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Randomized Controlled Trial
. 2007 Jun;63(6):680-8.
doi: 10.1111/j.1365-2125.2006.02829.x. Epub 2007 Jan 12.

The pharmacokinetics, CNS pharmacodynamics and adverse event profile of brivaracetam after single increasing oral doses in healthy males

Maria Laura Sargentini-Maier  1 , Paul Rolan, John Connell, Dominique Tytgat, Tom Jacobs, Etienne Pigeolet, Jean-Michel Riethuisen, Armel Stockis
Affiliations
Randomized Controlled Trial

The pharmacokinetics, CNS pharmacodynamics and adverse event profile of brivaracetam after single increasing oral doses in healthy males

Maria Laura Sargentini-Maier et al. Br J Clin Pharmacol. 2007 Jun.

Abstract

Aims: 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.

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Figures

Figure 1
Figure 1
Chemical structure of brivaracetam
Figure 2
Figure 2
Dose-dependency of pharmacodynamic effects (sedation, attention, alertness, motor control) of brivaracetam assessed as mean change from predose (SD) at 1 h postdose (n = 6/dose; n = 27 placebo group). For alertness, an increased VAS score indicates less alertness
Figure 3
Figure 3
Arithmetic mean plasma concentration vs. time profiles obtained after oral doses of 10 mg (▴), 20 mg (◊), 40 mg (✦), 80 mg (□), 150 mg (▪), 300 mg (▿), 600 mg (▾), 1000 mg (○), and 1400 mg (•) of brivaracetam (n = 6/dose)
Figure 4
Figure 4
The relationship between the geometric mean (90% CI; n = 6) AUC of brivaracetam vs. dose. The regression line was calculated over the dose range from 10 to 600 mg
Figure 5
Figure 5
Arithmetic mean plasma concentration vs. time profiles obtained after oral administration of single 150 mg doses of brivaracetam under fasted conditions (•) or after a high fat meal (○) (n = 8)
See this image and copyright information in PMC

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