Levetiracetam dosing in critically ill patients receiving prolonged intermittent renal replacement therapy

Levetiracetam can be significantly removed by prolonged intermittent renal replacement therapy (PIRRT) due to its pharmacokinetic properties. However, dosing guidance for this population is limited. This study aimed to evaluate the probability of target attainment (PTA) for various levetiracetam regimens in critically ill adults receiving PIRRT, using Monte Carlo simulation (MCS).

A one-compartment model with first-order elimination was developed using published pharmacokinetic data. Simulations incorporated PIRRT modalities (hemodialysis and hemofiltration), with an effluent rate of 18 L/h and varying durations (4, 6, 8, and 10 h). PIRRT was modeled as occurring early (at drug administration) or late (14-20 h post-dose). MCS was conducted in 10,000 virtual patients per regimen over 48 h. The pharmacodynamic target was an area under the concentration-time curve (AUC) of 222-666 mg·h/L. Regimens achieving ≥90 % PTA were considered optimal.

Several commonly used regimens failed to achieve adequate PTA. For alternate-day PIRRT with hemofiltration, 500 mg every 12 h or 1000 mg every 24 h were optimal. For alternate-day PIRRT with hemodialysis, 750 mg every 12 h or 1250 mg every 24 h were preferred. For daily PIRRT with either modality, 750 mg every 12 h consistently met PTA targets.

Standard dosing regimens may be inadequate for achieving therapeutic exposure in PIRRT. Optimal dosing varies by PIRRT modality, frequency, and timing. These findings support individualized dosing and highlight the need for clinical validation.