Steady-State Pharmacokinetics of Intravenous Levetiracetam in Neurocritical Care Patients

Study Objectives. To characterize the steady-state pharmacokinetics of intravenous levetiracetam in neurocritical care patients requiring seizure prophylaxis after a neurologic injury and to determine which dosing regimens achieve serum concentrations within the recommended therapeutic range of 6-20 mu g/ml. Design. Prospective, open-label, steady-state pharmacokinetic study. Setting. Neurocritical care unit in a tertiary care medical center. Patients. Twelve adults (five men, seven women) admitted to the neurocritical care unit who required prophylactic anticonvulsant therapy after subarachnoid hemorrhage, subdural hematoma, or traumatic brain injury. Intervention. Patients received an intravenous infusion of levetiracetam 500 mg over 15 minutes every 12 hours. Measurements and Main Results. Serial blood samples were collected from all patients after a minimum of four doses of therapy. Serum levetiracetam concentrations were determined by ultraperformance liquid chromatography with tandem mass spectrometry detection, and pharmacokinetic data were analyzed by compartmental and noncompartmental methods. Monte Carlo simulations were performed for multiple levetiracetam dosing regimens to determine the probability of achieving a target trough concentration of 6 mu g/ml or greater, 20 mu g/ml or greater, and 6-20 mu g/ml. The mean +/- SD levetiracetam maximum serum concentration was 28.0 +/- 8.0 mu g/ml, minimum serum concentration 3.1 +/- 1.8 mu g/ml, half-life 5.2 +/- 1.2 hours, systemic clearance 5.6 +/- 1.8 L/hour, and volume of distribution at steady state 36.8 +/- 6.3 L. Increasing the doses of levetiracetam increased the probability of achieving a target trough concentration of 6 mu g/ml or greater but also increased the probability of achieving trough concentrations greater than 20 mu g/ml. Levetiracetam doses of 1000 mg every 8 hours and 1500-2000 mg every 12 hours provided the highest probability of achieving a target trough concentration between 6 and 20 mu g/ml. Conclusion. Compared with previously published results in healthy volunteers and adults in status epilepticus, levetiracetam systemic clearance was faster and the terminal elimination half-life was shorter in neurocritical care patients. Higher doses or more frequent dosing may be needed to achieve target trough concentrations of 6-20 mu g/ml.