Abstracts

Rationale: Keppra (levetiracetam) has recently been approved for IV administration. We studied parenteral levetiracetam (LEV) in a rat model of acute generalized convulsive status epilepticus (GCSE) to determine its potential efficacy in GCSE and to determine the pharmacokinetics of LEV entry into blood and brain.Methods: Male 200-300 gram Sprague-Dawley rats were implanted with four stainless steel epidural electrodes for EEG recording. Twenty-five mg powdered cobalt was placed under the left frontal electrode to create a seizure focus. When the rat exhibited interictal polyspikes and/or right UE twitching, SE was induced by injecting 5.5 mM homocysteine thiolactone (HCT) intraperitoneally (IP). Immediately after the second generalized convulsion, levetiracetam (LEV) was administered IP and was considered effective if no further seizures occurred 10-30 min after injection. Animals were sacrificed at 30 minutes after LEV administration and blood and brains collected for LEV determination by HPLC. Because preliminary studies suggested that LEV at doses of 10-1000 mg/kg is not effective alone, we administered 0.1 mg/kg diazepam (ED₅₀ of DZM alone = ~5 mg/kg), simultaneously with 200-1800/kg LEV, to determine the ED₅₀ of LEV, based on a report by Mazarati et al. (Epilepsy Res 58:167-74, 2004) which suggested a synergistic effect of DZM with LEV in SE. When LEV failed to stop SE at any dose, even with DZM, we hypothesized there may be a delay in onset of its initial antiepileptic effect. To test this hypothesis we gave 200 mg/kg LEV IP 0, 30, 60, 90, 120, & 180 minutes prior to HCT. Rats were sacrificed 60 minutes after HCT to determine LEV serum concentrations. We also determined the time course of serum and brain concentrations of LEV after IP administration in 200 gram male rats. LEV was dissolved in saline and rats were given 200 mg/kg as a single bolus IP injection. Six rats were sacrificed at each of the follow time points: 5, 10, 15, 30, 45, 60, 90, 120, 150 & 180 min after LEV injection and serum and brains collected for LEV determination by HPLC. Results: LEV was not effective in the Co/HCT model of SE at doses from 10 mg/kg up to 1800 mg/kg, with or without 0.1 mg/kg DZM. Pretreatment with LEV (200 mg/kg IP) up to 180 min before giving HCT to induce SE did not prevent the development of GCSE. LEV serum concentration peaked 15 minutes after IP injection, with a mean concentration of ~270 μg/ml after the 200 mg/kg IP injection. Brain concentration (~85 μg/gm) did not peak until 60 minutes after injection and then remained fairly constant for the 180 minutes of the study.Conclusions: LEV is not effective acutely in the Co/HCT model of SE. LEV enters serum after IP injection at a rate similar to drugs (LZM, PB, PHT) used the treatment of status epilepticus (10-20 min to peak concentrations). However, the 60 min time to peak brain concentrations is longer than the 20-30 minutes seen for anti-SE drugs. This delay in brain entry, plus time required to interact with the SV2A protein, may partially explain the apparent lack of acute efficacy of LEV in a Co/HCT model of experimental SE. (Funded by UCB Pharma)