From AUC/MIC to AUCss and Cmin: Optimizing Micafungin Therapy in the Critically Ill through Model-Informed Precision...

Micafungin is an important echinocandin for invasive fungal infections, but its pharmacokinetics (PK) in critically ill patients is highly variable. This study aimed to characterize micafungin population PK in intensive care unit (ICU) patients, identify clinical covariates influencing exposure, and evaluate practical PK/pharmacodynamic (PD) indices, steady-state area under the curve (AUCss) and trough concentration (Cmin), as alternatives to the traditional AUC/minimum inhibitory concentration (MIC) ratio for therapeutic drug monitoring (TDM). Sixty critically ill adults received 100 mg/day intravenous micafungin, with rich PK sampling on Days 0, 4, and 14. Data were analyzed using a two-compartment model with first-order elimination in Monolix, and covariates were identified via forward-backward stepwise selection. The typical clearance was 1.56 L/h with high interindividual variability (coefficient of variation 59.9%), and total bilirubin was a significant predictor of clearance. Among 30 evaluable patients, the AUC/MIC ratio was a poor predictor of microbiological eradication (receiver operating characteristic [ROC] AUC = 0.579), whereas AUCss (ROC AUC = 0.656) and Cmin (ROC AUC = 0.641) demonstrated better performance. Time-to-event analysis showed that achieving AUCss > 90.15 mg·h/L (p = 0.045) or Cmin > 1.22 mg/L (p = 0.036) was significantly associated with faster eradication. In this heterogeneous ICU cohort, AUCss and Cmin were associated with microbiological outcomes and may offer pragmatic, MIC-independent monitoring metrics. These exploratory findings warrant prospective validation but incorporating simplified, exposure-guided dosing strategies may improve micafungin optimization and clinical outcomes in critically ill populations.