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Brivaracetam (UCB 34714) Neurotherapeutics: The Journal of the American Society for Experimental NeuroTherapeutics Brivaracetam (UCB 34714) Philipp von Rosenstiel Clinical Development, Therapeutic Area Neurology/Psychiatry, UCB, Belgium Summary: Brivaracetam (UCB 34714) is chemically related to emergent adverse events were mild to moderate, mostly of CNS levetiracetam (LEV, Keppra®). It possesses a binding affinity origin, and resolved within 24 hrs, with decreasing incidence for the synaptic vesicle protein 2A (SV2A) ten-fold above that after repeated intake. Drug-drug interaction studies with high of LEV and also shows an ability to inhibit Naϩ channels. This dose of brivaracetam (400 mg/d) showed a dose-dependent correlates with a higher potency in suppressing epileptiform increase of carbamazepine-epoxide levels. No significant inter- responses in vitro and a more potent and complete suppression action with low doses of phenytoin was observed at the same of different seizure types in animals with an acquired or genetic high dose levels of brivaracetam, and only a moderate phar- epilepsy. Brivaracetam has been tested in a comprehensive macokinetic interaction with an oral contraceptive, without im- safety pharmacology, toxicology, developmental toxicology, pact on hormonal levels or ovulation, was observed. The phar- and genotoxicity program. It is of low acute toxicity, target macokinetic profile of brivaracetam is unaltered in elderly organ for toxic effects is the hepatobiliary tract. Carcinogenic- subjects or those with impaired renal function. Clearance of ity studies are ongoing. Human pharmacology studies have brivaracetam is reduced in patients with hepatic insufficiency. shown that brivaracetam has a half-life of 8 h and nearly In the photoparoxysmal response model in patients with pho- complete bioavailability. Brivaracetam is primarily metabo- tosensitive epilepsy brivaracetam was effective at all tested lized via hydrolysis of the acetamide group and CYP2C8- doses (10 – 80 mg) in reducing or abolishing EEG discharges mediated hydroxylation. Its metabolites are not pharmacolog- evoked by a photic stimulus. Phase 2 studies in patients with ically active. Excretion of over 95% of the dose, including refractory partial onset seizures have recently been completed. metabolites, occurs renally within 72 h. Healthy volunteer stud- Key Words: Brivaracetam, UCB 34714, synaptic vesicle pro- ies demonstrated a favorable tolerability profile. Treatment tein 2A, SV2A ϭ 3 INTRODUCTION 7.1) than LEV (pKi 6.1) for SV2A. In addition to its affinity for SV2A it has shown inhibitory effects on The synaptic vesicle protein 2A (SV2A) is a widely ϩ voltage-dependent Na -currents in rat cortical neurons distributed CNS protein believed to be involved in the in culture.4 coordination of synaptic vesicle exocytosis and neuro- transmitter release.1 Binding affinity to SV2A of the ® antiepileptic drug levetiracetam (LEV, Keppra ), as well PHARMACOLOGY as of a series of LEV analogues, correlates highly with the seizure protection afforded by these compounds in Brivaracetam was tested in vitro in rat hippocampal animal models of epilepsy.2 The novel SV2A ligand slices following perfusion with a high potassium-low brivaracetam ((2S)-2-[(4R)-2-oxo-4-propylpyrrolidinyl] calcium-containing fluid at concentrations of 1–10 ␮M. butanamide) was identified in an extensive drug discov- In this model, brivaracetam significantly suppressed ery program aimed at enhancing the well-established evoked epileptiform responses (population spikes, PSs) antiepileptic properties of LEV. It is a 2-pyrrolidone recorded in the CA3 area. Active concentrations lay 10- derivative structurally related to LEV with a mol weight fold below those of LEV (3.2 ␮Mvs32␮M). It is of note ϭ of 212 and displays a markedly higher affinity (pKi that brivaracetam at the same concentrations also re- duced the occurrence of spontaneous bursts, while LEV is inactive against this drug-refractory marker of epilep- Address correspondence and reprint requests to: Philipp von Rosen- tiform activity.5,6 stiel, M.D., Clinical Development, Therapeutic Area Neurology/Psy- Brivaracetam has been extensively studied in in vivo chiatry, UCB, 1420 Braine-l’Alleud, Belgium; Ph: ϩ32 (2) 386 2557; Fax: ϩ32 (2) 386 2828; E-mail: Philipp.vonRosenstiel@UCB-Group. models of epilepsy and convulsion. The corneally kin- com. dled mouse is a model for partial epilepsy. In this para- 84 Vol. 4, 84–87, January 2007 © The American Society for Experimental NeuroTherapeutics, Inc. BRIVARACETAM 85 digm, brivaracetam at concentrations several-fold below nal effects have not been observed (UCB, data on file). those necessary with LEV protected animals from sec- The maximum nonlethal oral single dose in the rat lay ondarily generalized motor seizures (ED50 values ϭ 1.2 above 1000 mg/kg and a no-effect level of 500 mg/kg vs 7.3 mg/kg, i.p.). In a further model of focal epilepsy, was established in male and female rats based on clinical the amygdala-kindled rat, brivaracetam provided a more signs. profound suppression of both motor seizure severity and Chronic toxicity was assessed in dogs, rats and mon- after-discharge duration than LEV. The activity of bri- keys. The non- observed adverse effect level (NOAEL) varacetam was also investigated in models of generalized after 26 weeks of repeated administration in dogs was 15 seizures. Mice genetically susceptible to audiogenic sei- mg/kg/day with an area under the curve (AUC) of 34.7 zures were more potently protected from clonic convul- ␮g./mL. At higher doses hepatobiliary adverse effects sions with brivaracetam than with LEV (ED50 values ϭ were noted in these animals. Overall, the NOAEL in the 2.4 vs. 30 mg/kg, i.p.). In an experimental model of rat after 26 weeks of oral dosing was considered to be absence epilepsy, the genetic absence epilepsy rat from 450 mg/kg/day in both males and females (AUC of 257 Strasbourg (GAERS), a more complete suppression of and 464 ␮g.h/mL respectively), when male-rat-specific spike-wave-discharges with brivaracetam than with LEV hyaline droplet nephropathy, of no consequence for man, was observed.7 is set aside. 39 weeks of chronic administration of bri- In the same corneal kindling model, chronic pretreat- varacetam in monkeys allowed for the identification of ment prior to corneal stimulation with LEV or 10-fold the NOAEL at 900 mg/kg/day (AUC of 2351 ␮g.h/mL). lower doses of brivaracetam 2 x daily (1.7-54 mg/kg i.p. No adverse effects on fertility and early embryonic versus 0.21-6.8 mg/kg i.p.) led to a similar suppression development were detected up to the highest tested oral of kindling development.8 Most notably, the cessation of dose of 400 mg/kg/day. No effects on pregnancy or on treatment with continued corneal stimulation resulted in fetal development occurred at the highest tested dose of a more significant and persistent inhibition of the kin- 600 mg/kg/day in a fetal development study in the rat. dling process than that seen with LEV. The fetal/developmental NOAEL in the rabbit was iden- In order to assess the anticonvulsant properties of bri- tified at a dose of 120 mg/kg/day. varacetam in an acute seizure model, the activity of the Genotoxicity was investigated in a panel of studies compound against partially drug-resistant self-sustaining (Ames bacterial mutation, mouse lymphoma in vitro status epilepticus (SSSE) in rats was studied. This model mammalian cell mutation, Chinese hamster ovary in has shown that stimulation of excitatory pathways can vitro chromosomal aberration and an in vivo rat micro- create reverberating limbic circuits in which seizures are nucleus chromosomal aberration assay). Taken together self-sustaining and thereby induce damage to the brain.7 these studies suggested that brivaracetam is neither mu- This process, once set in motion, is refractory to standard tagenic nor clastogenic. anticonvulsants such as diazepam and, at a later point, Carcinogenicity studies are currently ongoing (UCB, phenytoin.9 SSSE was induced by perforant path stimu- data on file). lation (PPS) in adult male rats. The cumulative duration of active seizures was reduced dose-dependently to 11% CLINICAL PHARMACOKINETICS and 0.8% of controls at 20 and 300 mg/kg, respectively. This activity compares favorably to the result of 35% of Bioavailability of brivaracetam is rapid and almost controls achieved with 200 mg/kg of LEV and 15% of complete following oral administration. The drug shows controls with 10 mg/kg of diazepam. The combination of linear pharmacokinetics over a dose range from 10 to diazepam (1 mg/kg) and brivaracetam (1 mg/kg) reduced 600 mg. The metabolic clearance of brivaracetam is in- the duration of active seizures to 3% of controls, while creased in a time-dependent fashion at supratherapeutic either drug alone had little effect at these doses. This doses; a steady state is reached within 1 week of repeated experiments showed potent anticonvulsant activity of the administration. Plasma protein binding is weak (Յ 20%), compound in an animal model of status epilepticus.10 the volume of distribution, 0.6 l/kg, being close to that of total body water. The terminal elimination half-life of brivaracetam is approximately 8 h and does not vary with SAFETY PHARMACOLOGY AND the administered dose.11 TOXICOLOGY A pharmacoscintigraphy study (UCB, data on file) The acute oral toxicity of brivaracetam has been investigated the regional absorption profile of brivarac- shown to be low in mice, rats, and dogs, with transient etam. Brivaracetam was consistently absorbed through- CNS effects generally occurring at doses of 100 mg/kg out the GI tract, as evidenced by the relative AUC or above in a dose-dependent fashion. These effects re- (100%ϭstomach) of 101, 98, and 97% following deliv- gressed under continuous treatment within a few days. ery in the proximal jejunum, distal jejunum, and ascend- Significant cardiovascular, respiratory, or gastrointesti- ing colon respectively.
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