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

Abstract

Purpose: 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: PK/PD; augmented renal clearance; dose optimization; exposure; intensive care.

Conflict of interest statement

Erwin Dreesen and Isabel Spriet share senior authorship. BioNotus conducted the bioanalysis in support of this study and received financial compensation for this service. Pieter Annaert is co-founder of BioNotus GCV and is a full time employee of KU Leuven. Joost Wauters reports grants, non-financial support from MSD, grants, other from Gilead, grants, other from Pfizer, outside the submitted work. Erwin Dreesen reports grants from Research Foundation—Flanders (FWO), during the conduct of the study; consultancy fee (paid to the University) from Argenx and Janssen, outside the submitted work. The authors report no other conflicts of interest in this work.

© 2022 Gijsen et al.

Figures

Figure 1

Observed unbound meropenem plasma concentrations (mg/L) vs time relative to the start of the infusion (hours). Panel (A) represents the early sampling days, panel (B) represents the late sampling days. The dashed lines represent the 2 mg/L and 8 mg/L PK/PD target. The lines connect different observations within the same patient.

Figure 2

Prediction-corrected visual predictive check of the final model. The observed prediction-corrected meropenem concentrations are represented by circles. The black solid and dashed lines represent median and 2.5th and 97.5th percentile of the prediction-corrected observations, respectively. The shaded areas indicate 95% prediction-intervals of the median and 2.5th and 97.5th percentile of the simulated values.