The pharmacokinetics, CNS pharmacodynamics and adverse event profile of brivaracetam after single increasing oral doses in healthy males.
OBJECTIVE
The objective of the study was to evaluate the pharmacokinetics (and how they are affected by food), CNS pharmacodynamics and the adverse event profile of brivaracetam after single increasing doses.


METHODS
Healthy males (n = 27, divided into three alternating panels of nine subjects) received two different single oral doses of brivaracetam (10-1400 mg) and one dose of placebo during three periods of a randomized, double-blind, placebo-controlled study. The effect of food on its pharmacokinetics was assessed using a standard two-way crossover design in a further eight subjects who received two single oral doses of brivaracetam (150 mg) in the fasting state and after a high fat meal.


RESULTS
Adverse events, none of which were serious, were mostly CNS-related and included somnolence, dizziness, and decreased attention, alertness, and motor control. Their incidence, severity and duration were dose-related. The maximum tolerated dose was established to be 1000 mg. Severe somnolence lasting 1 day occurred in one subject following 1400 mg. Brivaracetam was rapidly absorbed under fasting conditions, with a median t(max) of approximately 1 h. C(max) was dose-proportional from 10 to 1400 mg, whereas AUC deviated from dose linearity above 600 mg. A high-fat meal had no effect on AUC (point estimate 0.99, 90%CI: 0.92-1.07) but delayed t(max) (3 h) and decreased C(max) (point estimate 0.72, 90%CI: 0.66-0.79).


CONCLUSIONS
Brivaracetam was well tolerated after increasing single doses that represent up to several times the expected therapeutic dose. Brivaracetam was found to have desirable pharmacokinetic properties. The most common adverse events were somnolence and dizziness.
Sargentini-Maier
Maria Laura
ML
UCB SA, Research and Development, Braine-l'Alleud, Belgium. laura.maier@ucb-group.com
Rolan
Paul
P
Connell
John
J
Tytgat
Dominique
D
Jacobs
Tom
T
Pigeolet
Etienne
E
Riethuisen
Jean-Michel
JM
Stockis
Armel
A
D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000927:Anticonvulsants / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004827:Epilepsy / Q000628:therapy; D006801:Humans; D008297:Male; D008875:Middle Aged; D011760:Pyrrolidinones / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use
D000927:Anticonvulsants; D011760:Pyrrolidinones; C482793:brivaracetam