Summary:Purpose: The primary objective of this placebocontrolled study was to evaluate the safety and tolerability of levetiracetam (LEV) administered intravenously (IV) at higher doses and/or at a faster infusion rate than proposed. The secondary objective was to assess LEV pharmacokinetics.Methods: Single ascending doses of LEV administered by IV infusion (2,000, 3,000, 4,000 mg over 15 min; 1,500, 2,000, 2,500 mg over 5 min) were evaluated in 48 healthy subjects in a randomized, single-blind, placebo-controlled study.Results: All randomized subjects completed the study. Adverse events reported after IV administration of LEV (≤4,000 mg infused over 15 min and ≤2,500 mg infused over 5 min) were primarily related to the CNS (dizziness, 52.8%; somnolence, 33.3%; fatigue, 11.1%; headache, 8.3%) and were consistent with the established safety profile for the oral formulation. Safety profiles were similar for each dose level of LEV and for both IV infusion rates, with no clear relation noted between incidence of adverse events and IV dose level or infusion rate. The pharmacokinetics of LEV administered by IV infusion was comparable across all dose groups and infusion rates. Respective geometric means (coefficient of variation) for 4,000 mg administered over 15 min and 2,500 mg infused over 5 min were maximum plasma concentration, 145 (24.6%) and 94.3 (36.2%) μg/ml; area under the plasma concentration-time curve, 1,239 (19.2%) and 585 (9.6%) μg/h/ml; terminal half-life, 8.0 (14.5%) and 7.0 (12.7%) h.Conclusions: LEV administered by IV infusion at dosages and/or infusion rates higher than those proposed was well tolerated in healthy subjects, and the pharmacokinetic profile was consistent with that for LEV administered orally.

AimsThe 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. MethodsHealthy 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. ResultsAdverse 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 tmax of approximately 1 h. Cmax was dose-proportional from 10 to1400 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 tmax (3 h) and decreased Cmax (point estimate 0.72, 90%CI: 0.66-0.79). ConclusionsBrivaracetam 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.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• The pharmacokinetic profile, metabolism and proof of concept of a single oral dose of brivaracetam have been reported.• Previous studies have shown that it was well absorbed, had linear kinetics and was well tolerated, and suggested effective doses of 10-80 mg in photoparoxysmal epilepsy. WHAT THIS STUDY ADDS• We now report the pharmacokinetics, pharmacodynamics and tolerability in healthy volunteers after multiple doses. AIMSBrivaracetam 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. METHODSThree 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. RESULTSBrivaracetam was rapidly absorbed (tmax~2 h) and eliminated (t1/2 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-b-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. CONCLUSIONSBrivaracetam 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.

SUMMARYObjective: Rapid distribution to the brain is a prerequisite for antiepileptic drugs used for treatment of acute seizures. The preclinical studies described here investigated the high-affinity synaptic vesicle glycoprotein 2A (SV2A) antiepileptic drug brivaracetam (BRV) for its rate of brain penetration and its onset of action. BRV was compared with levetiracetam (LEV). Methods: In vitro permeation studies were performed using Caco-2 cells. Plasma and brain levels were measured over time after single oral dosing to audiogenic mice and were correlated with anticonvulsant activity. Tissue distribution was investigated after single dosing to rat (BRV and LEV) and dog (LEV only). Positron emission tomography (PET) displacement studies were performed in rhesus monkeys using the SV2A PET tracer [11 C]UCB-J. The time course of PET tracer displacement was measured following single intravenous (IV) dosing with LEV or BRV. Rodent distribution data and physiologically based pharmacokinetic (PBPK) modeling were used to compute blood-brain barrier permeability (permeability surface area product, PS) values and then predict brain kinetics in man. Results: In rodents, BRV consistently showed a faster entry into the brain than LEV; this correlated with a faster onset of action against seizures in audiogenic susceptible mice. The higher permeability of BRV was also demonstrated in human cells in vitro. PBPK modeling predicted that, following IV dosing to human subjects, BRV might distribute to the brain within a few minutes compared with approximately 1 h for LEV (PS of 0.315 and 0.015 ml/min/g for BRV and LEV, respectively). These data were supported by a nonhuman primate PET study showing faster SV2A occupancy by BRV compared with LEV. Significance: These preclinical data demonstrate that BRV has rapid brain entry and fast brain SV2A occupancy, consistent with the fast onset of action in the audiogenic seizure mice assay. The potential benefit of BRV for treatment of acute seizures remains to be confirmed in clinical studies.

ABSTRACT:This study was designed to investigate the human absorption, disposition, and mass balance of 14