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

145 p.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

Augmented Renal Clearance in Critically Ill Patients: A Systematic Review

Background Traditionally, renal function in critically ill patients has been assessed to identify renal dysfunction, and dose adjustment is generally accepted in such a context. Nevertheless, augmented renal clearance (ARC) is a less well-studied phenomenon that could lead to faster elimination of drugs, resulting in subtherapeutic concentrations and poorer clinical outcomes when standard dosage guidelines are followed. Objective The aim of this systematic review was to gather and summarise all the available evidence on ARC in critically ill patients, including its definition, underlying mechanisms, epidemiology, diagnosis and impact on both drug pharmacokinetics and clinical outcomes. Method A systematic review was conducted to include all the original studies that provided information on ARC in critically ill patients, and is reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Results Augmented renal clearance, defined as a creatinine clearance (CrCl)[130 mL/min/1.73 m2, preferably measured in urine, is present in 20–65% of critically ill patients. Younger age, polytrauma and lower severity illness have been identified as risk factors. An influence of ARC on antimicrobial pharmacokinetics has been observed, with ARC consistently being associated with subtherapeutic antibiotic plasma concentrations. Conclusion ARC is a prevalent condition in critically ill patients, especially in young people, with urinary CrCl being the best diagnostic method because mathematical estimates tend to underestimate CrCl. ARC increases renal drug elimination and has a clear influence on certain antimicrobial plasma levels, but is yet to define its impact on clinical outcomes and on pharmacokinetics of other types of drugs. Research on the need to stage ARC and establish specific dosing guidelines is warranted.This study was financially supported by the University of the Basque Country (UPV/EHU) (PPG17/65)

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

[EN] 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.This research was funded by Department of Education of the Basque Government (PIBA 2019-57) and by the University of the Basque Country UPV/EHU (GIU20/048)

Population Pharmacokinetics of Levetiracetam and Dosing Evaluation in Critically Ill Patients with Normal or Augmented Renal Function

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.This research was funded by Department of Education of the Basque Government, grant number PIBA 2019-57; and by the University of the Basque Country UPV/EHU, grant number GIU20/048. A.A.-L. thanks the University of the Basque Country UPV/EHU for her research grant, number PIFG19/23