The pharmacokinetics, CNS pharmacodynamics and adverse event profile of brivaracetam after multiple increasing oral doses in healthy men.
OBJECTIVE
Brivaracetam is a novel synaptic vesicle protein 2A ligand that has shown potent activity in animal models of epilepsy. This study examined the pharmacokinetics, central nervous system pharmacodynamics and adverse event profile of multiple oral doses of brivaracetam in healthy male subjects.


METHODS
Three successive panels of 12 healthy male subjects received double-blind brivaracetam 200, 400 or 800 mg day(-1) (all doses well above the expected therapeutic range) or placebo (9 : 3), in two divided doses, for 14 days.


RESULTS
Brivaracetam was rapidly absorbed (t(max) approximately 2 h) and eliminated (t(1/2) 7-8 h). Volume of distribution was slightly lower than total body water. A small fraction of the dose (5-8%) was excreted unchanged in urine together with significant levels of metabolites, suggesting predominantly metabolic clearance. Based on 6-beta-hydroxycortisol/cortisol ratios in urine, there was no evidence of induction of CYP3A4 activity. Saliva and plasma brivaracetam levels were highly correlated. Adverse events were mostly mild to moderate, central nervous system-related and resolved within the first day of treatment. No clinically relevant changes were observed in laboratory tests, vital signs, physical examinations or ECGs. Pharmacodynamic tests showed dose-related sedation and decreased alertness that only persisted at 800 mg daily.


CONCLUSIONS
Brivaracetam was well tolerated by healthy male volunteers at doses of 200-800 mg daily for 2 weeks, well above the expected clinically effective dose range. Brivaracetam had a favourable pharmacokinetic profile in this population, characterized by rapid absorption, volume of distribution limited to total body water, apparent single-compartment elimination and dose proportionality.
Rolan
Paul
P
Medeval Ltd, Manchester, UK.
Sargentini-Maier
Maria Laura
ML
Pigeolet
Etienne
E
Stockis
Armel
A
D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000927:Anticonvulsants / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology; D019540:Area Under Curve; D002490:Central Nervous System / Q000187:drug effects*; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D006801:Humans; D006854:Hydrocortisone / Q000652:urine; D008297:Male; D008875:Middle Aged; D011594:Psychometrics; D011760:Pyrrolidinones / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology; D016896:Treatment Outcome
D000927:Anticonvulsants; D011760:Pyrrolidinones; C482793:brivaracetam; D006854:Hydrocortisone