Population pharmacokinetics and thrombocytopenia risk assessment of linezolid in liver transplant recipients

BACKGROUND: Linezolid is a commonly prescribed antibiotic for multidrug-resistant enterococcal infections in liver transplant recipients (LTRs). However, changes in pharmacokinetics due to fluctuations in liver and renal functions, combined with the increased risk of thrombocytopenia, complicate its clinical use. This study aimed to characterize the exposure-thrombocytopenia risk relationship of linezolid in LTRs, and to identify safe dosing thresholds to promote rational drug use. METHODS: A retrospective analysis was conducted on adult LTRs treated with linezolid at Zhongshan Hospital between January 2019 and May 2022. A population exposure-safety model was developed and used to establish a thrombocytopenia risk threshold and optimize initial dosing strategies through Monte Carlo simulations. An area under the concentration-time curve (AUC) calculator was developed to facilitate individualized dose adjustments. RESULTS: Exposure-safety analysis revealed that an AUCss,24h threshold of 291.7 mg/L·h was associated with an increased risk of thrombocytopenia. Monte Carlo simulations showed that current covariate-based initial dosing recommendations were suboptimal, highlighting the necessity of therapeutic drug monitoring (TDM) to improve outcomes in LTRs. The online AUC calculator developed in this study offers a practical tool for clinicians to implement timely dose adjustments (https://optimaldose.shinyapps.io/LinezolidAUC/). CONCLUSIONS: This study provides the first comprehensive analysis of linezolid exposure and its relationship to thrombocytopenia risk in LTRs. The findings underscore the importance of AUC-guided dosing and TDM in optimizing treatment outcomes.