Population Pharmacokinetics and Clinical Application of Vancomycin in Critically Ill Adults: A NONMEM-Based Review

Abstract: Vancomycin remains an important treatment for severe Gram-positive infections in the intensive care unit (ICU), but critically ill adults show highly variable pharmacokinetics, making conventional dosing unreliable. This review aimed to summarize Nonlinear Mixed-Effects Modeling (NONMEM)-based population pharmacokinetic studies of vancomycin in critically ill adults and identify clinically relevant covariates associated with exposure variability. PubMed, Embase, and Google Scholar were searched from inception to January 2026. Twelve original studies met the inclusion criteria. All focused on adult ICU populations and used nonlinear mixed-effects modeling with NONMEM. One-compartment models were most commonly used, although parameter estimates varied substantially across populations. Typical clearance ranged from 1.19 to 5.15 L/h. Excluding volume estimates that needed to be normalized to actual body weight, reported typical values ranged from 29.2 to 107 L. Covariate analyses consistently identified renal function and body weight as important determinants of clearance, whereas continuous renal replacement therapy (CRRT)/high-volume hemofiltration (HVHF) intensity and residual renal function were particularly relevant in patients receiving extracorporeal support. Mechanical ventilation was retained as a covariate on clearance in some models. Overall, these findings highlight the marked heterogeneity of vancomycin pharmacokinetics in critical illness and support more individualized dosing strategies, ideally combining early therapeutic drug monitoring with model-informed precision dosing. Factors influencing drug clearance: demographics, pathology, treatment.The illustration shows factors influencing drug clearance and distribution volume in patients. On the left, a patient is depicted in a hospital bed connected to medical devices, including mechanical ventilation, continuous renal replacement therapy (CRRT) and high-volume hemofiltration (HVHF). Demographic factors such as weight, age and gender are highlighted. Pathological factors include multiple organ dysfunction, hemodynamic instability, renal function, hypoalbuminemia and capillary leak. On the right, patient factors affecting clearance include higher creatinine clearance and age over 65 years, which results in lower clearance. Distribution volume is influenced by higher total body weight. Treatment factors impacting clearance include higher CRRT intensity, higher residual urine volume and mechanical ventilation, which leads to lower clearance. Arrows indicate the relationship between these factors and their impact on clearance and distribution volume. Keywords: vancomycin, population pharmacokinetics, critically ill adults, NONMEM, continuous renal replacement therapy, mechanical ventilation