Seletracetam (UCB 44212)

Abstract

Summary:Better pharmacotherapies for epilepsy are needed for patients who are refractory to or have tolerability difficulties with current treatments. Seletracetam, a new drug in epilepsy development, is a pyrrolidone derivative structurally related to levetiracetam (trade name Keppra). It was discovered because of its high binding affinity to the synaptic vesicle 2A (SV2A) protein, which is now known to be the binding site for this family of compounds. Seletracetam shows very potent seizure suppression in models of acquired or genetic epilepsy, as well as high CNS tolerability in various animal models. Pharmacokinetic studies in animals suggest that seletracetam is rapidly and highly absorbed, with linear and time-independent pharmacokinetics. Seletracetam appears neither to inhibit nor to induce the major human drug metabolizing enzymes, and it demonstrates low plasma protein binding (Ͻ10%), which suggests a low potential for drug-drug interactions. Initial studies in humans demonstrated first-order monocompartmental kinetics with a half-life of 8 h and an oral bioavailability of Ͼ90%. Studies in healthy volunteers showed that the treatment emergent adverse events were of mild to moderate severity, were mostly of CNS origin and were resolved within 24 h. Altogether, these results suggest that seletracetam represents a promising new antiepileptic drug candidate, one that demonstrates a potent, broad spectrum of seizure protection and a high CNS tolerability in animal models, with initial clinical findings suggestive of straightforward pharmacokinetics and good tolerability.

Down-regulation Synaptic Vesicle Protein 2A in the Anterior Temporal Neocortex of Patients with Intractable Epilepsy

“…In our previous study, synaptotagmin I was up-regulated in temporal lobe tissues of patients with IE (Xiao et al 2009). The observation that SV2A knockout mice develop lethal seizures soon after birth (Crowder et al 1999), along with evidence that SV2A is the binding site for the AED levetiracetam and its analogs (brivaracetam and seletracetam; Lynch et al 2004;Gillard et al 2006;Bennett et al 2007;von Rosenstiel 2007), indicates a role for SV2A in the antiepileptic properties of AEDs. Therefore, decreased SV2A expression may contribute to the progression of epilepsy.…”

SV2 regulates neurotransmitter release via multiple mechanisms

“…One of these is synaptic vesicle protein 2 (SV2), a membrane glycoprotein expressed exclusively in neurons and endocrine cells. SV2 is the binding site of a class of drugs typified by levetiracetam (5,17,26,29,31). Levetiracetam is a Food and Drug Administration-approved treatment for epilepsy (reviewed in Ref.…”

An overview on antiepileptic drugs

“…Apart from various similarities seletracetam differs from levetiracetam by a very potent and selective effect against Zn concentrations involving multiple high-voltage-operated Ca 2+ channels. In pharmacokinetic studies seletracetam was found to reach C max within 1 h. The linear, timeindependent pharmacokinetics of the drug combined with a rapid and almost complete absorption indicates that STM has a major uncomplicated pharmacokinetic profi le (60).…”