Broad-spectrum Antiepileptic Drug Research Articles

Topiramate for juvenile myoclonic epilepsy.

Topiramate is a newer broad-spectrum antiepileptic drug (AED). Some studies have shown the benefits of topiramate in the treatment of juvenile myoclonic epilepsy (JME). However, there are no current systematic reviews to determine the efficacy and tolerability of topiramate in people with JME. This is an update of a Cochrane Review first published in 2015, and last updated in 2017. To evaluate the efficacy and tolerability of topiramate in the treatment of JME. For the latest update, on 10 July 2018 we searched the Cochrane Register of Studies (CRS Web), which includes the Cochrane Epilepsy Group's Specialized Register and the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (Ovid 1946- ), and ClinicalTrials.gov. We also searched ongoing trials registers, reference lists and relevant conference proceedings, and contacted study authors and pharmaceutical companies. We included randomized controlled trials (RCTs) investigating topiramate versus placebo or other AED treatment for people with JME, with the outcomes of proportion of responders and proportion of participants experiencing adverse events (AEs). Two review authors independently screened the titles and abstracts of identified records, selected studies for inclusion, extracted data, cross-checked the data for accuracy and assessed the methodological quality. We performed no meta-analyses due to the limited available data. We included three studies with a total of 83 participants. For efficacy, a greater proportion of participants in the topiramate group had a 50% or more reduction in primarily generalized tonic-clonic seizures (PGTCS) compared with participants in the placebo group. There were no significant differences between topiramate and valproate in participants responding with a 50% or more reduction in myoclonic seizures or in PGTCS, or becoming seizure-free. Concerning tolerability, we ranked AEs associated with topiramate as moderate to severe, while we ranked 59% of AEs linked to valproate as severe complaints. Moreover, systemic toxicity scores were higher in the valproate group than the topiramate group.Overall we judged all three studies to be at high risk of attrition bias and at unclear risk of reporting bias. We judged all three studies to be at low to unclear bias for the remaining risk of bias domains (random sequence, allocation, blinding). We judged the quality of the evidence from the studies to be very low. We have found no new studies since the last version of this review was published in 2017. This review does not provide sufficient evidence to support topiramate for the treatment of people with JME. Based on the current limited available data, topiramate seems to be better tolerated than valproate, but has no clear benefits over valproate in terms of efficacy. Well-designed, double-blind RCTs with large samples are required to test the efficacy and tolerability of topiramate in people with JME.

Perampanel as monotherapy and adjunctive therapy for focal onset seizures, focal to bilateral tonic-clonic seizures and as adjunctive therapy of generalized onset tonic-clonic seizures

ABSTRACTIntroduction: Perampanel is an antiepileptic drug approved in the USA and Europe as monotherapy and adjunctive therapy for focal onset seizures and as adjunctive therapy for generalized tonic-clonic seizures.Areas covered: This an overview of animal data, pharmacokinetics, and clinical data published on Perampanel indexed in PubMed.Expert opinion: Pharmacological studies suggest that perampanel acts via noncompetitive antagonism of the ionotropic AMPA receptor of glutamate. The efficacy of perampanel has been shown in animal models of epilepsy and Phase II/III clinical trials. Efficacy and safety have been evaluated in the phase III trials of adjunctive treatment of focal epilepsy with median focal onset seizure reduction rates of 23% for 4 mg/d, 26–31% for 8 mg/day, and 18–35% for 12 mg/day. Fifty percent responder rates were 29% for 4 mg/day, 33–38% for 8 mg/day, and 34–36% for 12 mg/day. A pivotal Phase III trial in generalized onset tonic-clonic seizures showed a median seizure reduction by 76.5% (8 mg) versus 38.4% placebo and 50% seizure responder rate of 64.2% versus 30.9% placebo. Perampanel showed good safety and tolerability profile across 2–12 mg doses. Perampanel as a broad-spectrum antiepileptic drug has a potential to be an alternative treatment of multiple types of epileptic seizures.

Identification of 2-(2′-fluoro-[1,1′-biphenyl]-2-yl)acetamide as a Sodium Valproate-like broad spectrum anti-epileptic drug candidate

By further optimizing compound A [2′-fluoro-N-methyl-[1,1′-biphenyl]-2-sulfonamide], we identified DSP-0565 [2-(2′-fluoro-[1,1′-biphenyl]-2-yl)acetamide, 17a] as a strong, broad-spectrum anti-epileptic drug (AED) candidate. Our efforts mainly focused on finding an alternative polar group for the sulfonamide in order to improve ADME profile of compound A including good metabolic stability and no reactive metabolic production. This led to the identification of biphenyl acetamide as a new scaffold for development of broad-spectrum AED candidates. DSP-0565 showed anti-convulsant activity in various models (scPTZ, MES, 6 Hz and amygdala kindling) with good safety margin, and was therefore selected as a clinical candidate.

Type II Renal Tubular Acidosis Secondary to Topiramate: A Review.

Topiramate (TMP) is a broad-spectrum anticonvulsant drug used to treat a wide variety of seizure disorders, for migraine prophylaxis, and for many other indications. An important side effect of TMP is metabolic acidosis, which is mediated by renal tubular defects. TMP inhibits carbonic anhydrase, an enzyme that is necessary for acid handling in the proximal renal tubule. Patients can present with asymptomatic serum electrolyte derangements, acute change in mental status, hyperventilation, cardiac arrhythmias, or other sequelae of metabolic acidosis and associated respiratory compensation. If taken chronically, TMP can cause renal stone formation, bone mineralization defects, and several other effects secondary to changes in serum and urine pH and electrolytes. There is no well-studied way to prevent metabolic acidosis in patients taking TMP, but physicians should be vigilant when prescribing this drug to patients with the history of renal diseases and other comorbidities, and aware of this potential etiology of metabolic acidosis. We present a literature review of the underlying mechanisms involved in the development of renal tubular acidosis secondary to TMP and its clinical consequences.

A Physiologically Based Pharmacokinetic Model for Optimally Profiling Lamotrigine Disposition and Drug–Drug Interactions

Lamotrigine (Lamictal®) is a broad-spectrum antiepileptic drug available in both immediate-(IR) and extended-release (XR) formulations. Here, we present a new physiologically based pharmacokinetic (PBPK) model for IR and XR formulations of lamotrigine to predict disposition in adults and children, plus drug-drug interactions (DDIs). Models for lamotrigine IR and XR formulations were constructed using a Simcyp® Simulator. Concentration-time profiles were simulated for lamotrigine IR single (SD) and steady-state (SS) doses ranging from 25 to 200mg in adults, as well as 2mg/kg (SD), and 7.7-9.4mg/kg (SS) in children aged between 4 and 17years. Lamotrigine XR profiles were simulated for SD and SS doses ranging from 250 to 400mg. DDI prediction with lamotrigine was simulated in adults with enzyme-inducing drugs, rifampin(rifampicin) and ritonavir, as well as the enzyme inhibitor, valproic acid. The lamotrigine model predicted adult area-under-the-curve (AUC) and peak plasma concentration (Cmax) results for IR SD within 35% of observed data; lamotrigine IR SS dosing was within 10% and 30% of observed data, respectively. Pediatric lamotrigine IR SD AUC and Cmax values were within 10% and 15% of observed data, respectively. AUC and Cmax values for lamotrigine XR SD simulated in adults were within 20% of observed data; similarly lamotrigine XR SS parameters were within 10%. Concerning DDI simulation in adults, predicted-to-observed lamotrigine AUC ratios [AUCDDI/AUCalone] were within 15% for ritonavir and rifampin, and 20% for valproic acid. Our developed PBPK lamotrigine profile accurately predicts DDIs and lamotrigine IR/XR formulation disposition in adults and children. This PBPK model will be helpful in designing future DDI studies for co-administration of lamotrigine with other drugs and in designing individualized patient dosing regimens.

Carbamazepine versus phenobarbitone monotherapy for epilepsy: an individual participant data review.

Carbamazepine versus phenobarbitone monotherapy for epilepsy: an individual participant data review.

The effect of serum levetiracetam concentrations on therapeutic response and IL1-beta concentration in patients with epilepsy

ObjectiveAssessment 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. MethodsPatients 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. ResultsAlthough 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. ConclusionThe 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.

Neuroprotective effects of levetiracetam, both alone and combined with propylparaben, in the long-term consequences induced by lithium-pilocarpine status epilepticus

Status epilepticus (SE) is a neurological condition that frequently induces severe neuronal injury in the hippocampus, subsequent epileptogenesis and pharmacoresistant spontaneous recurrent seizures (SRS). The repeated administration of LEV (a broad-spectrum antiepileptic drug) during the post-SE period does not prevent the subsequent development of SRS. However, this treatment reduces SE-induced neurodegeneration in the hippocampus. Conversely, propylparaben (PPB) is a widely used antimicrobial that blocks voltage-dependent Na+ channels, induces neuroprotection and reduces epileptiform activity in vitro. The present study attempted to determine if the neuroprotective effects induced by LEV are augmented when combined with a sub-effective dose of PPB. Long-term SE-induced consequences (hyperexcitability, high glutamate release, neuronal injury and volume loss) were evaluated in the hippocampus of rats. LEV alone, as well as combined with PPB, did not prevent the occurrence of SRS. However, animals treated with LEV plus PPB showed high prevalence of low frequency oscillations (0.1–4 Hz and 8–90 bands, p < 0.001) and low prevalence of high frequency activity (90–250 bands, p < 0.001) during the interictal period. In addition, these animals presented lower extracellular levels of glutamate, decreased rate of neurodegeneration and a similar hippocampal volume compared to the control conditions. This study's results suggest that LEV associated with PPB could represent a new therapeutic strategy to reduce long-term consequences induced by SE that facilitate pharmacoresistant SRS.

Therapeutic Drug Monitoring of Levetiracetam in Select Populations.

Levetiracetam (LEV) is a broad spectrum antiepileptic drug (AED) that has a more favorable side effect profile compared to older AEDs. Therapeutic drug monitoring (TDM) of LEV is generally unnecessary given its linear and predictable dose-serum concentration relationship, lack of drug-drug interactions, and broad therapeutic window. However, there is growing evidence showing that alteration of LEV pharmacokinetics (PK) may occur in special populations calling for the need for TDM. The purpose of this review was to summarize current literature surrounding altered LEV PK in special patient populations and determine if there is a need for levetiracetam TDM. A literature search of MEDLINE (1946 - November 2017) database of available evidence pertaining to altered LEV PK in humans was conducted. A total of 51 articles were found. There has not been a positive correlation shown between LEV levels and efficacy or toxicity. Variable LEV levels are reported in the literature with respect to adverse effects, seizures and efficacy occurring below, within and above the supposed reference ranges. Age is a major contributor to altered pharmacokinetics of LEV as shown in elderly patients and pediatric patients. Compared to adults, clearance of LEV has been shown to be decreased by almost half in patients over 65 and increased by 30-40% in pediatric patients. LEV pharmacokinetics varied further when data from its use in neonates was explored. LEV clearance declined in a linear fashion with declining estimates of creatinine clearance but was variable in patients with end-stage renal failure or those requiring renal replacement therapy. In patients who were critically ill, LEV clearance may be augmented and these patients may require higher doses of medications to maintain drug levels. In patients who are pregnant, LEV levels are likely to decline as pregnancy progresses due to changes in glomerular filtration rate and remain variable in the post-partum period. Routine TDM of levetiracetam is not recommended for all populations, however, it may be beneficial to maintain an individual therapeutic range in patients where the PK of LEV may be altered, such as in patients who are critically ill patients, pregnant, pediatrics or elderly.

Perampanel: Does it have broad-spectrum potential?

This article reviews the profile of perampanel, a novel noncompetitive α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) receptor antagonist, and its role as a potential broad-spectrum antiepileptic drug in the treatment of epilepsy. For this narrative review, data were collected using specified search criteria. Articles reporting the evidence for perampanel's efficacy from preclinical models, phase 3 clinical studies, observational studies, and descriptive evidence were included. AMPA receptors play a key role in mediating the action of glutamate at the excitatory synapse. Preclinical research showed the AMPA receptor blockade to constitute a promising target for antiepileptic drug therapy. In animal models, perampanel proved to be protective against seizures and reduce seizure severity and duration. Four phase-3 randomized controlled trials (3 in patients with focal seizures and one in primary generalized tonic-clonic seizures in idiopathic generalized epilepsy) have been completed. In focal (partial) onset seizures, perampanel (4, 8, and 12mg) significantly reduced seizure frequency per 28days (23.3%-28.8% vs 12.8%; P<.01) and responder rates (≥50% reduction in seizures) (28.5%-35.3% vs 19.3%; P<.05) compared with placebo. In primary generalized tonic-clonic seizures, perampanel 8mg resulted in greater reduction in seizure frequency per 28days (-76.5% vs -38.4%; P<.0001) and responder rate (64.2% vs 39.5%; P=.0019) than placebo. The efficacy, safety, and tolerability of perampanel have been reproduced in real-world clinical practice, and the agent has been shown to be effective in other epilepsy syndromes. Perampanel is a potentially broad-spectrum antiepileptic drug with a novel mechanism of action that may be a useful addition for patients with epilepsy with various seizure types. The availability of novel antiepileptic drugs for epilepsy treatment enables more individualized treatment for these patients.

F01. Paroxysmal fast activity and genetic generalized epilepsies

Paroxysmal fast activity is the hallmark of “symptomatic generalized” epilepsy of the Lennox Gastaut type, often occurring with slow spike-wave complexes. Generalized, synchronous epileptiform discharges are considered the typical abnormality on EEG in genetic generalized epilepsy (GGE). Recent literature suggests that generalized paroxysmal fast activity (GPFA) may occur in the context of GGE, and may contribute to clinical heterogeneity. Here, we present three patients with generalized fast spike-wave discharges and polyspikes with concurrent GPFA. Institutional databases of EEG tracings and the electronic medical records were reviewed for cases of GPFA with an electro-clinical diagnosis of GGE. All three patients had onset of their seizures in childhood from age 8–13. Two of the three had mild cognitive impairment. MRI of all three patients were unremarkable. Their seizures were all medically intractable, requiring at least 3–5 broad spectrum antiepileptic drugs, and all 3 were recommended to pursue or chose to have a vagal nerve stimulator implanted. Seizure subtypes included generalized tonic clonic (most frequent) followed by automotor, myoclonic, and astatic seizures. All three EEGs showed brief generalized spike-wave complexes at 3–6 Hz lasting 1–4 s, and generalized paroxysmal fast activity (12–20 Hz) lasting 5–20 s. One tracing showed evolution of GPFA to polyspikes that correlated to a clinical myoclonic seizure. GPFA is classically associated with symptomatic generalized epilepsies of the Lennox-Gastaut type, but these three cases demonstrate GPFA can be seen in GGE. Such patients may be more refractory than the usual GGE, and may belong on a continuum between GGE and LGS.

Effects of Paullinia cupana extract on lamotrigine pharmacokinetics in rats: A herb-drug interaction on the gastrointestinal tract with potential clinical impact

Paullinia cupana-containing preparations are being consumed worldwide for weight reduction. As obesity and epilepsy are common comorbidities and lamotrigine (LTG) is a broad-spectrum antiepileptic drug, it is likely to find epilepsy patients taking P. cupana and LTG simultaneously. Thus, this work aimed to investigate the potential interaction between P. cupana extract and LTG in rats. In a study, rats were orally co-administered with a single-dose of P. cupana extract (821 mg/kg) and LTG (10 mg/kg). In another study, rats were orally pre-treated for 14 days with P. cupana extract (821 mg/kg/day) receiving LTG (10 mg/kg, p.o.) on the 15th day. Rats of the respective control groups received the corresponding volume of the extract vehicle. LTG concentrations were determined at several post-dose time-points and submitted to a non-compartmental pharmacokinetic analysis. The co-administration of P. cupana and LTG induced a significant reduction of LTG Cmax and AUC0-24 and prolonged the mean residence time. However, no significant effects were observed on LTG pharmacokinetics following a 14-day pre-treatment period with the extract. In this study changes in the body weight of rats and in some biochemical parameters were also evaluated. Overall, the results revealed a pharmacokinetic-based herb-drug interaction between P. cupana extract and LTG, mainly after their co-administration.

Levetiracetam monotherapy for the treatment of infants with epilepsy

PurposeLevetiracetam is a broad-spectrum anti-epileptic drug that is effective against both focal and generalized epilepsies. In this study, we aimed to evaluate the efficacy, tolerability and safety of levetiracetam monotherapy in the management of different seizure types in children with epilepsy under the age of two. MethodThis retrospective study was conducted on children with a diagnosis of epilepsy from January 2014 to January 2017. To be included in the study, patients were required to be less than two years of age at the time levetiracetam was initiated as initial monotherapy and to be followed clinically for at least 6 months. ResultsOf the 92 patients, 61 (66%) patients were seizure free. Fifty-eight percent of the patients (31 of 53) with focal epilepsy were seizure free and 77% (30 of 39) generalized epilepsy were seizure free. We found that levetiracetam monotherapy was effective in both focal and generalized epilepsy. Levetiracetam monotherapy was significantly more effective in patients with unknown etiologies (p = 0.004). Seizure freedom rate under levetiracetam monotherapy was significantly higher in patients with normal psychomotor development (p = 0.000). Seizure freedom rate under levetiracetam monotherapy was significantly higher in patients with unknown etiologies and normal psychomotor development. Normal psychomotor development was the strongest predictor of seizure control under levetiracetam monotherapy (OR = 6; 95% CI = 2.3–16.0; p < 0.001). Five children (1%) reported irritability. No hematological or biochemical, or behavioral adverse side effects except irritability were reported in any children. No patient discontinued levetiracetam therapy because of treatment-related side effects. ConclusionOur study showed levetiracetam to be an effective, well tolerated and safe agent for the treatment of a variety of seizure types and etiologies seen in infants.

Emergence of Nipah Virus: Need More R&amp;D and Public Health Infrastructure

Emergence of Nipah Virus: Need More R&amp;D and Public Health Infrastructure

Valproic-induced Hyperammonemic Encephalopathy in a Known Case of Epilepsy

Valproic acid, a broad-spectrum anticonvulsant drug, commonly causes elevated ammonia levels, which is usually asymptomatic in most cases. On rare occasions, potentially fatal hyperammonemia-induced encephalopathy can occur. We present a case of a 24-year-old female who presented to the emergency department with status epilepticus that was being managed with valproic acid. Further workup was done because of prolonged postictal state, which revealed increased ammonia levels; she was eventually diagnosed with valproic-induced hyperammonemic encephalopathy. Discontinuing valproic acid resulted in drastically improved symptoms and a gradual decline in ammonia levels. A clinician should be aware of rare drug adverse effects and drug interactions to conclusively reach the correct diagnosis. A prolonged postictal state should warrant further workup to rule out other possible etiologies.

Association of Insulin Resistance with Sodium Valproate Therapy among Epileptic Patient

Background: Epilepsy is a common neurological disorder. Sodium valproate is one of the commonest broad spectrum antiepileptic drugs and it is used worldwide. Weight gain is the common side effect which is known to be associated with insulin resistance. The aim of this study was to see the association of sodium valproate therapy with insulin resistance among epileptic patients.&#x0D; Methods: It was a cross-sectional analytical study. Total 102 patients (51 epileptic patients with valproate monotherapy for at least one year and another 51 age and sex matched newly diagnosed epileptic patients without any anti-epileptic drugs) were selected in this study. The study was carried out from March 2016 to April 2017 for one year in the epilepsy clinic and outpatient Department of Neurology at Bangabandhu Sheikh Mujib Medical University, Dhaka. Participants underwent anthropometric evaluations and biochemical tests including fasting blood sugar and fasting insulin level. Insulin resistance (IR) index was calculated.&#x0D; Result: In this study mean duration of valproate treatment was 3.12±1.26 years and mean sodium valproate dose was 1133±440.5 mg/day (17.7±6.65 mg/kg/day). This study revealed serum fasting insulin level in valproate group and non-valproate group was 11.05±4.86 (ìU/ml) and 7.39±2.01 (ìU/ml) respectively. Fasting blood glucose was 4.71±0.79 (mmol/L) in valproate group and 4.41±0.62 (mmol/L) in non- valproate group. Calculated IR index in valproate group and non-valproate group was 2.17±0.55 and 1.46±0.39 respectively. IR index, fasting insulin and blood glucose all were significantly higher in valproate group than non- valproate group. This study also revealed mild positive correlation of IR index with dose and duration of valproate treatment.&#x0D; Conclusion: Sodium valproate treated patient had significantly higher IR index than control group.&#x0D; Bangladesh Journal of Neuroscience 2017; Vol. 33 (2): 63-69

N-alkyl-[1,1′-biphenyl]-2-sulfonamide derivatives as novel broad spectrum anti-epileptic drugs with efficacy equivalent to that of sodium valproate

In order to develop phenyl sulfonamides as a novel class of anti-epileptic drugs (AED) for both general and partial seizure, we initiated in vivo screening of our chemical library in the mice MES and sc-PTZ models and found compounds 1 and 2 as lead compounds. Optimization of 1 and 2 led to the discovery of compound 21, which showed potent anticonvulsant effect in MES, scPTZ and rat amygdala kindling models. These findings indicate that compound 21 could be a useful new broad spectrum AED like sodium valproate and provide an opportunity to struggle current therapy-resistant epilepsy.

Topiramate monotherapy for juvenile myoclonic epilepsy.

Topiramate is a newer broad-spectrum antiepileptic drug (AED). Some studies have shown the benefits of topiramate monotherapy in the treatment of juvenile myoclonic epilepsy (JME). However, there are no current systematic reviews to determine the efficacy and tolerability of topiramate monotherapy in people with JME. This is an updated version of the original Cochrane Review published in Issue 12, 2015. To evaluate the efficacy and tolerability of topiramate monotherapy in the treatment of JME. For the latest update, on 21 February 2017 we searched Cochrane Epilepsy's Specialized Register, CENTRAL, MEDLINE, and ClinicalTrials.gov. We also searched ongoing trials registers, reference lists and relevant conference proceedings, and contacted study authors and pharmaceutical companies. We included randomized controlled trials (RCTs) investigating topiramate monotherapy versus placebo or other AED treatment for people with JME, with the outcomes of proportion of responders or experiencing adverse events (AEs). Two review authors independently screened the titles and abstracts of identified records, selected studies for inclusion, extracted data, cross-checked the data for accuracy and assessed the methodological quality. We performed no meta-analyses due to the limited available data. We included three studies with 83 participants. For efficacy, a greater proportion of participants in the topiramate group had a 50% or more reduction in primarily generalized tonic-clonic seizures (PGTCS) compared with participants in the placebo group. There were no significant differences between topiramate versus valproate in participants responding with a 50% or more reduction in myoclonic seizures or in PGTCS or seizure-free. Concerning tolerability, we ranked AEDs associated with topiramate as moderate-to-severe, while we ranked 59% of AEDs linked to valproate as severe complaints. Moreover, systemic toxicity scores were higher in the valproate group than the topiramate group. We judged the quality of the evidence from the studies to be very low. Since the last version of this review we found no new studies. This review does not provide sufficient evidence to support topiramate for the treatment of people with JME. Based on the current limited available data, topiramate seems to be better tolerated than valproate, but there were no more benefits of efficacy in topiramate compared with valproate. In the future, well-designed, double-blind RCTs with large samples are required to test the efficacy and tolerability of topiramate in people with JME.

Levetiracetam Clinical Pharmacokinetic Monitoring in Pediatric Patients with Epilepsy.

Levetiracetam is a broad-spectrum antiepileptic drug (AED) with a unique mechanism of action. Older AEDs can cause serious short- and long-term adverse drug reactions and complications, rendering them undesirable to use in pediatric patients. Characteristics that make levetiracetam a near-ideal AED include its broad spectrum of activity, good tolerability profile, and minimal drug-drug interactions. Clinical pharmacokinetic monitoring (CPM) is often recommended in pediatric patients for certain AEDs due to large interindividual pharmacokinetic differences and unpredictable drug disposition. Our objective was to determine whether monitoring levetiracetam concentrations is warranted for pediatric patients with epilepsy, using a previously published 9-step decision-making algorithm. A literature search of the MEDLINE (1946-August 2016), EMBASE (1974-August 2016), CENTRAL, and Google Scholar databases was performed to identify relevant English-language articles and answer the questions posed in the algorithm for levetiracetam CPM in pediatric epilepsies. Additional articles were identified from a manual bibliographic review of the relevant literature. We found that levetiracetam CPM met some criteria of the algorithm: levetiracetam is an appropriate adjunctive or monotherapy for pediatric patients with either focal or generalized seizures; it is readily measurable in plasma, with an appropriate degree of sensitivity, accuracy, and precision; it exhibits interindividual variation in pharmacokinetics; often, its pharmacologic effect cannot be easily measured; and the duration of therapy is expected to be long-term. However, important criteria not met include the following: there is no clear evidence for a concentration-response relationship for efficacy or toxicity; the proposed therapeutic range of 12-46μg/mL is not well-defined and is generally considered as wide. Thus, clinical decision making is unlikely to be affected as a result of routine levetiracetam CPM. In general, routine CPM of levetiracetam cannot be recommended for pediatric patients with epilepsy. However, CPM may be beneficial in select cases, such as patients in whom noncompliance is suspected, those who have severe overdoses, those switching between product brands, or patients for whom an 'individual therapeutic concentration' is documented. Nonetheless, in the majority of pediatric patients with epilepsy, measurement of levetiracetam concentrations is not expected to yield a therapeutic benefit. Thus, clinical assessment and judgment, without measuring drug concentrations, remain the monitoring strategy of choice for levetiracetam therapy.

Influence of age and co-medication on the steady-state pharmacokinetics of valproic acid in Tunisian patients with epilepsy

AimValproic acid (VPA) is a widely prescribed broad-spectrum antiepileptic drug. However, the use of VPA is complicated in clinical practice by its remarkably wide variability of pharmacokinetics. The objective of this study was to investigate the effects of demographic factors and associated therapies on steady-state plasma VPA concentrations in patients with epilepsy. MethodsThis retrospective cohort study was carried out using the routine therapeutic drug monitoring (TDM) database. Stepwise logistic regression analysis was used to compare serum VPA levels in 78 epilepsy patients treated with VPA in association with at least one other drug that could have interacted with CYP2C9, CYP2C19 or UGT enzymes. ResultsThe frequency of subtherapeutic serum VPA levels was significantly increased with younger age (P<0.02), the number of co-medications (P<0.007) and use of enzyme-inducing co-medications (P<0.02). No significant correlations between VPA dose and trough plasma concentrations were found, as the latter did not increase in proportion to the dose. ConclusionRoutine monitoring of VPA serum levels would be extremely useful in epilepsy patients in the pediatric age group and in those who require associated enzyme-inducing medications.