Received for publication July 9, 2007.
Revised September 26, 2007.
Accepted for publication September 26, 2007.

Pharmacokinetics and metabolism of ¹⁴C-brivaracetam, a novel SV2A ligand, in healthy subjects

Abstract

This study was designed to investigate the human absorption, disposition and mass balance of ¹⁴C-brivaracetam, a novel high affinity SV2A ligand with potent anticonvulsant activity. Six healthy male subjects received a single oral dose of ¹⁴C-brivaracetam (150 mg, 82 µCi or 3.03 MBq). Serial blood and complete urine and feces were collected until 144 h post-dose. Expired air samples were obtained until 24h. Brivaracetam was rapidly absorbed, with C_max of 4 µg/mL occurring within 1.5 h of dosing. Unchanged brivaracetam amounted to 90% of the total plasma radioactivity, suggesting a modest first pass effect. Plasma protein binding of radioactivity was low (17.5%). Urinary excretion exceeded 90% after 2 days and the final mass balance reached 96.8% of the radioactivity in urine and 0.7% in feces. Only 8.6% of the radioactive dose was recovered in urine as unchanged brivaracetam, the remainder being identified as non-CYP and CYP dependent biotransformation products resulting from hydrolysis of the amide moiety (M9, 34.2%), hydroxylation of the n-propyl side chain (M1b, 15.9%), and a combination of these two pathways leading to the hydroxyacid (M4b, 15.2%). Minor amounts of taurine and glucuronic acid conjugates and other oxidized derivatives were also identified. Brivaracetam is completely absorbed, is weakly bound to plasma proteins, extensively biotransformed through several metabolic pathways and eliminated renally.

Key words: CNS pharmacokinetics, human pharmacokinetics, metabolite identification