Focale Mechanism of Action

Pharmacology: Pharmacodynamics: Levetiracetam, a pyrrolidine derivative, is an anticonvulsant agent that is structurally unrelated to other available anticonvulsants. The mechanism of anticonvulsant action of levetiracetam is unknown.
In vitro and in vivo recordings of epileptiform activity from the hippocampus showed that levetiracetam inhibits burst firing without affecting normal neuronal excitability. This suggests that levetiracetam may selectively prevent hypersynchronization of epileptiform burst firing and propagation of seizure activity.
At concentrations of up to 10μM, levetiracetam did not exhibit binding affinity for benzodiazepines, γ-aminobutyric acid (GABA), glycine or N-methyl-D-aspartate (NMDA) receptors, reuptake sites, or second messenger systems. In vitro studies have failed to find an effect of levetiracetam on neuronal voltage-gated sodium or T-type calcium currents; levetiracetam does not appear to directly facilitate GABAergic neurotransmission. However, in vitro studies have shown that the drug opposes the activity of negative modulators of GABA- and glycine-gated currents and partially inhibits N-type calcium currents in neuronal cell culture.
Levetiracetam has been shown in in vitro studies to bind to a specific site in rodent brain tissue, the synaptic vesicle protein 2A, believed to be involved in vesicle fusion and neurotransmitter exocytosis. Levetiracetam's affinity for binding to the synaptic vesicle protein 2A correlates to the potency of its anti-seizure protection in the mouse audiogenic model of epilepsy and suggests that such interaction contributes to the drug's antiepileptic mechanism of action.
Pharmacokinetics: Levetiracetam is rapidly and close to 100% absorbed after oral administration. The pharmacokinetics are linear (over the dose range of 500 to 5,000 mg) and time invariant with low intra- and inter-subject variability. Peak plasma concentrations (C_max) are achieved in about an hour after oral dose in fasted subjects. Steady state is achieved after two days of a multiple twice-daily dosing. Peak concentrations are typically 31 g/mL and 43 µg/mL after a single 1,000 mg dose and repeated 1,000 mg twice daily dose, respectively. The extent of absorption is dose-independent. Coadministration with food does not affect the bioavailability but reduces the C_max by 20% and delays it by 1.5 hours.
Neither levetiracetam nor its metabolite (ucbL057) are significantly protein-bound (<10%); clinically significant interaction with other drugs through competition for protein binding sites are therefore unlikely. Levetiracetam's volume of distribution is 0.5 to 0.7 L/kg, a value close to the volume of intracellular and extracellular water.
Levetiracetam is only partially metabolized and the major metabolic pathway is the enzymatic hydrolysis of the acetamide group, which produces the carboxylic acid metabolite, ucbL057 (24% of the dose) and is not dependent on any liver cytochrome P450 isoenzymes. Two minor metabolites were identified.
One was obtained as the product of hydroxylation of the 2-oxo-pyrrolidine ring in position 5 (1% of dose). In healthy volunteers, the time of maximum serum concentration (t_max) of the drug is approximately one hour, and the half-life (t_½) is 7 to 8 hours which is unaffected by either dose, route of administration or repeated administration. The t_½ is 2.5 hours longer in the elderly.
Levetiracetam's mean total body clearance is 0.96 mL/min/kg. The major route of excretion is via urine, accounting for a mean 95% of the dose, with approximately 93% of the dose excreted within 48 hours. Excretion via feces accounted for only 0.3% of the dose. The cumulative urinary excretion of levetiracetam and its major metabolite (ucb L057) accounted for 66% and 24% of the dose, respectively, during the first 48 hours. Levetiracetam's renal clearance is 0.6 mL/min/kg, indicating that it is excreted by glomerular filtration with subsequent tubular reabsorption. The renal clearance of the major metabolite, ucb L057, is 4.2 mL/min/kg indicating active tubular secretion in addition to glomerular filtration.