OBJECTIVES: A number of population pharmacokinetic (popPK) models of imipenem in critically ill patients are available for dosing optimization, but they represent only a narrow range of kidney functions. This study evaluates the target attainment of on-label regimens through popPK modelling and simulation in patients across different kidney functions. METHODS: A popPK model was built based on two datasets from Switzerland (model development population, 151 patients, 322 concentrations) and externally validated on two datasets from the Czech Republic (19 patients, 111 concentrations) and Vietnam (43 patients, 85 concentrations). Monte Carlo simulations were performed to evaluate the probability of target attainment from a MIC of 0.125 mg/L to 32 mg/L. We estimated the cumulative fraction of response against Pseudomonas aeruginosa (the epidemiological cut-off value was 4 mg/L) across a broad range of Cockcroft-Gault creatinine clearance values (CLCRCG 15-130 mL/min). Targets of 40% and 100%ƒT > MIC (percentage of dosing interval estimated free concentrations above MIC) were investigated. RESULTS: Decreased kidney function estimated glomerular filtration rate by the Chronic Kidney Disease Epidemiology Collaboration 2021 (eGFRCKD-EPI <90 mL/min) was observed in 70 of 151 patients (46.4%) within the model development population, and in 11 of 19 (57.9%) and 24 of 43 (55.8%) patients in the Czech Republic and Vietnam, respectively. CLCRCG significantly influenced the imipenem clearance described by a two-compartment model. For probability of target attainment, all regimens achieved 40% ƒT > MIC2mg/L. With a 100%ƒT > MIC target, 500 mg q6h (CLCRCG 30-60 mL/min) could only cover an MIC of up to 1 mg/L, irrespective of infusion time. For cumulative fraction of response, no dosing regimen could cover susceptible P. aeruginosa for 100%ƒT > MIC. DISCUSSION: The highest on-label imipenem dosing regimens failed to attain 100% ƒT > MIC4mg/L in patients with decreased kidney function. Higher dosing may be necessary to cover MIC of 4 mg/L. Future trials should explore their efficacy, toxicity, and the utility of model-informed precision dosing in this population.

2nd Faculty of Medicine Charles University Prague Czech Republic

Department of Hospital Pharmacy Erasmus University Medical Center Rotterdam The Netherlands; Rotterdam Clinical Pharmacometrics Group Rotterdam The Netherlands

Department of Hospital Pharmacy Erasmus University Medical Center Rotterdam The Netherlands; Rotterdam Clinical Pharmacometrics Group Rotterdam The Netherlands; National Drug Information and Adverse Drug Reaction Monitoring Centre Hanoi University of Pharmacy Hanoi Vietnam

Division of General Internal Medicine Geneva University Hospitals Geneva Switzerland; Clinical Pharmacology and Toxicology Service Anesthesiology Pharmacology and Intensive Care Department Geneva University Hospitals Geneva Switzerland

Division of Infectious Diseases Geneva University Hospitals Faculty of Medicine Geneva Switzerland

Intensive Care Unit Bach Mai Hospital Hanoi Vietnam

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