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A systematic review of the effect of continuous renal replacement therapy on levetiracetam pharmacokinetics in critically ill patients. Do recommended doses achieve therapeutic drug concentrations?
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  • James Sweatman,
  • Sarraa Al-Mahdi,
  • Dagan Lonsdale,
  • Andrew Rhodes,
  • Susannah Leaver
James Sweatman
Royal Free London NHS Foundation Trust
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Sarraa Al-Mahdi
London North West University Healthcare NHS Trust
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Dagan Lonsdale
St George's, University of London

Corresponding Author:[email protected]

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Andrew Rhodes
St George's University Hospitals NHS Foundation Trust
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Susannah Leaver
St George's University Hospitals NHS Foundation Trust
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AIM Levetiracetam is a widely used anti-epileptic in the critical care setting that is almost exclusively (>90%) renally excreted. A significant number of critically unwell patients develop renal failure requiring haemofiltration. This paper investigates the pharmacokinetics of levetiracetam in such patients and the implications on dosing strategies. METHODS A systematic review of the available literature from 2000 was conducted. 7 articles were identified for inclusion from 54 records. A novel hybrid model was used to evaluate the quality of pharmacokinetic and haemofiltration data. Simulations were performed using pooled pharmacokinetic data to evaluate various dosing strategies. RESULTS Total clearance was 3.49 – 4.63L/hr (mean 3.55, S.D. 0.52). Elimination half-life was 5.66 – 12.88 hours (mean 9.41, S.D. 2.86). Volume of distribution was 0.45 – 0.73 L/kg. Levetiracetam clearance from CRRT was 52 – 73% (mean 54.7%, S.D. 13.5). At 72 hours, a significant proportion of simulated patients who received the recommended dose of levetiracetam demonstrated sub-therapeutic drug concentrations. Conversely, the majority who received a standard loading dose (60mg/kg) and twice daily doses in excess of 750mg demonstrated more consistent therapeutic drug concentrations. CONCLUSION Levetiracetam clearance in haemofiltration is similar to healthy adults with normal renal function. The current recommendation to dose as in CKD Stage 3b is likely to result in sub-therapeutic drug concentrations in a high number of patients. A twice daily dosing of 500 – 1,000 mg with an initial loading dose of 60mg/kg should be considered in such patients alongside therapeutic drug monitoring.
25 Jul 2023Submitted to British Journal of Clinical Pharmacology
26 Jul 2023Assigned to Editor
26 Jul 2023Submission Checks Completed
26 Jul 2023Review(s) Completed, Editorial Evaluation Pending
17 Aug 2023Reviewer(s) Assigned