Potential Contributing Factors for Supratherapeutic and Subtherapeutic Voriconazole Trough Concentrations

Background Therapeutic drug monitoring (TDM) is recommended by measurement of blood trough concentrations (Cmin) for optimizing voriconazole (VRZ) therapy. This study aims to investigate and compare potential factors associated with supratherapeutic and subtherapeutic VRZ trough levels under steady‐state conditions. Methods We retrospectively analyzed the clinical data of patients aged ≥ 13 years who were hospitalized and received VRZ treatment from January 2022 to December 2024. Contributing factors for VRZ Cmin ≥ 5.5 mg/L and VRZ Cmin ≤ 1.0 mg/L were identified by binary logistic regression analysis. The diagnostic performances of the final models were assessed using receiver operating characteristic (ROC) curves. Values of the identified independent variables were stratified, and the proportions of supratherapeutic and subtherapeutic VRZ trough concentrations were analyzed. Results Significant factors associated with VRZ Cmin ≥ 5.5 mg/L included older age (OR 1.026 per year; p < 0.001), higher daily VRZ dose (OR 1.250 per 50 mg; p = 0.001), and elevated C‐reactive protein (CRP) (OR 1.503 per 50 mg/L; p < 0.001). For VRZ Cmin ≤ 1.0 mg/L, significant contributors were younger age (OR 0.959 per year; p < 0.001), lower daily VRZ dose (OR 0.620 per 50 mg; p < 0.001), decreased CRP (OR 0.540 per 50 mg/L; p = 0.015), and nasogastric administration (OR 4.807; p = 0.001). The areas under the ROC curves for predicting VRZ Cmin ≥ 5.5 and ≤ 1.0 mg/L were 0.722 (95% CI 0.673–0.770) and 0.823 (95% CI 0.749–0.898), respectively. Nonlinear patterns were observed in the incidences of supratherapeutic VRZ trough concentrations across the entire ranges of the variables, with proportions changing sharply at specific threshold levels. Conclusions Our analysis identified age, daily VRZ dose, and CRP as common contributors to both supratherapeutic and subtherapeutic VRZ trough concentrations; meanwhile, the nasogastric administration route was found to have an independent association with subtherapeutic VRZ trough levels, suggesting that the contributing factors for these two types of off‐target concentrations may not be identical. The findings may facilitate targeted interventions to maintain therapeutic concentrations, thereby potentially preventing suboptimal treatment outcomes or adverse events.