Meropenem Target Attainment and Population Pharmacokinetics in Critically Ill Septic Patients with Preserved or Increased Renal Function

Abstract

Matthias Gijsen,1,2 Omar Elkayal,1 Pieter Annaert,1,3 Ruth Van Daele,1,2 Philippe Meersseman,4 Yves Debaveye,4 Joost Wauters,4 Erwin Dreesen,1 Isabel Spriet1,2 1Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium; 2Pharmacy Department, University Hospitals Leuven, Leuven, Belgium; 3BioNotus, Niel, Belgium; 4Department of Cellular and Molecular Medicine, KU Leuven, Leuven, BelgiumCorrespondence: Matthias GijsenPharmacy Department, University Hospitals Leuven, Herestraat 49, Leuven, 3000, BelgiumTel [phone]Fax [phone]Email [email protected]: Critically ill patients with preserved or increased renal function have been shown to be at risk of underexposure to meropenem. Although many meropenem population pharmacokinetic (PK) models have been published, there is no large prospective population PK study with rich sampling focusing on patients most at risk of suboptimal pharmacokinetic/pharmacodynamic (PK/PD) target attainment. Therefore, the aim of the present study was to evaluate PK/PD target attainment and to perform a thorough covariate screening using population PK modelling of meropenem in septic patients with preserved or increased renal function.Patients and Methods: A single-centre prospective observational PK study was performed in the intensive care unit (ICU) of the University Hospitals Leuven. Patients with severe sepsis or septic shock and treated with meropenem in the ICU were screened for inclusion. Patients were excluded if they received renal replacement therapy or had an estimated glomerular filtration rate according to the Chronic Kidney Disease Epidemiology collaboration equation < 70 mL/min/1.73m2 on the day of PK sampling. Successful PK/PD target attainment was defined as an unbound meropenem trough concentration above 2 mg/L or 8 mg/L. Population PK modelling was performed with NONMEM7.4.Results: In total, 58 patients were included, contributing 345 plasma samples over 70 dosing intervals. The 2 mg/L and 8 mg/L targets were successfully attained in 46% and 11% of all dosing intervals, respectively. A two-compartment population PK model with linear elimination and interindividual variability on clearance best described meropenem PK. The estimated creatinine clearance according to the Cockcroft-Gault equation was the only covariate retained during population PK analysis.Conclusion: This study provided detailed insight into meropenem PK in critically ill patients with preserved or increased renal function. We observed poor PK/PD target attainment, for which renal function was the only significant covariate.Trial Registration: This study is registered at ClinicalTrials.gov (NCT03560557).Keywords: intensive care, PK/PD, exposure, dose optimization, augmented renal clearance

Keywords

• intensive care
• pk/pd
• exposure
• dose optimization
• augmented renal clearance