Impact of Augmented Renal Clearance in Critically Ill Patients: Population Pharmacokinetics of Levetiracetam and Dosing Evaluation

Abstract

Introduction: Augmented renal clearance (ARC) is a phenomenon recently identified in critically ill patients.ARC has the potential to influence the pharmacokinetic profile of any drug that is renally cleared andknown to have a direct correlation between renal clearance (CL) and creatinine clearance (CrCl), such aslevetiracetam. Objective: The aim of this thesis was initially to evaluate the adequacy of levetiracetamdosing for the achievement of therapeutic levels in patients with normal or high renal clearance admittedto the ICU by the characterization of its pharmacokinetics by population modelling and simulation.Alternative dosage regimens able to achieve target concentrations in this population have been alsoproposed using stochastic simulations and considering biopharmaceutical and pharmacokinetic aspects.Methods: A systematic review on ARC phenomenon was conducted. A multicentre prospective study incritically ill patients treated with levetiracetam was carried out. A population pharmacokinetic model oflevetiracetam in critically ill patients was developed. Alternative dosage regimens were evaluated byMonte Carlo simulation. Results and discussion: The systematic review showed that ARC, defined as a CrCl>130 mL/min/1.73 m2 measured in urine, is present in 20 to 65% of critically ill patients, being youngerage, polytrauma and lower severity illness identified risk factors. Twenty-seven critically ill patients wereincluded in the pharmacokinetic study. A two-compartment model best described levetiracetampharmacokinetics in this population, only CrCl was found to be a significant covariate of its CL. In criticallyill patients with ARC conventional dosage regimens (500-1500 mg twice daily in a short infusion) do notallow to obtain trough plasma concentrations in the defined target, between 12 and 46mg/L. Newdosage regimens to be implemented in critically ill patients with ARC were proposed by using MonteCarlo simulations based on the population pharmacokinetic model developed and consideringbiopharmaceutical and pharmacokinetics aspects.