Levetiracetam dosing in continuous renal replacement therapy: A systematic review and development of a novel pharmacokinetic model to optimise dosing in critically ill patients. Do recommended doses achieve therapeutic drug concentrations?

Abstract

Aim: Levetiracetam is a widely used anti-epileptic in the critical care setting that is almost exclusively (>90%) renally excreted. The altered pharmacokinetics of levetiracetam have been widely studied in intermittent haemodialysis but the evidence and guidance on dosage in continuous renal replacement therapy is varied and poorly defined. Understanding this is critical as a significant number of critically unwell patients develop renal failure requiring continuous renal replacement therapy. The aim of this systematic review is to investigate the pharmacokinetics of levetiracetam in such patients and to understand the implications on dosing strategies.

Methods: A systematic review of the available literature from 2000 to November 2022 was conducted. Seven articles were identified for inclusion from 54 records. A novel hybrid model was developed to evaluate the quality of pharmacokinetic and haemofiltration data. This data was used to develop a one-compartment model that simulated dosing strategies in 10,000 patients based on an assumed steady state of 72 hr and target trough concentrations of 12-46 mcg/mL.

Results: From the seven articles included, pharmacokinetic data was retrieved for 24 individual patients. Total clearance was 3.49-4.63 L/hr (mean 3.55, S.D. 0.52). Elimination half-life was 5.66-12.88 hr (mean 9.41, S.D. 2.86). Volume of distribution was 0.45-0.73 L/kg. The proportion of total clearance attributable to continuous renal replacement therapy was 52%-73% (mean 54.7%, S.D. 13.5). Our simulations demonstrate that more than half of patients who received twice daily doses of 750 mg or greater without a loading dose achieved therapeutic drug concentrations. The time to achievement of therapeutic drug concentrations was greatly reduced by the addition of a 60 mg/kg loading dose (up to a maximum of 4.5 g). The use of a reduced loading dose or twice daily doses of 500 mg or less without loading were more likely to result in prolonged sub-therapeutic drug concentrations.

Conclusion: Levetiracetam clearance in haemofiltration is similar to healthy adults with normal renal function (GFR > 90 mL/min). The use of reduced doses due to renal failure in critically ill patients may result in sub-therapeutic drug concentrations in a high number of patients. A twice daily dosing of 750-1000 mg with an initial loading dose of 60 mg/kg should be considered in such patients alongside therapeutic drug monitoring.