Population pharmacokinetics/pharmacodynamics of linezolid in sepsis patients with and without continuous renal replacement therapy

Ide, Takeshi; Takesue, Yoshio; Ikawa, Kazuro; Morikawa, Norifumi; Ueda, Takashi; Takahashi, Yoshiko; Nakajima, Kazuhiko; Takeda, Kazuyuki; Nishi, Shinichi

doi:10.1016/j.ijantimicag.2018.01.021

Cited by 35 publications

(53 citation statements)

References 36 publications

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“…In our study, Clcr was calculated based on creatinine measured in urine, and when it was included as covariate in the model, the IIV of the total clearance decreased from 97.8% to 61.5%. The overall high variability found among patients was consistent with other population PK models performed in critically ill patients, such as that described by Taubert et al [13] or by Ide et al [14].…”

Section: Discussionsupporting

confidence: 90%

“…In this study, we developed a population pharmacokinetic model for linezolid in critically ill patients. Data were best supported by a two-compartment model, in accordance with previously published manuscripts [13,14]. The volume of distribution (45.2 L), which approximated the total body water, was similar to values obtained in other studies in critically ill patients [13,14], and it did not differ from patients with or without CRRT.…”

Section: Discussionsupporting

confidence: 87%

“…Data were best supported by a two-compartment model, in accordance with previously published manuscripts [13,14]. The volume of distribution (45.2 L), which approximated the total body water, was similar to values obtained in other studies in critically ill patients [13,14], and it did not differ from patients with or without CRRT. Moreover, the volume of distribution was similar to that described by Slatter et al [15] and by MacGowan et al [16] in healthy volunteers.…”

Section: Discussionsupporting

confidence: 87%

“…The inclusion of this covariate in the PK model is controversial. Thus, while some authors found a correlation between Clcr and total clearance [14,17], others concluded that no strong relationship could be demonstrated [13,18]. The poor correlation might be attributable to the use of the Cockcroft-Gault equation to calculate Clcr, which is not accurate enough for critically ill patients [19].…”

Section: Discussionmentioning

confidence: 99%

“…However, our study was useful to detect the limitation of the standard dose of linezolid to achieve the PK/PD targets for the clinical breakpoints and to show the advantage of the continuous infusion. In fact, adjustment of linezolid dosing in critically ill patients has been suggested, since recent studies have shown a substantial percentage of subtherapeutic levels [5][6][7]14]. Empirical therapy should cover the clinical breakpoints: in the case of linezolid 2 mg/mL for enterococci (according the Clinical and Laboratory Standard Institute (CLSI) [28]) and 4 mg/L for staphylococci and enterococci (according to the European Committee on Antimicrobial Susceptibility Testing (EUCAST) [29].…”

Section: Discussionmentioning

confidence: 99%

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Novel Population Pharmacokinetic Model for Linezolid in Critically Ill Patients and Evaluation of the Adequacy of the Current Dosing Recommendation

et al. 2020

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Antimicrobial treatment in critically ill patients remains challenging. The aim of this study was to develop a population pharmacokinetic model for linezolid in critically ill patients and to evaluate the adequacy of current dosing recommendation (600 mg/12 h). Forty inpatients were included, 23 of whom were subjected to continuous renal replacement therapies (CRRT). Blood and effluent samples were drawn after linezolid administration at defined time points, and linezolid levels were measured. A population pharmacokinetic model was developed, using NONMEM 7.3. The percentage of patients that achieved the pharmacokinetic/pharmacodynamic (PK/PD) targets was calculated (AUC24/MIC > 80 and 100% T>MIC). A two-compartment model best described the pharmacokinetics of linezolid. Elimination was conditioned by the creatinine clearance and by the extra-corporeal clearance if the patient was subjected to CRRT. For most patients, the standard dose of linezolid did not cover infections caused by pathogens with MIC ≥ 2 mg/L. Continuous infusion may be an alternative, especially when renal function is preserved.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionsupporting

confidence: 87%

Section: Discussionsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Novel Population Pharmacokinetic Model for Linezolid in Critically Ill Patients and Evaluation of the Adequacy of the Current Dosing Recommendation

et al. 2020

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Population pharmacokinetics and dosage optimization of linezolid in Chinese older patients

Li,

Fang,

et al. 2024

Eur J Clin Pharmacol

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Purpose The objective of this study was to assessed the pharmacokinetics and pharmacodynamics of linezolid in a retrospective cohort of hospitalized Chinese older patients.Methods Patients >60 years of age, who received intravenous linezolid 600 mg, were included. A population pharmacokinetics (PPK) model was established using nonlinear mixed-effects modeling. The predictive performance of the nal model was assessed using goodness-of-t plots, bootstrap analyses, and visual predictive checks. Monte Carlo simulations were used to evaluate the achievement of a pharmacodynamics target for the area under the serum concentration-time curve/minimum inhibitory concentration (AUC 0-24 /MIC).Results A total of 210 samples were collected from 120 older patients. A one-compartment PPK model with linear elimination was found to best predict the linezolid plasma concentrations. Linezolid clearance (CL) was 4.22 L h -1 and the volume of distribution (V d ) was 45.80 L along with serum uric acid (SUA) as a signi cant covariate of CL. ConclusionBased on the study results, we concluded that the standard dose was associated with a risk of overexposure in older patients, particularly those with high SUA values; these patients would bene t from a lower dose (300 mg every 12 h). This study would help in the therapeutic drug monitoring of linezolid in older patients in the future.

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A Review of Population Pharmacokinetic Analyses of Linezolid

et al. 2022

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In recent years, many studies on population pharmacokinetics of linezolid have been conducted. This comprehensive review aimed to summarize population pharmacokinetic models of linezolid, by focusing on dosage optimization to maximize the probability of attaining a certain pharmacokinetic-pharmacodynamic parameter in special populations. We searched the PubMed and EMBASE databases for population pharmacokinetic analyses of linezolid using a parametric non-linear mixed-effect approach, including both observational and prospective trials. Of the 32 studies, 26 were performed in adults, four in children, and one in both adults and children. High between-subject variability was determined in the majority of the models, which was in line with the variability of linezolid concentrations previously detected in observational studies. Some studies found that patients with renal impairment, hepatic failure, advanced age, or low body weight had higher exposure and adverse reactions rates. In contrast, lower concentrations and therapeutic failure were associated with obese patients, young patients, and patients who had undergone renal replacement techniques. In critically ill patients, the inter-individual and intra-individual variability was even greater, suggesting that this population is at an even higher risk of underexposure and overexposure. Therapeutic drug monitoring may be warranted in a large proportion of patients given that the Monte Carlo simulations demonstrated that the one-size-fits-all labeled dosing of 600 mg every 12 h could lead to toxicity or therapeutic failure for high values of the minimum inhibitory concentration of the target pathogen. Further research on covariates, including renal function, hepatic function, and drug-drug interactions related to P-glycoprotein could help to explain variability and improve linezolid dosing regimens.

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Population pharmacokinetics/pharmacodynamics of linezolid in sepsis patients with and without continuous renal replacement therapy

Cited by 35 publications

References 36 publications

Novel Population Pharmacokinetic Model for Linezolid in Critically Ill Patients and Evaluation of the Adequacy of the Current Dosing Recommendation

Novel Population Pharmacokinetic Model for Linezolid in Critically Ill Patients and Evaluation of the Adequacy of the Current Dosing Recommendation

Population pharmacokinetics and dosage optimization of linezolid in Chinese older patients

A Review of Population Pharmacokinetic Analyses of Linezolid

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