Population pharmacokinetics of isavuconazole in hematologic patients: implications for model-informed precision dosing

Abstract

Background: 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. Materials and method: Prospective, non-controlled study performed in adult hematologic patients receiving isa vuconazole 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 de tector. 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. Results: A one-compartment model with first-order absorption and elimination described adequately 121 isa vuconazole 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 perfor mance, supporting its use for individualized isavuconazole dosing in this population. Conclusions: BSA and serum ALB were identified as covariates influencing isavuconazole clearance in adult he matologic patients. Further studies are needed to better characterize the absorption of isavuconazole and im plications on dosage recommendations, especially for higher proposed doses.