Optimizing Vancomycin Dosing in Continuous Renal Replacement Therapy: A Systematic Review of Population Pharmacokinetic Studies in Adult Critically Ill Patients

<b>Background:</b> Vancomycin dosing during continuous renal replacement therapy (CRRT) remains challenging due to profound pharmacokinetic (PK) variability and lack of standardized guidance. Population pharmacokinetic (PopPK) models provide a quantitative framework to identify covariates affecting drug disposition and support individualized dosing. <b>Methods:</b> This systematic review, registered in PROSPERO (CRD420250655157), comprehensively identified PopPK studies evaluating vancomycin in critically ill adults undergoing CRRT. PubMed, Embase, Web of Science, and Cochrane Library were searched from inception to 28 February 2025. Eligible studies reported PopPK analyses or simulations providing PK parameters and/or dosing recommendations. Data were extracted on study characteristics, CRRT settings, PK findings, and dose optimization strategies. In addition, covariates were categorized based on whether they were merely explored or statistically confirmed within the respective PopPK models, as commonly reported in similar pharmacometrics studies. Due to the methodological nature of population pharmacokinetic model development studies, no standardized risk-of-bias tool was applied; instead, a structured descriptive methodological appraisal was performed. Results were synthesized narratively given the heterogeneity in structural models, covariate strategies, and CRRT modalities. <b>Results:</b> Twelve PopPK studies published between 2013 and 2023 met the inclusion criteria. Considerable heterogeneity was observed across study designs, CRRT modalities, and dosing strategies. Reported vancomycin clearance ranged from 0.7 to 3.0 L/h, and volume of distribution from 0.8 L/kg to >100 L. Effluent rate consistently emerged as the primary determinant of clearance, while residual diuresis, albumin concentration, and vasopressor use acted as relevant covariates. Loading doses of 25-30 mg/kg (up to 35 mg/kg at high effluent rates) and effluent-adjusted maintenance regimens achieved therapeutic AUC24/MIC targets more consistently when supported by early and repeated therapeutic drug monitoring (TDM). <b>Conclusions:</b> Vancomycin PK during CRRT is highly variable and driven by effluent intensity and patient-specific factors. Fixed regimens are inadequate; individualized dosing guided by effluent flow, renal function, and TDM is essential for optimal exposure. Prospective, multicenter PopPK studies integrating pharmacodynamic targets and clinical outcomes are warranted to refine and validate CRRT-specific dosing strategies.