Valentina Franco

Novel treatment options for epilepsy: focus on perampanel.

Perampanel is a new chemical entity recently approved in the United States (US) and European Union (EU) as adjunctive treatment of partial-onset seizures with and without secondary generalization in patients with epilepsy aged 12 years and older. Pharmacological studies suggest that perampanel acts with a new mechanism of action via non-competitive antagonism of the ionotropic α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA) receptor of glutamate, the main mediator of excitatory neurotransmission in the central nervous system. Perampanel is completely absorbed after oral administration. The drug is 95% bound to plasma proteins and is extensively metabolized by oxidation followed by glucuronidation. Perampanel has an elimination half-life of approximately 52-129h, allowing once daily dosing, with peak plasma levels observed 0.25-2h post-dose. Randomized placebo-controlled trials of adjunctive treatment have demonstrated that once-daily perampanel doses of 4-12mg/day significantly reduced partial-onset seizure frequency in patients with pharmacoresistant epilepsy along with a favorable tolerability profile. In perampanel pivotal trials, the most frequently reported treatment emergent adverse events (>10%) included dizziness, somnolence, fatigue and headache. Perampanel therapeutic response was maintained in patients included in the long term open-label extension studies for up to 4 years. Based on these data, perampanel offers a valuable option in the add-on treatment of partial-onset and secondarily generalized seizures.

Antiepileptic drugs and brain maturation: fetal exposure to lamotrigine generates cortical malformations in rats.

Intake of antiepileptic drugs (AEDs) during pregnancy can provoke severe and subtle fetal malformations associated with deleterious sequelae, reflecting the need for experimental investigations on the comparative teratogenic potential of these agents. We recently reported that prenatal exposure to vigabatrin and valproate, two AEDs which act through GABAergic mechanisms, induces hippocampal and cortical dysplasias in rodents. We have now investigated the effects of phenobarbital (PB, 30 mg/kg day) i.p.), a drug also endowed with GABAergic effects, and the new generation AEDs lamotrigine (LTG, 5-20mg/kg/day i.p.), topiramate (TPM, 10mg/kg/day i.p.), and levetiracetam (LEV, 50mg/kg/day i.p.) on brain development. Prenatal exposure to LTG induced hippocampal and cortical malformations in a dose-dependent manner, at maternal plasma concentrations within the clinically occurring range. These abnormalities were not observed after exposure to PB, TP and LEV. These observations raise concerns about potential clinical correlates and call for detailed comparative investigations on the consequences of AED use during pregnancy.

Challenges in the clinical development of new antiepileptic drugs

Despite the current availability in the market of over two dozen antiepileptic drugs (AEDs), about one third of people with epilepsy fail to achieve complete freedom from seizures with existing medications. Moreover, currently available AEDs have significant limitations in terms of safety, tolerability and propensity to cause or be a target for clinically important adverse drug interactions. A review of the evidence shows that there are many misperceptions about the viability of investing into new therapies for epilepsy. In fact, there are clear incentives to develop newer and more efficacious medications. Developing truly innovative drugs requires a shift in the paradigms for drug discovery, which is already taking place by building on greatly expanded knowledge about the mechanisms involved in epileptogenesis, seizure generation, seizure spread and development of co-morbidities. AED development can also benefit by a review of the methodology currently applied in clinical AED development, in order to address a number of ethical and scientific concerns. As discussed in this article, many processes of clinical drug development, from proof-of-concept-studies to ambitious programs aimed at demonstrating antiepileptogenesis and disease-modification, can be facilitated by a greater integration of preclinical and clinical science, and by application of knowledge acquired during decades of controlled epilepsy trials.

Characteristics of a large population of patients with refractory epilepsy attending tertiary referral centers in Italy.

The characteristics of 1,124 consecutive adults and children with refractory epilepsy attending 11 tertiary referral centers in Italy were investigated at enrollment into a prospective observational study. Among 933 adults (age 16–86 years), the most common syndromes were symptomatic (43.7%) and cryptogenic (39.0%) focal epilepsies, followed by idiopathic (8.1%) and cryptogenic/symptomatic generalized (6.2%) epilepsies. The most common syndrome among 191 children was symptomatic focal epilepsy (35.1%), followed by cryptogenic focal (18.8%), cryptogenic/symptomatic generalized (18.3%), undetermined whether focal or generalized (16.8%), and idiopathic generalized (7.3%). Primarily and secondarily generalized tonic–clonic seizures were reported in 27.8% of adults and 16.8% of children. The most commonly reported etiologies were mesial temporal sclerosis (8.0%) and disorders of cortical development (6.2%) in adults, and disorders of cortical development (14.7%) and nonprogressive encephalopathies (6.8%) in children. More than three‐fourths of subjects in both age groups were on antiepileptic drug (AED) polytherapy.

Changes in Lamotrigine Pharmacokinetics during Pregnancy and the Puerperium

To assess changes in the pharmacokinetics of the anti-epileptic drug lamotrigine (LTG) during pregnancy, plasma LTG concentrations at steady-state were determined at different intervals during 11 pregnancies in 10 women with epilepsy stabilized on long-term LTG therapy. In the five pregnancies that could be assessed both during gestation and after delivery, plasma LTG concentrations increased on average by 164% (range +75 to +351%) between the last observation during pregnancy and the puerperium (P < 0.05). When all pregnancies monitored during pregnancy were considered, plasma LTG concentrations declined by an average of 20% (range -64% to +13%) between the first and the last assessment before delivery. These findings confirm that plasma LTG concentrations decrease markedly during pregnancy and that, at least in some cases, this effect occurs as early as the first trimester. Because there is a large interindividual variability in the magnitude and time course of the pregnancy-associated pharmacokinetic changes, it is desirable to establish baseline plasma LTG concentrations in all women of childbearing potential and to monitor LTG levels at frequent intervals during pregnancy and the puerperium.

A novel enantioselective microassay for the high-performance liquid chromatography determination of oxcarbazepine and its active metabolite monohydroxycarbazepine in human plasma

Abstract: A simple and innovative assay is described that allows the determination of the antiepileptic drug oxcarbazepine and the chiral separation of the two enantiomers of its active metabolite monohydroxycarbazepine (licarbazepine). The assay requires liquid-liquid extraction of the sample (200 μL) into tert-butyl methyl ether and dichloromethane, drying of the organic phase under a nitrogen stream, reconstitution with the mobile phase, and injection in the high-performance liquid chromatography system after filtering. Separation of oxcarbazepine, R-(−)-monohydroxycarbazepine, S-(+)-monohydroxycarbazepine, and the second-step metabolite 10,11-trans-dihydroxycarbamazepine (racemate) is achieved with a Chiralcel ODR column and potassium hexafluorophosphate/acetonitrile as mobile phase. Detection is by ultraviolet absorbance at 210 nm. Standard curves are linear (r2 ≥ 0.999) over the range of 0.1 to 25 μg/mL for each analyte with a limit of quantification of 0.1 μg/mL (1 ng injected) for all compounds. Within-day and between-day precision is better than 12% and within-day and between-day accuracy is between 99% and 116% for each compound. These performance characteristics are adequate for pharmacokinetic studies and for therapeutic drug monitoring. However, because the two enantiomers of monohydroxycarbazepine exhibit similar pharmacologic activity, nonenantioselective assays are likely to be more cost-effective for therapeutic drug monitoring purposes.

Tolerability of new antiepileptic drugs: a network meta-analysis

ObjectiveThe objective of this study was to perform a comparative assessment of tolerability of all licensed new antiepileptic drugs (AEDs) through a network meta-analysis (NMA) including all placebo-controlled double-blind clinical trials (RCTs) in all conditions in which these drugs have been tested.MethodsNMA with a frequentist approach was used to compare proportions of patients withdrawing because of adverse events (AEs). Analyses were conducted for all therapeutic doses pooled and specifically for high therapeutic doses. Patients treated with non-therapeutic doses of each drug were excluded.ResultsA total of 195 RCTs were included in the current analysis, comprising a total of 28,013 patients treated with AEDs and 17,908 patients treated with placebo. RCTs included in the analysis were 8 for brivaracetam; 5 for eslicarbazepine; 22 for gabapentin; 7 for lacosamide; 14 for levetiracetam; 14 for lamotrigine; 6 for oxcarbazepine; 9 for perampanel; 50 for pregabalin; 5 for tiagabine; 36 for topiramate; 7 for zonisamide; 4 for gabapentin-extended formulation (ER); 2 each for levetiracetam-ER, lamotrigine-ER, and topiramate-ER; and 1 each for oxcarbazepine-ER and pregabalin-ER. Brivaracetam, gabapentin, gabapentin-ER, and levetiracetam had a significantly lower withdrawal rate compared to several other AEDs, while eslicarbazepine, lacosamide, oxcarbazepine, and topiramate had a higher withdrawal rate. Perampanel, lamotrigine, pregabalin, tiagabine, and zonisamide showed an intermediate pattern of tolerability. Additional analysis has been conducted through selection of highly recommended doses for each drug. This analysis has roughly confirmed results of head to head comparisons of the all-dose analysis, with some exceptions. A further analysis has been conducted after exclusion of RCTs in which patients were allocated to the therapeutic dose of the experimental drug without titration, and it failed to show clinically important differences.SignificanceRelevant differences in short-term tolerability of AEDs have been observed between AEDs. Brivaracetam, gabapentin, and levetiracetam show the best tolerability profile while other AEDs are at higher risk for intolerable adverse effects.

Perampanel effects in the WAG/Rij rat model of epileptogenesis, absence epilepsy, and comorbid depressive-like behavior.

Perampanel (PER), a selective non‐competitive α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA)‐receptor antagonist, exhibits broad‐spectrum anticonvulsant activity in several seizure models, but its potential disease‐modifying effects have not been investigated. Because of the relevance of AMPA receptors in epileptogenesis and psychiatric comorbidities, we studied the effects of PER in the WAG/Rij rat model of epileptogenesis, absence epilepsy, and depressive‐like comorbidity.

The pharmacogenomics of epilepsy

Genetic factors contribute to the high interindividual variability in response to antiepileptic drugs. However, most genetic markers identified to date have limited sensitivity and specificity, and the value of genetic testing in guiding antiepileptic drug (AED) therapy is limited. The best defined indication for testing relates to HLA-B*15:02 genotyping to identify those individuals of South Asian ethnicity who are at high risk for developing serious adverse cutaneous reactions to carbamazepine. The indication for HLA-A*31:01 testing to identify individuals at risk for skin reactions from carbamazepine, or for CYP2C9 genotyping to identify individuals at risk for serious skin reactions from phenytoin is less compelling. The use of genetic testing to guide epilepsy treatment is likely to increase in the future, as better understanding of the function of epilepsy genes will permit the application of precision medicine targeting the biological mechanisms responsible for epilepsy in the specific individual.

CYP2C9 polymorphisms and phenytoin metabolism: implications for adverse effects

Introduction: Phenytoin, a widely prescribed old-generation antiepileptic drug, requires careful individualization of dosage to compensate for its prominent pharmacokinetic variability. This article reviews the contribution of genetic polymorphisms affecting the activity of CYP2C9, the main enzyme responsible for phenytoin metabolism, to the variation in phenytoin clearance and susceptibility to adverse effects. Areas covered: Comprehensive and critical review of available evidence concerning the influence of CYP2C9 genetic polymorphism on phenytoin pharmacokinetic and safety profile. Expert opinion: There is extensive evidence that CYP2C9 polymorphisms are an important determinant of the rate of phenytoin metabolism, although other factors including expression of other enzymes such as CYP2C19 and the influence of drug interactions, physiological and disease-related factors may also play a role. Patients carrying CYP2C9 genotypes associated with reduced phenytoin clearance are at greater risk of developing CNS adverse effects as well as serious cutaneous adverse reactions when given usual dosages of phenytoin. The clinical value and cost-effectiveness of CYP2C9 genotyping in improving the safety of phenytoin therapy, however, have not been clearly established and require formal testing in well-designed prospective studies.