Pharmacokinetics of Linezolid Dose Adjustment for Creatinine Clearance in Critically Ill Patients: A Multicenter, Prospective, Open-Label, Observational Study

Abstract

The aim of this study is to use a population pharmacokinetic (PK) approach to evaluate the optimal dosing strategy for linezolid (LNZ) in critically ill patients. Methods: This multicenter, prospective, open-label, observational study was conducted in 152 patients, and 117 of them were included in the PK model, whereas the rest were in the validation group. The percentage of therapeutic target attainment (PTTA) comprising two pharmacodynamic indices and one toxicity index was used to evaluate dosing regimens based on Monte Carlo simulations stratified by low, normal, and high renal clearance for MICs of 0.25-4 mg/L. Results: A single-compartment model with a covariate creatinine clearance (CrCL) was chosen as the final model. The PK parameter estimates were clearance of 5.60 L/h, with CrCL adjustment factor of 0.386, and a distribution volume of 43.4 L. For MIC ≤2 mg/L, the standard dosing regimen (600 mg q12h) for patients with severe renal impairment (CrCL, 40 mL/min) and standard dosing or 900 mg q12h for patients with normal renal functions (CrCL, 80 mL/min) could achieve PTTA ≥74%. The dose of 2400 mg per 24-h continuous infusion was ideal for augmented renal clearance (ARC) with MIC ≤1 mg/L. For MICs >2 mg/L, rare optimal dose regimens were found regardless of renal function. Conclusion:In critically ill patients, the standard dose of 600 mg q12h was sufficient for MIC ≤2 mg/L in patients without ARC. Moreover, a 2400 mg/day 24-h continuous infusion was recommended for ARC patients.

A Review of Population Pharmacokinetic Analyses of Linezolid

“…Studies were published between 2005 and 2021, and the number of subjects ranged from 5 to 603, with a median of 44.5. Of the 32 publications, 27 were conducted in adult patients [19,34,37,53,58,[62][63][64][65][66][67][68][69][70][71][72][73][74][75][76][77][78][79][80], four in pediatric patients [81][82][83][84] and one in both populations [33]. Intravenous administration was the only route in 16 of the publications [34, 37, 62, 65, 66, 69-72, 74, 75, 79-82, 84], while both intravenous and oral formulations were included in 11 studies [18,19,33,53,63,64,67,68,77,78,85].…”

“…The basic internal validation method of goodness of fit was performed in all of the included models, while bootstrapping was used in 17 of the studies [33, 53, 64, 67, 70, 71, 73-75, 77-79, 81, 82, 84-86]. The vast majority also included advanced internal validation methods, such as visual predictive check or prediction-corrected visual predictive check [18, 19, 33, 34, 37, 53, 58, 63, 68-74, 76, 77, 79, 81-86], normalized prediction distribution errors [18,34,72,81], or case-deletion diagnostics [67]. In two studies, an external validation was also performed [71,72].…”

“…The vast majority also included advanced internal validation methods, such as visual predictive check or prediction-corrected visual predictive check [18, 19, 33, 34, 37, 53, 58, 63, 68-74, 76, 77, 79, 81-86], normalized prediction distribution errors [18,34,72,81], or case-deletion diagnostics [67]. In two studies, an external validation was also performed [71,72].…”

Plasma and Intrapulmonary Pharmacokinetics, and Dosage Regimen Optimization of Linezolid for Treatment of Gram-Positive Cocci Infections in Patients with Pulmonary Infection After Cerebral Hemorrhage

“…The volume of distribution (73.94 L) was higher in healthy volunteers than that in patients who were critically ill or had liver dysfunction (58.3 L to 36.5 L) ( Table 2 ). 26 , 29–31 These differences may be related to disease status in cerebral hemorrhage acute renal failure and the differences of combined drugs, 32 which highlighted the need to characterize pharmacokinetics in this population.…”

Augmented Renal Clearance: What Have We Known and What Will We Do?

“…The issue is that dosage regimens of ARC patients proposed by pharmacokinetic simulation software are always higher than empirical doses to achieve PK/PD targets ( Mahmoud and Shen, 2017 ; Abdalla et al, 2020 ; Wang et al, 2021 ), which might be viewed with caution and have hardly been promoted in clinical practice.…”