Abstract
Levetiracetam is a broad-spectrum antiepileptic drug commonly used in intensive care units (ICUs). The objective of this study is to evaluate the adequacy of levetiracetam dosing in patients with normal or augmented renal clearance (ARC) admitted to the ICU by population modelling and simulation. A multicentre prospective study including twenty-seven critically ill patients with urinary creatinine clearance (CrCl) > 50 mL/min and treated with levetiracetam was developed. Levetiracetam plasma concentrations were best described by a two-compartment model. The parameter estimates and relative standard errors (%) were clearance (CL) 3.5 L/h (9%), central volume of distribution (V1) 20.7 L (18%), intercompartmental clearance 31.9 L/h (22%), and peripheral volume of distribution 33.5 L (13%). Interindividual variability estimates were, for the CL, 32.7% (21%) and, for V1, 56.1% (29%). The CrCl showed significant influence over CL. Simulations showed that the administration of at least 500 mg every 8 h or 1000 mg every 12 h are needed in patients with normal renal function. Higher doses (1500 or 2000 mg, every 8 h) are needed in patients with ARC. Critically ill patients with normal or ARC treated with levetiracetam could be at high risk of being underdosed.
Highlights
The aim of this study is to evaluate the adequacy of levetiracetam dosing for the achievement of therapeutic levels in patients with normal or high renal clearance admitted to the intensive care units (ICUs) by the characterization of the levetiracetam pharmacokinetics by population modelling and simulation
The high variability observed in levetiracetam concentrations, partially explained by patients’ renal function, suggested the need for dosing optimization in patients with augmented renal clearance (ARC) and Monte Carlo simulations revealed the need of high doses to attain the target concentrations
A population pharmacokinetic model has been developed for levetiracetam in critically ill patients with normal or ARC
Summary
Pharmaceutics 2021, 13, 1690 safety profile and ease of use compared to other conventional antiepileptic drugs such as phenytoin, it is frequently used in the treatment of status epilepticus and in seizure prophylaxis after a neurologic injury, being a commonly used treatment in intensive care units (ICUs) [1,2,3]. It is rapidly and almost completely absorbed when administered orally, with a time to reach the peak concentration (Tmax) of. Renal clearance represents the main elimination mechanism with a 66% of the dose excreted unchanged in urine, which leads to a good correlation between levetiracetam clearance and a patient‘s creatinine clearance (CrCl). The metabolites have no known pharmacological activity and are renally excreted [1,4,5]
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