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Antiepileptic Drugs
Published in Sahab Uddin, Rashid Mamunur, Advances in Neuropharmacology, 2020
Both levetiracetam and brivaracetam are used as adjunctive treatment of focal seizures in adults and children, for primary onset tonic–clonic seizures, and for myoclonic seizures of JME. Levetiracetam is found to be effective for refractory generalized myoclonic seizures as adjunctive therapy (Crespel et al., 2013).
Hydrolytic Enzymes for the Synthesis of Pharmaceuticals
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Sergio González-Granda, Vicente Gotor-Fernández
Brivaracetam, namely (2S)-2-[(4R)-2-oxo-4-propyltetrahydro-1H-pyrrol-1-yl]butanamide is a novel antiepileptic drug approved for the treatment of partial onset seizures in patients with epilepsy. The enzymatic resolutions of ester precursors have been described through hydrolytic procedures (Scheme 9.3). After a screening of 30 esterases, 30 lipases, 15 proteases and one acylase, Bacillus subtilis protease was selected as the most stereoselective catalyst in a phosphate buffer at pH 7.5 (Schülé et al., 2016). Remarkably, the ethyl ester was effectively hydrolysed, keeping untouched the tert-butyl ester group. The protease C from Bacillus subtilis allowed the access to the remaining (S)-ester in 99% ee and the (R)-succinic acid in 95% ee (E = 210) using acetone as cosolvent. Further studies related to the reaction conditions were undertaken, searching for ideal scale-up conditions including the work-up and isolation of the optically active products. Special efforts were done in the replacement of the phosphate buffer used in the screenings by water, so the best conditions for the 1 kg substrate biotransformation yielded 394.4 g of the (R)-2-propylsuccinic acid 4-tert-butyl ester in 97% ee and 42% final yield. Protease-catalysed KR of a Brivaracetam precursor by hydrolysis in water.
Current safety concerns about the use of antiseizure medications in pregnancy
Published in Expert Opinion on Drug Safety, 2022
Giovanni Falcicchio, Emilio Russo, Antonio Fabiano, Micaela Scalese, Giovanni Boero, Maria Trojano, Marina de Tommaso, Angela La Neve
Despite covering long intervals of time and collecting huge quantities of data, all the registries provide little information on the newer ASMs. EURAP, for example, recorded only 39 pregnancies with lacosamide monotherapy, three with brivaracetam monotherapy, and none with perampanel monotherapy [55]. The number of pregnancies exposed to new-generation ASMs increased when polytherapy was considered (lacosamide, n = 101; brivaracetam, n = 8; perampanel, n = 17). MCMs were observed in 4.3% of cases treated with a monotherapy and 6.3% of those treated with a polytherapy, but the ASMs involved were not reported [55]. Moreover, NAREP reported only 64 pregnancies with lacosamide monotherapy, with a 0% risk of MCMs during the first trimester. No pregnancies in women receiving brivaracetam or perampanel monotherapy were reported [54].
Pharmacokinetic and pharmacodynamic modeling of levetiracetam: investigation of factors affecting the clinical outcome
Published in Xenobiotica, 2020
Eleni Karatza, Sophia L. Markantonis, Andria Savvidou, Anastasia Verentzioti, Anna Siatouni, Athanasia Alexoudi, Stylianos Gatzonis, Evgenia Mavrokefalou, Vangelis Karalis
Regarding levetiracetam pharmacodynamics (PD), a rather limited number of population studies have been reported. Kim et al. (2018) analyzed the time to seizure recurrence in children aged 1 month to 16 years with epilepsy. The investigators found that the Weibull distribution model described the time to seizure recurrence well; while no statistically significant predictor for the time to seizure was identified (Kim et al., 2018). Based on this and on a population PK model, the investigators proved that dose selection based on weight is the most appropriate in pediatric patients. In another study, a pharmacokinetic–pharmacodynamic (PKPD) model was constructed for adult epileptic patients receiving brivaracetam, the n-propyl analogue of levetiracetam. This model described daily seizure counts using a negative binomial distribution, taking previous day seizures into account, and using a mixture model to separate “placebo-like” and “response” subpopulations. Simulations aiming to define the dose–response curve were performed, suggesting maximum response is obtained with a brivaracetam dose of 150–200 mg/day (Schoemaker et al., 2016).
Brivaracetam efficacy and safety in focal epilepsy
Published in Expert Review of Neurotherapeutics, 2019
Yamane Makke, Bassel Abou-Khalil
Brivaracetam is currently approved in the USA for the treatment of focal-onset seizures in patients aged ≥4 years. The new policy of the US FDA allowed extrapolation of efficacy in adjunctive therapy to monotherapy use and efficacy in adults to pediatric use after demonstration of safety and equivalent pharmacokinetics in children. The European Union indication specifies that it should be used as adjunctive therapy. The recommended starting dose is 50 mg twice daily, allowing for later dose increase or dose reduction depending on efficacy and tolerability. The recommended maximal dose is 200 mg/day. The pediatric starting dose is 0.5–1 mg/kg twice daily for patients weighing less than 50 Kg. BRV current cost may be an obstacle to widespread use. Its most clear-cut indication will be in patients who could not tolerate LEV due to behavioral adverse effects or patients at risk of behavioral adverse effects from LEV. Patients who have previously failed LEV due to lack of efficacy may still benefit from BRV, but are less likely to do so than patients who are LEV-naïve. BRV has not been sufficiently investigated for generalized epilepsy, though its preclinical profile suggested broad spectrum.