Safety and pharmacokinetics of intravenous levetiracetam infusion as add‐on in status epilepticus

Abstract

PURPOSE: To evaluate the feasibility and safety of intravenous (iv) levetiracetam (LEV) added to the standard therapeutic regimen in adults with status epilepticus (SE), and as secondary objective to assess a population pharmacokinetic (PK) model for ivLEV in patients with SE. METHODS: In 12 adults presenting with SE, 2,500 mg ivLEV was added as soon as possible to standardized protocol, consisting of iv clonazepam and/or rectal diazepam, as needed followed by phenytoin or valproic acid. ivLEV was administered over approximately 5 min, in general after administration of clonazepam, regardless the need for further treatment. During 24-h follow-up, patients were observed for any clinically relevant side-effects. Blood samples for PK analysis were available in 10 patients. A population PK model was developed by iterative two-stage Bayesian analysis and compared to PK data of healthy volunteers. RESULTS: Eleven patients with a median age of 60 years were included in the per protocol analysis. Five were diagnosed as generalized-convulsive SE, five as partial-convulsive SE, and one as a nonconvulsive SE. The median time from hospital admission to ivLEV was 36 min. No serious side effects could be related directly to the administration of ivLEV. During PK analysis, four patients showed a clear distribution phase, lacking in the others. The PK of the population was best described by a two-compartment population model. Mean (standard deviation, SD) population parameters included volume of distribution of central compartment: 0.45 (0.084) L/kg; total body clearance: 0.0476 (0.0147) L/h/kg; distribution rate constants, central to peripheral compartment (k(12)): 0.24 (0.12)/h, and peripheral to central (k(21)): 0.70 (0.22)/h. Mean maximal plasma concentration was 85 (19) mg/L. DISCUSSION: The addition of ivLEV to the standard regimen for controlling SE seems feasible and safe. PK data of ivLEV in patients with SE correspond to earlier values derived from healthy volunteers, confirming a two-compartment population model