Prospective study of pharmacokinetics of isavuconazole in critically ill patients undergoing continuous hemodialysis with and without acute-on-chronic liver failure.

Background: Patients with acute-on-chronic liver failure (ACLF) are highly vulnerable to invasive fungal infections often requiring renal replacement therapy (RRT). The pharmacokinetics (PK) of isavuconazole, an antifungal against Methods: This prospective observational cohort study was conducted at the University Medical Center Hamburg-Eppendorf across twelve intensive care units with 140 beds. We included critically ill adults receiving isavuconazole and continuous RRT. Patients <18 years or with extracorporeal circuits other than RRT were excluded. Plasma, ultrafiltrate, and pre-/postfilter blood samples were analyzed using high-performance liquid chromatography. Key areas of interest were the effect of ACLF and continuous RRT on isavuconazole pharmacokinetics, particularly on clearance. Population PK modeling was performed using, inter alia, the integrated dialysis pharmacometric model in NONMEM®. Probability of target attainment (PTA) for established PK/PD thresholds developed in mice (50% or 90% survival) was assessed using Monte Carlo simulations. Results: Thirteen patients were enrolled, including 4 with ACLF. A two-compartment model best described the data. Median clearance was similar between ACLF (4.2 L/h) and non-liver failure (4.8 L/h) groups (p = 0.92). Dialysis clearance was negligible (<1% of dose). The 50% efficacy target (AUC Conclusion: ACLF did not significantly alter isavuconazole clearance during RRT. However, high PK variability and frequent subtherapeutic exposures support routine therapeutic drug monitoring in critically ill patients.