative to serum for monitoring lacosamide therapy in patients with epilepsy., (Wiley Periodicals, Inc. © 2010 International League Against Epilepsy.)

Lacosamide is a new antiepileptic drug (AED) apparently devoid of major pharmacokinetic interactions. Data from a small postmarketing assessment suggest people who had lacosamide co-prescribed with a voltage-gated sodium channel (VGSC)-blocking AED seemed more likely to discontinue lacosamide because of tolerability problems. Among 39 people with refractory epilepsy who developed neurotoxicity (diplopia, dizziness, drowsiness) on lacosamide treatment given in combination with VGSC-blocking AEDs, we identified 7 (17.9%) without any changes in serum levels of other AEDs in whom the symptoms were ameliorated by dose reduction of the concomitant VGSC-blocking AED. Symptoms in these people seem to have arisen from a pharmacodynamic interaction between lacosamide and other VGSC-blocking AEDs. Slow-inactivated VGSCs targeted by lacosamide might be more sensitive to the effects of conventional VGSC-blocking AEDs. Advising people to reduce concomitantly the conventional VGSC-blocking AEDs during lacosamide uptitration in cases of neurotoxicity might improve the tolerability of combination treatment., (Copyright © 2010 Elsevier Inc. All rights reserved.)

The standardised mortality ratio in people with epilepsy is raised to between 2 and 3 compared with the general population. Some biomarker levels, including higher C-reactive protein (CRP), higher glycosylated haemoglobin (HbA1c) and lower estimated glomerular filtration rate (eGFR), are associated with an increase risk of premature mortality. These biomarkers were measured in 125 people with refractory epilepsy to estimate the potential effect of antiepileptic drug (AED) use on these markers. Multiple regression analysis showed that valproate (N=50) use was associated with 55% lower mean CRP concentrations and higher mean eGFR values; and phenytoin (N=32) use with 4% lower mean HbA1c values. These potentially represent health markers improved by AEDs. On the other hand, lamotrigine use (N=48) was associated with 13% lower mean eGFR and this may represent a negative effect on a health marker. These preliminary observations clearly require further controlled studies ideally in people on AED monotherapy., (Copyright © 2010 Elsevier B.V. All rights reserved.)

The aim of this study was to characterize the anticonvulsant effects of stiripentol (STP) in combination with clobazam [CLB], and valproate [VPA]) in the mouse maximal electroshock (MES)-induced seizure model using the type I isobolographic analysis for parallel and non-parallel dose-response relationship curves (DRRCs). Potential adverse-effect profiles of interactions of STP with CLB and VPA at the fixed-ratio of 1:1 in the MES test with respect to motor performance, long-term memory and skeletal muscular strength were measured along with total brain antiepileptic drug concentrations. In the mouse MES model, STP administered singly had its DRRC non-parallel to that for CLB and, simultaneously, parallel to that for VPA. With type I isobolography for parallel DRRCs, the combinations of STP with VPA at three fixed-ratios of 1:3, 1:1 and 3:1 exerted sub-additive (antagonistic) interaction. Isobolography for non-parallel DRRCs revealed that the combination of STP with CLB at the fixed-ratio of 1:1 produced additive interaction. For all combinations, neither motor coordination, long-term memory nor muscular strength was affected. Total brain antiepileptic drug concentrations revealed bi-direction changes with the most profound being an 18.6-fold increase in CLB by STP and a 2.3-fold increase in STP by VPA. In conclusion, the additive interaction between STP and CLB was associated with a concurrent pharmacokinetic interaction and these data may explain the clinical efficacy seen with this combination. In contrast, the antagonism between STP and VPA was surprising since synergism is observed clinically.

A simple high-performance liquid chromatographic micromethod is described for the quantitation of the new antiepileptic drug lacosamide in serum of patients. Serum (100 microL) was first precipitated with 10 microL 60% perchloric acid and 10 microL supernatant injected directly into the high-performance liquid chromatograph. Chromatographic separation was achieved by use of a steel cartridge column (125 x 3 mm inside diameter) packed with Hypersil BDS C-18, at 40 degrees C, and with a gradient elution system comprising methanol, formic acid and water. The eluent was monitored at 215 nm by diode array detection and the calibration curve was linear in the range of 10 to 250 micromol/L. Recovery ranged from 99% to 106%. The limit of quantification was 1 micromol/L and the intrabatch and interbatch coefficients of variation were less than 5%. No interference from commonly prescribed antiepileptic drugs (clobazam, clonazepam, carbamazepine, carbamazepine-10,11-epoxide, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, phenobarbital, phenytoin, primidone, pregabalin, valproic acid, and vigabatrin) was observed, so the method can be used to routinely monitor lacosamide in patients on polytherapy antiepileptic drug regimens.

During the period 1989-2009, 14 new antiepileptic drugs (AEDs) were licensed for clinical use and these can be subdivided into new second- and third-generation AEDs. The second-generation AEDs comprise felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, rufinamide, stiripentol, tiagabine, topiramate, vigabatrin and zonisamide. The third-generation AEDs comprise eslicarbazepine acetate and lacosamide. The interaction propensity of AEDs is very important because all new AEDs are licensed, at least in the first instance, as adjunctive therapy. The present review summarizes the interactions (pharmacokinetic and pharmacodynamic) that have been reported with the newer AEDs. The pharmacokinetic interactions include those relating to protein-binding displacement from albumin in blood, and metabolic inhibitory and induction interactions occurring in the liver. Overall, the newer AEDs are less interacting because their pharmacokinetics are more favorable and many are minimally or not bound to blood albumin (e.g., eslicarbazepine, felbamate, gabapentin, lacosamide levetiracetam, rufinamide, topiramate and vigabatrin) and are primarily renally excreted or metabolized by noncytochrome P450 or uridine glucoronyl transferases (e.g., gabapentin, lacosamide levetiracetam, rufinamide, topiramate and vigabatrin) as opposed to hepatic metabolism which is particularly amenable to interference. Gabapentin, lacosamide, levetiracetam, pregabalin and vigabatrin are essentially not associated with clinically significant pharmacokinetic interactions. Of the new AEDs, lamotrigine and topiramate are the most interacting. Furthermore, the metabolism of lamotrigine is susceptible to both enzyme inhibition and enzyme induction. While the metabolism of felbamate, tiagabine, topiramate and zonisamide can be induced by enzyme-inducing AEDs, they are less vulnerable to inhibition by valproate. Noteworthy is the fact that only five new AEDs (eslicarbazepine, felbamate, oxcarbazepine, rufinamide and topiramate) interact with oral contraceptives and compromise contraception control. The most clinically significant pharmacodynamic interaction is that relating to the synergism of valproate and lamotrigine for complex partial seizures. Compared with the first-generation AEDs, the new second- and third-generation AEDs are less interacting, and this is a desirable development because it allows ease of prescribing by the physician and less complicated therapeutic outcomes and complications for patients.

This study was designed so as to characterize the interactions between levetiracetam (LEV) and the conventional antiepileptic drugs (AEDs) clonazepam (CZP), ethosuximide (ETS), phenobarbital (PB), and valproate (VPA) in suppressing pentylenetetrazole (PTZ)-induced clonic seizures in mice by use of type II isobolographic analysis. Adverse-effect profiles of the drugs in combination were determined and brain AED concentrations were measured. The combinations of VPA and ETS with LEV at the fixed-ratio of 1:2, CZP with LEV (1:20,000), and PB with LEV (1:20) were supra-additive (synergistic) in suppressing seizures. In contrast, VPA and ETS with LEV (1:1, 2:1, and 4:1), CZP with LEV (1:1000, 1:5000, and 1:10,000), and PB with LEV (1:1, 1:5, and 1:10) were additive. No adverse effects were observed. ETS significantly reduced brain LEV concentrations but no other pharmacokinetic changes were observed. The combinations of CZP with LEV (1:20,000); VPA and ETS with LEV (1:2); and PB with LEV (1:20) appear to be favorable combinations exerting supra-additive interactions in suppressing PTZ-induced seizures.

The aim of this study was to characterize the anticonvulsant effects of levetiracetam (LEV) in combination with the various antiepileptic drugs (clonazepam [CZP], oxcarbazepine [OXC], phenobarbital [PB], tiagabine [TGB], and valproate [VPA]), in the mouse 6 Hz psychomotor seizure model. Limbic (psychomotor) seizure activity was evoked in albino Swiss mice by a current (32 mA, 6 Hz, 3s stimulus duration) delivered via ocular electrodes and isobolographic analysis for parallel and non-parallel dose-response effects was used to characterize the consequent anticonvulsant interactions between the various drug combinations. Potential concurrent adverse-effect profiles of interactions between LEV and CZP, OXC, PB, TGB, and VPA at the fixed-ratio of 1:1 were evaluated in the chimney (motor performance), passive avoidance (long-term memory), and grip-strength (muscular strength) tests. LEV administered singly was associated with a dose-response relationship curve (DRRC) that was parallel to that for CZP and non-parallel to that for OXC, PB, TGB and VPA. With isobolography for parallel DRRCs, the combination of LEV with CZP at three fixed-ratios of 1:3, 1:1 and 3:1 was additive in nature. With isobolography for non-parallel DRRCs the combinations of LEV with OXC, TGB and VPA at the fixed-ratio of 1:1 were also additive. In contrast, the isobolography for non-parallel DRRCs revealed that the interaction for the combination of LEV with PB at the fixed-ratio of 1:1 was supra-additive (synergistic). None of the combinations were associated with any concurrent adverse effects with regards to motor coordination, long-term memory or muscular strength. LEV is associated with favorable anticonvulsant synergism with PB and is additive with regards to CZP, OXC, TGB and VPA in the mouse 6 Hz psychomotor seizure model.

Caffeine has been reported to be proconvulsant and to reduce the anticonvulsant efficacy of a variety of antiepileptic drugs (carbamazepine, phenobarbital, phenytoin, valproate and topiramate) in animal models of epilepsy and to increase seizure frequency in patients with epilepsy. Using the mouse maximal electroshock model, the present study was undertaken so as to ascertain whether caffeine affects the anticonvulsant efficacy of the new antiepileptic drugs lamotrigine, oxcarbazepine and tiagabine. The results indicate that neither acute nor chronic caffeine administration (up to 46.2 mg/kg) affected the ED(50) values of oxcarbazepine or lamotrigine against maximal electroshock. Similarly, caffeine did not modify the tiagabine electroconvulsive threshold. Furthermore, caffeine had no effect on oxcarbazepine, lamotrigine and tiagabine associated adverse effects such as impairment of motor coordination (measured by the chimney test) or long-term memory (measured by the passive avoidance task). Concurrent plasma concentration measurements revealed no significant effect on lamotrigine and oxcarbazepine concentrations. For tiagabine, however, chronic caffeine (4 mg/kg) administration was associated with an increase in tiagabine concentrations. In conclusion, caffeine did not impair the anticonvulsant effects of lamotrigine, oxcarbazepine, or tiagabine as assessed by electroconvulsions in mice. Also, caffeine was without effect upon the adverse potential of the studied antiepileptic drugs. Thus caffeine may not necessarily adversely affect the efficacy of all antiepileptic drugs and this is an important observation.

Levetiracetam (Keppra) is an antiepileptic drug (AED) characterized by a novel mechanism of action, unique profile of activity in seizure models, and broad-spectrum clinical efficacy. The present report critically reviews several preclinical studies focused on combination therapy with levetiracetam and other anticonvulsants in various seizure and epilepsy models. Administration of levetiracetam together with many different clinically used AEDs or other anticonvulsants generally enhances their protective activity and, among existing AEDs, this was particularly prevalent with valproate. The protective activity of other AEDs was also enhanced by levetiracetam, which seems to be a universal finding that is independent of seizure model or drug combination studied. However, particularly strong enhancement was observed when levetiracetam was combined with agents either enhancing GABAergic or reducing glutamatergic neurotransmission. Importantly, these combinations were not associated with exacerbation of side effects or pharmacokinetic interactions. Based on the available preclinical data, it appears that combination treatment with levetiracetam and other anticonvulsants provides additional therapeutic benefit that may be attributed to its novel and distinct mechanism of action. Moreover, combinations of levetiracetam with clinically used AEDs that enhance GABAergic inhibition may be considered for rational polytherapy, which is often necessary in drug-resistant patients.

To characterize the interactions between levetiracetam and the antiepileptic drugs gabapentin, tiagabine, and vigabatrin in suppressing pentylenetetrazole-induced clonic seizures in mice, type II isobolographic analysis was used. Clonic seizures were evoked in Albino Swiss mice by subcutaneous injection of pentylenetetrazole at its CD(97)(98 mg/kg). Adverse-effect profiles with respect to motor performance, long-term memory and skeletal muscular strength were measured along with total brain antiepileptic drug concentrations. The combination of gabapentin with levetiracetam at the fixed-ratios of 2:1, 1:1, 1:2, and 1:4 were supra-additive (synergistic) in terms of seizure suppression whilst the combination at the fixed-ratio of 4:1 was additive. Tiagabine with levetiracetam and vigabatrin with levetiracetam at the fixed-ratios of 1:25, 1:50, 1:100, 1:200, and 1:400 and at 2:1, 3:1, 4:1, 6:1, 8:1, and 16:1 were additive, respectively. No acute adverse effects were observed. Measurement of total brain antiepileptic drug concentrations revealed that levetiracetam in combination with gabapentin at the fixed-ratio of 1:4 significantly elevated (21%) total brain gabapentin concentrations. In contrast, levetiracetam was without affect on tiagabine or vigabatrin concentrations and co-administration with gabapentin, tiagabine or vigabatrin had no effect on levetiracetam brain concentrations, indicating the pharmacodynamic nature of interaction between these antiepileptic drugs in the mouse pentylenetetrazole model. The combination of gabapentin with levetiracetam at the fixed-ratios of 2:1, 1:1, 1:2, and 1:4 appears to be particularly favorable combination exerting supra-additive interaction in suppressing pentylenetetrazole-induced seizures, although there is a pharmacokinetic contribution to the interaction between levetiracetam and gabapentin at the fixed-ratio of 1:4. Levetiracetam in combination with tiagabine and vigabatrin appear to be neutral combinations producing only additivity in the mouse pentylenetetrazole model.

Purpose: To investigate the pharmacokinetic interrelationship of vigabatrin in blood and the brain (frontal cortex vs. hippocampus) and to ascertain the relationship between brain extracellular vigabatrin concentrations and concurrent gamma-aminobutyric acid (GABA) concentrations., Methods: Sprague-Dawley rats were implanted with a jugular vein catheter for blood sampling, and microdialysis probes in the frontal cortex and hippocampus for extracellular fluid (ECF) sampling. Vigabatrin was administered intraperitoneally at two different doses (500 and 1,000 mg/kg), and blood and ECF were collected at timed intervals up to 8 h. Rats were freely moving and behaving. Vigabatrin (sera and ECF) and GABA (ECF) concentrations were measured with use of high performance liquid chromatography (HPLC)., Results: Vigabatrin concentrations in blood rose linearly and dose-dependently, and vigabatrin rapidly appeared in the brain as evidenced by the detection of vigabatrin in the ECF of both the frontal cortex and hippocampus at time of first sampling (15 min). However, frontal cortex concentrations were twofold greater than those of the hippocampus. Furthermore, GABA concentrations increased five-fold in the frontal cortex but were unaffected in the hippocampus. In addition, GABA concentrations began to increase approximately 3 h after vigabatrin administration at a time when vigabatrin concentrations were in exponential decline., Conclusions: Vigabatrin distribution in the brain is region specific, with frontal cortex concentrations substantially greater than those seen in the hippocampus. Elevation of GABA concentrations did not reflect the concentration profile of vigabatrin but reflected its regional distribution.

The aim of this study was to characterize the pharmacodynamic, pharmacokinetic and adverse-effect profiles of vigabatrin and gabapentin. Isobolographic analysis was used in two mouse experimental models of epilepsy: the maximal electroshock seizure threshold test and pentylenetetrazole-induced seizures. In the maximal electroshock seizure threshold test, electroconvulsions were produced by a current with various intensities whilst in the pentylenetetrazole test a CD(97) dose (100 mg/kg) was used. Potential adverse-effect profiles of interactions of vigabatrin with gabapentin at three fixed-ratios of 1:3, 1:1 and 3:1 from both seizure tests were evaluated in the chimney (motor performance) and grip-strength (skeletal muscular strength) tests. Vigabatrin and gabapentin total brain concentrations were determined with high performance liquid chromatography. Vigabatrin and gabapentin administered singly increased the electroconvulsive threshold (TID(20) - 226.2 and 70.0 mg/kg, respectively). With isobolography, the combination of vigabatrin with gabapentin at the fixed-ratio of 1:3 exerted supra-additive (synergistic) interactions whilst at 1:1 and 3:1 additivity occurred. Similarly, vigabatrin and gabapentin administered singly suppressed the pentylenetetrazole-induced seizures (ED(50) values - 622.5 and 201.1 mg/kg, respectively). Isobolography revealed that vigabatrin with gabapentin in combination at the fixed-ratio of 1:1 produced supra-additive (synergistic) interaction whilst at 1:3 and 3:1 additivity occurred. In combination neither motor coordination nor skeletal muscular strength was affected. Total vigabatrin and gabapentin brain concentrations revealed that neither drug affected the pharmacokinetics of the other. Vigabatrin and gabapentin have a favorable pharmacodynamic interaction in animal seizure models in the absence of acute adverse effects or concurrent pharmacokinetic changes.

Although no randomized studies have demonstrated a positive impact of therapeutic drug monitoring (TDM) on clinical outcome in epilepsy, evidence from nonrandomized studies and everyday clinical experience does indicate that measuring serum concentrations of old and new generation antiepileptic drugs (AEDs) can have a valuable role in guiding patient management provided that concentrations are measured with a clear indication and are interpreted critically, taking into account the whole clinical context. Situations in which AED measurements are most likely to be of benefit include (1) when a person has attained the desired clinical outcome, to establish an individual therapeutic concentration which can be used at subsequent times to assess potential causes for a change in drug response; (2) as an aid in the diagnosis of clinical toxicity; (3) to assess compliance, particularly in patients with uncontrolled seizures or breakthrough seizures; (4) to guide dosage adjustment in situations associated with increased pharmacokinetic variability (e.g., children, the elderly, patients with associated diseases, drug formulation changes); (5) when a potentially important pharmacokinetic change is anticipated (e.g., in pregnancy, or when an interacting drug is added or removed); (6) to guide dose adjustments for AEDs with dose-dependent pharmacokinetics, particularly phenytoin.

Fatty acids (FAs) determine membrane properties and may affect cardiac and neuronal function. In this study, FA profiles were determined in 56 patients with epilepsy who participated in a 12-week double-blind randomized trial of omega-3 FA supplementation (1 g eicosapentaenoic acid and 0.7 g docosahexaenoic acid daily). At baseline, subjects on carbamazepine (CBZ) had lower docosahexaenoic acid levels, lower levels of long-chain omega-3 FAs, and a lower Omega-3 Index (a risk factor for coronary heart disease mortality), whereas those on oxcarbazepine had higher total polyunsaturated FAs and a higher Omega-3 Index. Following omega-3 FA supplementation, the Omega-3 Index, eicosapentaenoic acid, and docosahexaenoic acid concentrations significantly increased. Patients on CBZ exhibited a less favorable FA profile, associated with a greater risk of coronary heart disease mortality. As arrhythmias are thought to be an important mechanism in coronary heart disease mortality and sudden unexplained death in epilepsy (SUDEP), the effect of CBZ effect in reducing omega-3 FAs might potentially explain some cases of SUDEP among patients prescribed CBZ.

Using the mouse maximal electroshock-induced seizure model, indicative of tonic-clonic seizures in humans, the present study was aimed at characterizing the interaction between remacemide and valproate, carbamazepine, phenytoin, and phenobarbital. Isobolographic analysis indicated additive interactions between remacemide and valproate, carbamazepine, and phenytoin (for all fixed ratios of tested drugs: 1:3, 1:1, and 3:1). Additivity was also observed between remacemide and phenobarbital applied in proportions of 1:1 and 3:1. In contrast, the combination of remacemide and phenobarbital at the fixed-ratio of 1:3 resulted in antagonism. Neither motor performance nor long-term memory was impaired by remacemide or by carbamazepine, phenobarbital, phenytoin, and valproate whether or not these drugs were administered singly or in combination. In combination with remacemide, brain concentrations of carbamazepine, phenobarbital, and phenytoin were increased by 71, 21, and 16%, respectively. Although brain valproate concentrations were unaffected by remacemide co-administration, brain concentrations of remacemide and its active metabolite, desglycinyl-remacemide, were increased by 68 and 162%, respectively. In contrast, phenobarbital co-administration was associated with decreases in brain remacemide (27%) and desglycinyl-remacemide (9%) concentrations, whereas only remacemide concentrations (increased by 131%) were affected by carbamazepine co-administration. In conclusion, significant and desirable pharmacodynamic interactions were observed between remacemide and valproate, carbamazepine, phenytoin, and phenobarbital. However, the concurrent pharmacokinetic interactions associated with remacemide complicate these observations and do not make remacemide a good candidate for adjunctive treatment of epilepsy.

Purpose: Polytherapy with two or more antiepileptic drugs (AEDs) is generally required for approximately 30% of patients with epilepsy, who do not respond satisfactorily to monotherapy. The potential usefulness of AED combinations, producing synergistic anticonvulsant efficacy and minimal adverse effects, is therefore of significant importance. The present study sought to ascertain the potential usefulness of levetiracetam (LEV) and felbamate (FBM) in combination in the mouse maximal electroshock (MES)-induced seizure model., Methods: The anticonvulsant interaction profile between LEV and FBM in the mouse MES-induced seizure model was determined using type II isobolographic analysis. Acute adverse effects (motor performance) were ascertained by use of the chimney test. LEV and FBM brain concentrations were measured by HPLC in order to determine any pharmacokinetic contribution to the observed antiseizure effect., Results: LEV in combination with FBM, at the fixed ratios of 1:2, 1:1, 2:1, and 4:1, were supraadditive, whereas at the fixed ratio of 1:4, additivity was observed in the mouse MES model. Furthermore, none of the investigated combinations altered motor performance in the chimney test. Brain FBM concentrations were unaffected by concomitant LEV administration. In contrast, FBM significantly increased LEV brain concentrations., Conclusions: LEV in combination with FBM was associated with pharmacodynamic supraadditivity in the MES test. However, this anticonvulsant supraadditivity was associated with a concurrent increase in brain LEV concentrations indicating a pharmacokinetic contribution to the observed pharmacodynamic interaction between LEV and FBM.

Despite the major advances in antiepileptic drug (AED) therapeutics, about one third of patients with epilepsy still do not have adequate seizure control with currently available AEDs when prescribed as monotherapy. Typically, in this setting polytherapy with two or more AEDs is used. Zonisamide (ZNS) is a new AED effective in the treatment of refractory epilepsy and since it is only prescribed in polytherapy regimens, its interactions with other AEDs is of particular importance. The aim of this study was to isobolographically determine interactions between ZNS and four conventional AEDs: carbamazepine (CBZ), phenytoin (PHT), phenobarbital (PB), and valproate (VPA), in the mouse maximal electroshock (MES)-induced seizure model. The total brain concentrations of conventional AEDs and ZNS were measured with immunofluorescence and high-pressure liquid chromatography (HPLC), respectively, in order to determine any pharmacokinetic contribution in any observed interactions. With isobolography, synergistic interactions were observed for the combination of ZNS plus VPA and ZNS plus PHT at the fixed-ratio of 1:1, while additivity was observed for their combinations at the remaining dose ratios of 1:3 and 3:1. In contrast, the interactions between ZNS and PB and between ZNS and CBZ, applied at the fixed-ratios of 1:3, 1:1 and 3:1 proved to be additive. None of these AED combinations were associated with motor and long-term memory impairment. Furthermore, whilst brain AED concentrations were unaffected by ZNS, PHT significantly increased and PB reduced brain ZNS concentrations. Thus, the resultant interactions between ZNS and PHT and between ZNZ and PB were consequent to both pharmacodynamic and pharmacokinetic components. Finally, one can conclude that because of the synergistic pharmacodynamic interaction between ZNS and VPA, this combination might be useful in clinical practice.

The aim of this study was the isobolographic evaluation of interactions between losigamone (LSG), valproate (VPA), carbamazepine (CBZ), phenytoin (PHT), and phenobarbital (PB) in the maximal electroshock (MES) test in mice. Electroconvulsions were produced by means of an alternating current (ear-clip electrodes, 0.2-s stimulus duration, and tonic hindlimb extension taken as the endpoint). Adverse effects were evaluated in the chimney test (motor coordination) and the passive avoidance task (long-term memory). Brain concentrations of antiepileptic drugs (AEDs) were measured by immunofluorescence or high-performance liquid chromatography. Isobolographic analysis indicated synergistic interactions between LSG and VPA. For example, in the proportion of 1:1 the theoretically calculated 50% effective dose for additivity (ED(50add)) was 138 mg/kg, while the experimentally derived ED(50) for the mixture (ED(50mix)) was 85.2 mg/kg. The difference was significant at p<0.001. LSG combined with CBZ or PHT showed additivity, whereas the combinations of LSG with PB were either additive, for the fixed ratios of 1:3 and 1:1, or antagonistic for the ratio of 3:1 (ED(50add)=18.4 mg/kg versus ED(50mix)=26.7 mg/kg, p<0.05). Impairment of long-term memory was noted only in the case of VPA given at its ED(50), however this AED did not affect motor performance. LSG, CBZ, PHT and PB (applied at their ED(50) values) and co-administration of LSG with conventional AEDs (including VPA) impaired neither motor performance nor long-term memory. LSG did not affect the brain concentration of VPA or PB, but significantly elevated the brain concentrations of CBZ and PHT. In contrast, VPA, CBZ and PHT significantly increased the brain concentration of LSG, indicating a pharmacokinetic contribution to the observed pharmacodynamic interactions. Although LSG exhibited some favorable pharmacodynamic interactions with various AEDs, these were complicated by pharmacokinetic interactions and emphasize the importance of measuring AED concentrations in studies designed to identify desirable AED combinations.