Pharmacokinetics and Monte Carlo Simulation of Meropenem in Critically Ill Adult Patients Receiving Extracorporeal Membrane Oxygenation.

Jae Ha Lee,Hye Sook Choi,Dong-Hwan Lee,Yong Kyun Kim,Se Hun Kim,Won-Beom Jung,Kyung Ran Jun,Ji Hoon Jang,Jin Soo Kim,Woon Heo,Kyeong Min Jo,Hang-Jea Jang,Junghae Ko,Ho Young Lee,Tae-Hoon No

doi:10.3389/fphar.2021.768912

Abstract

Objectives: There have been few clinical studies of ECMO-related alterations of the PK of meropenem and conflicting results were reported. This study investigated the pharmacokinetics (PK) of meropenem in critically ill adult patients receiving extracorporeal membrane oxygenation (ECMO) and used Monte Carlo simulations to determine appropriate dosage regimens. Methods: After a single 0.5 or 1 g dose of meropenem, 7 blood samples were drawn. A population PK model was developed using nonlinear mixed-effects modeling. The probability of target attainment was evaluated using Monte Carlo simulation. The following treatment targets were evaluated: the cumulative percentage of time during which the free drug concentration exceeds the minimum inhibitory concentration of at least 40% (40% fT>MIC), 100% fT>MIC, and 100% fT>4xMIC. Results: Meropenem PK were adequately described by a two-compartment model, in which creatinine clearance and ECMO flow rate were significant covariates of total clearance and central volume of distribution, respectively. The Monte Carlo simulation predicted appropriate meropenem dosage regimens. For a patient with a creatinine clearance of 50–130 ml/min, standard regimen of 1 g q8h by i. v. infusion over 0.5 h was optimal when a MIC was 4 mg/L and a target was 40% fT>MIC. However, the standard regimen did not attain more aggressive target of 100% fT>MIC or 100% fT>4xMIC. Conclusion: The population PK model of meropenem for patients on ECMO was successfully developed with a two-compartment model. ECMO patients exhibit similar PK with patients without ECMO. If more aggressive targets than 40% fT>MIC are adopted, dose increase may be needed.

Highlights

Extracorporeal membrane oxygenation (ECMO) therapy provides life support to patients with cardiac, respiratory, or cardiopulmonary failure by adding oxygen and removing carbon dioxide (Squiers et al, 2016)
This plot shows that 176 of the 210 observed concentrations (83.8%) fell within the 80% prediction intervals, and the observed 10th, 50th, and 90th percentiles fell within the 95% confidence intervals (CIs) of the simulated 10th, 50th, and 90th percentiles. These results suggest that the final PK model appropriately describes the observed data and has acceptable predictive performance
To the best of our knowledge, this study was the largest prospective study to date: we investigated the PK/ PD index for meropenem in 30 adult patients on ECMO

Summary

Introduction

Extracorporeal membrane oxygenation (ECMO) therapy provides life support to patients with cardiac, respiratory, or cardiopulmonary failure by adding oxygen and removing carbon dioxide (Squiers et al, 2016). One of the antimicrobials typically used in ECMO patients, is a parenteral carbapenem antimicrobial agent and has a broad spectrum of antibacterial activity against Gram-positive, Gram-negative, and anaerobic pathogens. It is indicated for the treatment of complicated intra-abdominal infection, complicated skin and skin structure infections, bacterial meningitis, pneumonia, intra- and post-partum infections, and febrile neutropenia (Leroy et al, 1992; Wiseman et al, 1995; Hurst and Lamb, 2000; Lowe and Lamb, 2000; Baldwin et al, 2008; Mohr, 2008). These indicate a lack of understanding of the PK changes and the appropriate dosing strategy for meropenem in patients undergoing ECMO therapy

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