Inadequate imipenem dosing in patients with decreased kidney function: a global clinical pharmacokinetic study

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216208%3A11130%2F25%3A10498776" target="_blank" >RIV/00216208:11130/25:10498776 - isvavai.cz</a>

Výsledek na webu

<a href="https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=DvQqlz.co7" target="_blank" >https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=DvQqlz.co7</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.cmi.2025.05.005" target="_blank" >10.1016/j.cmi.2025.05.005</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Inadequate imipenem dosing in patients with decreased kidney function: a global clinical pharmacokinetic study

Popis výsledku v původním jazyce

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 (CL(CRCG) 15-130 mL/min). Targets of 40% and 100%ƒT &gt; 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 (eGFR(CKD-EPI) &lt;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. CL(CRCG) significantly influenced the imipenem clearance described by a two-compartment model. For probability of target attainment, all regimens achieved 40% ƒT &gt; MIC(2mg/L). With a 100%ƒT &gt; MIC target, 500 mg q6h (CL(CRCG) 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 &gt; MIC. DISCUSSION: The highest on-label imipenem dosing regimens failed to attain 100% ƒT &gt; MIC(4mg/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.

Název v anglickém jazyce

Inadequate imipenem dosing in patients with decreased kidney function: a global clinical pharmacokinetic study

Popis výsledku anglicky

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 (CL(CRCG) 15-130 mL/min). Targets of 40% and 100%ƒT &gt; 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 (eGFR(CKD-EPI) &lt;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. CL(CRCG) significantly influenced the imipenem clearance described by a two-compartment model. For probability of target attainment, all regimens achieved 40% ƒT &gt; MIC(2mg/L). With a 100%ƒT &gt; MIC target, 500 mg q6h (CL(CRCG) 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 &gt; MIC. DISCUSSION: The highest on-label imipenem dosing regimens failed to attain 100% ƒT &gt; MIC(4mg/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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30104 - Pharmacology and pharmacy

Projekt

—

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2025

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Clinical Microbiology and Infection

ISSN

1198-743X

e-ISSN

1469-0691

Svazek periodika

31

Číslo periodika v rámci svazku

9

Stát vydavatele periodika

GB - Spojené království Velké Británie a Severního Irska

Počet stran výsledku

8

Strana od-do

1518-1525

Kód UT WoS článku

001603145900017

EID výsledku v databázi Scopus

2-s2.0-105007849859