Background: Therapeutic drug monitoring (TDM) of voriconazole is recommended for personalizing doses. The objective of this study was to compare the enzyme immunoassay developed by ARK ^TM Diagnostics Inc. for the quantification of voriconazole adapted to the Architect C4000 autoanalyzer (Abbott®) with ultra-performance liquid chromatography using ultraviolet detector (UPLC-UV) method. Materials and Methods: Linearity, precision and accuracy of both methods were validated according to the Food and Drug Administration (FDA) and European Medicines Agency guidelines. The limit of quantification (LOQ) of the UPLC-UV method was determined experimentally. Both methods were applied to the analysis of 62 samples from patients. Correlation was evaluated by Passing-Bablok analysis and the concordance by the Bland–Altman method. Dosage recommendations were generated; the discordances according to the technique were evaluated. Results: All validation parameters determined for UPLC-UV met the criteria set out and LOQ of 0.1 μg/mL was established. However, when the enzyme immunoassay was used to determine concentrations ≤1 μg/ml, CVs were >20%. A linear correlation between both methods was found. However, an overestimation of immunoassay (systematic error of 0.39 μg/mL) was detected. In 11.3% of the samples, the differences in concentrations when they were determined by different techniques would imply a different therapeutic regime. These samples had concentrations close to 1 μg/mL. Conclusion: Although both techniques can be used for TDM of voriconazole, when a value close to the lower limit of the therapeutic range is determined by the ARK ^TM immunoassay, it would be better to verify the result by a non-automated technique to avoid possible underdosing.

Therapeutic drug monitoring (TDM) is routinely recommended for most antifungal triazoles to ensure efficacy and safety. Isavuconazole, however, was initially approved without this recommendation due to its predictable pharmacokinetic profile. Later clinical data have raised concerns about subtherapeutic exposures in certain populations. This prospective, single-center study aimed to assess the need for TDM of isavuconazole in critically ill and hematologic patients with invasive fungal infections. Between March 2022 and November 2023, patients receiving standard dosing of isavuconazole were enrolled, and plasma concentrations were measured to determine the proportion of patients with values outside the therapeutic range (1–4 µg/mL), particularly focusing on subtherapeutic levels. A total of 65 isavuconazole plasma concentrations from 24 patients (9 critically ill and 15 hematologic) were analyzed. Critically ill patients had lower initial concentrations than hematologic patients (median [range]: 0.75 [not detectable (ND)–5.18] vs. 3.03 [1.03–6.65] µg/mL), with 66.7% showing levels outside the therapeutic range and 55.5% having subtherapeutic concentrations. The coefficient of variation (CV%) of concentrations values at the first TDM was 124.7% in critically ill patients and 57.3% in hematologic patients. After dose adjustment in critically ill patients, the proportion with levels outside the therapeutic range decreased to 28.6%. These findings suggest that, despite initial assumptions, isavuconazole exhibits considerable pharmacokinetic variability in specific populations, particularly in critically ill patients, and the findings support the implementation of TDM to optimize antifungal therapy and improve patient outcomes in real-world clinical settings.

Isavuconazole is a broad-spectrum antifungal agent used for treating invasive fungal infections (IFIs). Its pharmacokinetics may be impacted in hematologic patients due to concomitant clinical and therapeutic factors potentially affecting drug exposure. The aim of this study was to develop a population pharmacokinetic (popPK) model of isavuconazole in adult hematologic patients to support model-informed precision dosing. Prospective, non-controlled study performed in adult hematologic patients receiving isavuconazole for IFIs and followed up by a therapeutic drug monitoring (TDM) program. Isavuconazole plasma concentrations were quantified using an ultra-high-performance liquid chromatography (UPLC) with UV detector. A popPK model was developed using NONMEM v.7.5.0. Simulations were based on the final model to evaluate the differences across physiological variables with impact on drug exposure. A one-compartment model with first-order absorption and elimination described adequately 121 isavuconazole concentrations from 52 patients. Body surface area (BSA) and serum albumin (ALB) significantly influenced drug clearance. The final popPK model showed good precision, robustness, and predictive performance, supporting its use for individualized isavuconazole dosing in this population. BSA and serum ALB were identified as covariates influencing isavuconazole clearance in adult hematologic patients. Further studies are needed to better characterize the absorption of isavuconazole and implications on dosage recommendations, especially for higher proposed doses.