Optimization of levetiracetam dosing regimen in critically ill patients with augmented renal clearance: a Monte Carlo simulation study

Journal of Intensive Care

Helena Barrasa¹  Javier Maynar¹  Eduardo Asín-Prieto²  José Ángel Sánchez-Izquierdo³  María Ángeles Solinís⁴  Alicia Rodríguez-Gascón⁴  Idoia Bilbao-Meseguer⁴  Arantxazu Isla⁴ 

[1] Bioaraba, Intensive Care Unit;Inserm U1070: Pharmacologie des anti-infectieux, Pôle Biologie Santé-Bâtiment B36, Université de Poitiers;Intensive Care Unit, Doce de Octubre Hospital;Pharmacokinetic, Nanotechnology and Gene Therapy Group (PharmaNanoGene), Faculty of Pharmacy, Centro de Investigación Lascaray Ikergunea, University of the Basque Country UPV/EHU;

关键词: Levetiracetam;    Dosing;    Pharmacokinetics;    Pharmacodynamics;    Monte Carlo simulation;    Augmented renal clearance;   

DOI  :  10.1186/s40560-022-00611-w

来源: DOAJ

【 摘 要 】

Abstract Background Levetiracetam pharmacokinetics is extensively altered in critically ill patients with augmented renal clearance (ARC). Consequently, the dosage regimens commonly used in clinical practice may not be sufficient to achieve target plasma concentrations. The aim of this study is to propose alternative dosage regimens able to achieve target concentrations in this population. Furthermore, the feasibility of the proposed dosing regimens will be discussed from a clinical point of view. Methods Different dosage regimens for levetiracetam were evaluated in critically ill patients with ARC. Monte Carlo simulations were conducted with extended or continuous infusions and/or high drug doses using a previously developed population pharmacokinetic model. To assess the clinical feasibility of the proposed dosages, we carried out a literature search to evaluate the information on toxicity and efficacy of continuous administration or high doses, as well as the post-dilution stability of levetiracetam. Results According to the simulations, target concentrations in patients with CrCl of 160 or 200 mL/min can be achieved with the 3000 mg daily dose by prolonging the infusion time of levetiracetam. For patients with CrCl of 240 mL/min, it would be necessary to administer doses higher than the maximum recommended. Available evidence suggests that levetiracetam administration in continuous infusion or at higher doses than those approved seems to be safe. It would be desirable to re-examinate the current recommendations about drug stability and to achieve a consensus in this issue. Conclusions Conventional dosage regimens of levetiracetam (500–1500 mg twice daily in a short infusion) do not allow obtaining drug plasma concentrations among the defined target in critically ill patients with ARC. Therefore, new dosing guidelines with specific recommendations for patients in this subpopulation are needed. This study proposes new dosages for levetiracetam, including extended (4 or 6 h) infusions, continuous infusions or the administration of doses higher than the recommended in the summary of product characteristics (> 3000 mg). These new dosage recommendations take into account biopharmaceutical and pharmacokinetic aspects and meet feasibility criteria, which allow them to be transferred to the clinical environment with safety and efficacy. Nevertheless, further clinical studies are needed to confirm these results.

【 授权许可】

Unknown