Population Pharmacokinetics/Pharmacodynamics and Clinical Outcomes of Meropenem in Critically Ill Patients.

Abstract

Several pathophysiological changes can alter meropenem pharmacokinetics in critically ill patients, thereby increasing the risk of subtherapeutic concentrations and affecting therapeutic outcomes. This study aimed to characterize the population pharmacokinetic (PPK) parameters of meropenem, evaluate the relationship between the pharmacokinetic/pharmacodynamic index of meropenem and treatment outcomes, and evaluate the different dosage regimens that can achieve 40%, 75%, and 100% of the dosing interval for which the free plasma concentrations remain above the MIC of the pathogens (fT>MIC) targets. Critically ill adult patients treated with meropenem were recruited for this study. Five blood samples were collected from each patient. PPK models were developed using a nonlinear mixed-effects modeling approach, and the final model was subsequently used for Monte Carlo simulations to determine the optimal dosage regimens. A total of 247 concentrations from 52 patients were available for analysis. The two-compartment model with linear elimination adequately described the data. The mean PPK parameters were clearance (CL) of 4.8 L/h, central volume of distribution (VC) of 11.4 L, peripheral volume of distribution (VP) of 14.6 L, and intercompartment clearance of 10.5 L/h. Creatinine clearance was a significant covariate affecting CL, while serum albumin level and shock status were factors influencing VC and VP, respectively. Although 75% of the drug-resistant infection patients had fT>MIC values of >40%, approximately 83% of them did not survive the infection. Therefore, 40% fT>MIC might not be sufficient for critically ill patients, and a higher target, such as 75 to 100% fT>MIC, should be considered for optimizing therapy. A 75% fT>MIC could be reached using approved doses administered via a 3-h infusion.