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Seletracetam (UCB 44212) Neurotherapeutics: The Journal of the American Society for Experimental NeuroTherapeutics Seletracetam (UCB 44212) Barbara Bennett,* Alain Matagne,† Philippe Michel,‡ Michèle Leonard,§ Miranda Cornet,§ Marie-Anne Meeus,¶ and Nathalie Toublanc¶ *CNS Clinical Development, UCB Atlanta, Smyrna, Georgia 30080; †Preclinical CNS, ‡Chemistry, §Non-clinical Development, and ¶Clinical Pharmacology, UCB Braine-l’Alleud, Belgium Summary: Better pharmacotherapies for epilepsy are needed demonstrates low plasma protein binding (Ͻ10%), which sug- for patients who are refractory to or have tolerability difficulties gests a low potential for drug–drug interactions. Initial studies with current treatments. Seletracetam, a new drug in epilepsy in humans demonstrated first-order monocompartmental kinet- development, is a pyrrolidone derivative structurally related to ics with a half-life of 8 h and an oral bioavailability of Ͼ90%. levetiracetam (trade name Keppra). It was discovered because Studies in healthy volunteers showed that the treatment emer- of its high binding affinity to the synaptic vesicle 2A (SV2A) gent adverse events were of mild to moderate severity, were protein, which is now known to be the binding site for this mostly of CNS origin and were resolved within 24 h. Alto- family of compounds. Seletracetam shows very potent seizure gether, these results suggest that seletracetam represents a suppression in models of acquired or genetic epilepsy, as well promising new antiepileptic drug candidate, one that demon- as high CNS tolerability in various animal models. Pharmaco- strates a potent, broad spectrum of seizure protection and a high kinetic studies in animals suggest that seletracetam is rapidly CNS tolerability in animal models, with initial clinical findings and highly absorbed, with linear and time-independent phar- suggestive of straightforward pharmacokinetics and good tol- macokinetics. Seletracetam appears neither to inhibit nor to erability. Key Words: Seletracetam, epilepsy, SV2A, pharma- induce the major human drug metabolizing enzymes, and it cokinetics, kindled, anticonvulsant INTRODUCTION Pharmacotherapy is the primary treatment for epileptic patients; however, despite the introduction of second- Epilepsy and the need for new antiepileptic drugs generation anticonvulsants, refractory epilepsy is still a Epilepsy is a chronic, often lifelong, neurological dis- significant clinical problem. Outcome studies examining order that requires continuous pharmacotherapy to main- tain seizure control. The age-adjusted incidence of epi- either traditional or newer anticonvulsants show that lepsy in developed countries is approximately 50 per fewer than 50% of patients with epilepsy become sei- 1 zure-free after beginning an initial antiepileptic medica- 100,000 persons per year, with a lifetime chance of 4 getting epilepsy of 3–5%.2 Epilepsy has a tremendous tion. Approximately 30% of patients (adults and chil- impact not only on the individuals afflicted with this dren) with partial onset seizures cannot be adequately disease, but also on their families, as well as on society controlled with existing antiepileptic drugs (AEDs), be- 5 in general, because of the resultant personal and financial cause of either lack of efficacy or toxicity. Most refrac- burdens. Epilepsy is characterized by recurrent involun- tory patients have partial epilepsy; the generalized epi- 6 tary seizures, caused by disturbances in the normal elec- lepsies tend to respond better to current AED therapy. trical activity of the brain, that affect awareness, move- Furthermore, these refractory patients are at risk for cog- ment, or sensations.3 These seizures may occur in just nitive and psychiatric disorders, suicide, accidental inju- one area of the brain (partial seizures) or may affect ries, and sudden death. There continues to be a need for neuronal networks throughout the brain (generalized sei- new antiepileptic drugs, both to improve upon the estab- zures). lished drugs and also to treat those refractory to current pharmacotherapies. Address correspondence and reprint requests to: Barbara A. Bennett, Current drugs for the treatment of epilepsy Ph.D., UCB, Inc., Clinical Development, Neurology/Psychiatry Ther- apeutic Area, 1950 Lake Park Drive, Smyrna, GA 30080. E-mail: Classical (or first-generation) anticonvulsants, such as [email protected]. phenobarbital, phenytoin, carbamazepine, and valproate, Vol. 4, 117–122, January 2007 © The American Society for Experimental NeuroTherapeutics, Inc. 117 118 BENNETT ET AL. the other known binding sites within the CNS (e.g., receptors, uptake systems, and ion channel proteins).9 Thus, it appears that SV2A represents a novel molecular target that seems to have an important role in the phar- macological activity of seletracetam. The effect of seletracetam on several voltage-depen- dent ionic and receptor-gated currents has been charac- terized. Seletracetam, like levetiracetam, does not appear to have any effect on voltage-dependent Naϩ channels.12 Likewise, seletracetam (1–100 ␮mol/L) had no effect on FIG. 1. Structural formula for seletracetam. voltage-gated Kϩ currents (both the A-type and the de- layed rectifier) recorded in mouse hippocampal neurons are used as standard therapy in partial epilepsy. Clinical in culture.13 Seletracetam, like levetiracetam, appears to problems associated with these drugs include nonlinear inhibit high-voltage-activated (HVA) Ca2ϩ currents, but pharmacokinetics, narrow therapeutic index, significant does not appear to modulate the low-voltage-activated drug interactions, and adverse central nervous system (T-type) Ca2ϩ currents.14 Levetiracetam has been shown effects.7 The entrance to the market of vigabatrin, fel- to inhibit the N-type channel15 and possibly the P-type bamate, lamotrigine, oxcarbazepine, topiramate, zoni- channel to a much smaller extent.16 samide, gabapentin, levetiracetam, tiagabine, and pre- Seletracetam was found to be devoid of any direct gabalin increased the therapeutic options and improved effect on GABA- and strychnine-sensitive glycine-elic- treatment. However, most of these new drugs have a ited currents, similarly to levetiracetam.17 In contradis- limited tolerability profile. Serious toxicity problems tinction, seletracetam revealed a selectivity toward the have been identified, including fatal idiosyncratic hepatic glycine receptors (levetiracetam affects both). At phar- failure and aplastic anemia with felbamate, fatal allergic macologically relevant concentrations, seletracetam did rashes with lamotrigine, and serious visual field defects not modify NMDA-, kainate-, or AMPA-induced cur- with vigabatrin. New AEDs with improved risk–benefit rents. These data suggest that the pharmacological prop- ratios are therefore needed for refractory epilepsy pa- erties of seletracetam may derive principally from the tients,8 both as adjunctive treatment and in monotherapy. potent and selective interaction of seletracetam with the SV2A protein, as well as from the moderate effects of the SELETRACETAM drug on calcium channels and strychnine-sensitive gly- Preclinical beginnings cine receptors. The interface between the CNS binding Seletracetam is a small-molecule AED (FIG. 1), non- site, SV2A, and these cellular effects is not known; cor- ionized in water, and with solubility properties not ex- respondingly, whether any alleged interaction would ex- pected to lead to any solubility- or dissolution-related ist, direct or indirect, is also unknown. absorption problems after oral administration. Activity in animal models of seizures and epilepsy Pharmacological background Seletracetam, like levetiracetam, shows no anticonvul- Seletracetam is a structural analog of the antiepileptic sant activity in the two classical screening tests for drug levetiracetam, and its pharmacological activity ap- AEDs: the maximal electroshock test (MES; tonic con- pears to relate principally to an interaction with a novel vulsions in the hind limbs) and the pentylenetetrazol test binding site, synaptic vesicle protein 2A (SV2A).9,10 (PTZ; generalized clonic convulsions), both acute sei- Seletracetam binds selectively, stereospecifically, and zure models.18 In distinct contrast, seletracetam shows with high affinity (10-fold greater affinity than levetirac- potent seizure suppression in models of acquired or ge- etam) to SV2A, which is thought to be involved with netic epilepsy (TABLE 1).18 Seletracetam displayed po- synaptic vesicle exocytosis and neurotransmitter release. tent protection against secondary generalized motor sei- Both classic AEDs, such as carbamazepine, phenytoin, zures in fully corneally kindled mice (ED50 of 0.31 mg/ valproate, phenobarbital, and clonazepam, and new kg) and hippocampally kindled rats (minimal active AEDs, such as gabapentin, tiagabine, vigabatrin, felbam- dose, MAD, of 0.23 mg/kg).18 ate, and zonisamide, are devoid of significant affinity for The genetically sound-susceptible mouse model is SV2A. (S)-stereoisomer analogs of levetiracetam show a an experimental genetic model of epilepsy, mimicking rank order of affinity for [3H]levetiracetam binding that generalized reflex convulsive epilepsy in humans. Sele- correlates with their seizure protection,10,11 suggesting a tracetam provided dose-dependent protection in the ge- functional correlation between binding and anticonvul- netically sound-susceptible mouse against clonic convul- sant activity. Seletracetam did not induce a significant sions induced by an acoustic stimulus with an ED50 of displacement
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