Population Pharmacokinetic Analysis of Meropenem in Critically Ill Patients With Acute Kidney Injury Treated With Continuous Hemodiafiltration

Abstract

Background: The aim of this study was to conduct a population pharmacokinetic (PK) analysis of meropenem and to explore the optimal dosing strategy for meropenem in critically ill patients with acute kidney injury receiving treatment with continuous hemodiafiltration (CHDF). Methods: Blood samples were obtained on days 1, 2, and 5 after the start of meropenem administration, immediately before dosing, and at 1, 2, 6, and 8 hours after dosing. Population PK model analysis was performed and concentration-time profiles were simulated using the Nonlinear Mixed Effects Model software. Results: Twenty-one patients receiving CHDF in our intensive care unit were enrolled and 350 serum concentration–time data points were obtained. The PKs of meropenem were best described using a 2-compartment model. Typical total and intercompartmental clearance values were 4.22 L/h and 7.84 L/h, respectively, whereas the central and peripheral compartment volumes of distribution were 14.82 L and 11.75 L, respectively. Estimated glomerular filtration rate was identified as a significant covariate of meropenem total clearance. In simulations of patients with renal failure receiving CHDF, the dose was affected by estimated glomerular filtration rate; a dose of 0.5 g every 8 hours or 1 g every 12 hours showed the probability of target attainment of achieving 100% time above the minimum inhibitory concentration for bacteria with a minimum inhibitory concentration ≤2 mg/L. Conclusions: A population PK model was developed for meropenem in critically ill patients with acute kidney injury receiving CHDF. Our results indicated that a meropenem dosage of 0.5 g every 8 hours or 1 g every 12 hours was suitable in this population and for susceptible bacteria.

Key Challenges in Providing Effective Antibiotic Therapy for Critically Ill Patients with Bacterial Sepsis and Septic Shock

“…Six of the studies enrolled only subjects on renal replacement therapy. The most commonly reported covariate on meropenem clearance was CL CR as a covariate on total or renal clearance (in 8 of 11 studies that included patients not on renal replacement therapy), [70][71][72][73][74][75][76][77][78] in agreement with meropenem being primarily cleared by urinary excretion.…”

Systematic Evaluation of Pharmacokinetic Models for Model-Informed Precision Dosing of Meropenem in Critically Ill Patients Undergoing Continuous Renal Replacement Therapy

“…Only the model by Burger et al 2018 ( 24 ) included total flow rate as a structural covariate on clearance. Further covariates for clearance were described by either residual diuresis in two models (O’Jeanson et al [ 8 ] and Ulldemolins et al [ 25 ]) or eGFR in two models (Niibe et al 2022 [ 26 ] and Hanberg et al [ 27 ]). Nevertheless, most models ( n = 6) included only one significant covariate.…”

“…S7 and S9, Table S8). The models by Shekar et al 2014 ( 28 ), Burger et al 2018 ( 24 ), Grensemann et al 2020 ( 29 ), and Niibe et al 2020 ( 26 ) showed no bias in the goodness-of-fit (GOF) plots ( Fig. 1 ) and an accuracy and precision of MPE |20%| and MAPE of <35%, respectively, whereas the models by Onichimowski et al 2020 ( 30 ) and Hanberg et al 2018 ( 27 ) showed a strong visual bias in the GOF plots, a MAPE of >90% and a misfit in the pcVPCs ( Fig.…”

“…The models by Shekar et al 2014 ( 28 ), Grensemann et al 2020 ( 29 ), Niibe et al 2020 ( 26 ), and Burger et al 2018 ( 24 ) showed almost acceptable model performance. In contrast to physiological considerations, most previously published models did not identify the type of CRRT or CRRT intensity in terms of flow rate as a significant covariate.…”

“…Although the well-predicting models differed in structure and included covariates, the parameter values for the clearance with the median patients characteristics for covariates of our data set were comparable (Burger et al 2018 [ 24 ]: 4.7 L/h [with median total flow rate of 2,000 mL/h], Grensemann et al 2020 [ 29 ]: 5.06 L/h, O’Jeanson et al 2021 [ 8 ]: 5.78 L/h [with no residual diuresis], Shekar et al 2014 [ 28 ]: 5.1 L/h, Niibe et al 2020 [ 26 ]: 4.4 L/h [with median eGFR (Cockcroft-Gault) of 31 mL/min/1.73 m 2 ]. However, the models with a clear bias either overestimated or underestimated the clearance in our data set (Onichimowski et al 2020 [ 30 ]: 15 L/h, Hanberg et al 2018 [ 27 ]: 1.9 L/h [with median eGFR (CKD-EPI) of 41 mL/min], respectively).…”