Pharmacokinetics of Isavuconazole in Critically Ill Patients Receiving Extracorporeal Membrane Oxygenation (ECMO)...

Background: Isavuconazole, a broad-spectrum triazole antifungal, exhibits high lipophilicity and extensive plasma protein binding, properties that may predispose it to sequestration within extracorporeal membrane oxygenation (ECMO) circuits. This study aimed to characterize the pharmacokinetics (PK) of isavuconazole and to evaluate drug sequestration within the ECMO circuit in critically ill patients receiving ECMO support. Methods: We conducted a prospective, exploratory, single-center observational study including critically ill patients receiving ECMO (veno-venous (VV) or veno-arterial (VA)) and treated with intravenous isavuconazole. Serial blood samples were collected simultaneously from the patient's arterial line and from pre- and post-membrane oxygenator sampling sites. Non-compartmental analysis was performed on arterial line samples to estimate PK measures, and concentration differences across sampling sites were analyzed to estimate circuit-related drug loss. PK/pharmacodynamic (PD) target attainment was assessed using established efficacy thresholds (AUC_0-24/MIC ≥ 25 and Cmin > 2 mg/L). Results: A total of 41 plasma samples from 3 critically ill patients (2 VV-ECMO, 1 VA-ECMO) were included in the analysis. Limited, component-specific isavuconazole loss was observed in tubing and connectors (6.62% ± 20.8%, p = 0.294) and across the entire ECMO circuit (7.74% ± 20.2%, p = 0.211). Likewise, no relevant concentration difference was detected across the membrane oxygenator (0.849% ± 6.15%, p = 0.642). Interindividual variability was observed across PK parameters, particularly in measures of elimination and distribution. All patients achieved predefined PK/PD efficacy targets, with mean Cmin and AUC_0-24/MIC of 3.07 ± 0.261 mg/L and 85.3 ± 4.03, respectively, and none exceeded the established toxicity threshold. Conclusions: Preliminary results showed variable concentration differences across ECMO sampling sites, with no consistent pattern of isavuconazole loss across the ECMO circuit under the conditions evaluated. All patients achieved predefined PK/PD efficacy targets using currently recommended dosing regimens; however, interindividual PK variability was observed, supporting the potential value of therapeutic drug monitoring (TDM) to guide individualized dosing decisions in this population. Larger population PK studies are warranted to further characterize determinants of isavuconazole exposure during ECMO support and refine evidence-based dosing strategies.