https://orcid.org/0000-0001-5684-2475
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Abstract
Purpose
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.
Acknowledgments
The authors would like to thank all the doctors, nurses, technicians, and patients involved in the ICU for their dedication to the study.
Abbreviations
AGE, age of the patient in years; ALT, alanine aminotransferase; APACHE II, acute physiology and chronic health evaluation II; ARC, augmented renal clearance; ARDS, acute respiratory distress syndrome; AST, aspartate aminotransferase; AUC, area under the receiver operating characteristic curve; BMI, body mass index; CI, confidence interval; CL, clearance of the central compartment; CLINTER VAR, the inter-individual variability of CL; Cmax, the peak concentration post dose; Cmin, the trough concentration; CNS, central nervous system; COV, covariates; COVave, average covariate values; CrCL, creatinine clearance; CRRT, continuous renal replacement therapy; DBIL, direct bilirubin; F, the bioavailability; GOF, goodness-of-fit; ICU, intensive care unit; IPRED, individual predicted concentrations; LNZ, linezolid; MIC, minimum inhibitory concentration; MPE, mean prediction error; MRSA, methicillin-resistant Staphylococcus aureus; NPDE, normalized prediction distribution error; OFV, objective function value; PD, pharmacodynamic; P-gp, P-glycoprotein; PK, pharmacokinetic; PLT, platelet count; PRED, population predicted concentration; PTTA, percentage of therapeutic target attainment; q12h, every 12 hour; RMSE, root mean square error; RV, residual variability; sCr (μM), serum creatinine concentration in μM; SOFA, sequential organ failure assessment; TBIL, total bilirubin; V, the distribution volume of the central compartment; VINTER VAR, the inter-individual variability of V; WT, weight; θCrCL-CL, the adjusting factor of the CrCL on the CL.
Data Sharing Statement
The datasets generated and/or analyzed during this study are not publicly accessible due to currently ongoing research studies, but the data are available from the corresponding author on reasonable request.
Ethics Approval and Consent to Participate
The protocol was approved by the Ethics Committee of Guangdong Provincial People’s Hospital, Nanfang Hospital, Guangzhou First People’s Hospital, and Guangzhou 999 Brain Hospital. Written informed consent was obtained from each patient or from suitable surrogates for patients who were unable to consent.
Consent for Publication
Not applicable. No individual personal data are included in the study. All patients provided the necessary consent to participate in the present study.
Author Contributions
All authors made substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; took part in drafting the article or revising it critically for important intellectual content; agreed to submit to the current journal; gave final approval of the version to be published; and agree to be accountable for all aspects of the work. These four authors contributed equally to this study; co-first author: Xipei Wang, Yifan Wang, Fen Yao, and Shenglong Chen.
Disclosure
The authors declare that they have no conflicts of interest for this work.