Background and importance Extracorporeal membrane oxygenation (ECMO) can modify drug pharmacokinetics and pharmacodynamics. We report two cases of critically ill patients on ECMO receiving isavuconazol.

Aim and objectives Primary aim: to assess the correlation between the dose of isavuconazol administered and its plasma drug concentrations (IsaPlasmConc). Secondary aim: to analyse differences in IsaPlasm at different points in the ECMO circuit to study drug sequestration.

Material and methods Prospective study in critically ill patients treated with intravenous isavuconazol and receiving ECMO in the intensive care unit (ICU) from August to October 2021. Isavuconazol area under the curve (AUCisa) was calculated using the trapezoidal method. Blood samples were drawn from an arterial catheter and from ECMO circuit pre- and post-oxygenator at 0 (predose) and 1 hour (end of infusion), and from an arterial catheter at 2, 4, 6 and 12 hours after isavuconazol infusion.

A therapeutic goal of IsaPlasmConc 2.5–10 µg/mL was established. The analytical method used was high-pressure liquid chromatography. Differences greater than 10% on ECMO sites were considered as possible drug sequestration.

Results Both patients received a loading dose of isavuconazole 200 mg/8 hours over 48 hours. No relevant drug interactions were identified.

Patient 1: male, 61 years, 65 kg. Pulmonary aspergillosis treated with isavuconazole 200 mg/24 hours intravenously (IV). On day 4, IsaPlasmConc (arterial, pre-oxygenator and post-oxygenator) were: C0h: 1.39, 1.36 and 1.34, respectively; C1h: 2.83, 2.64 and 3.02; C2h: 2.28; C4h: 1.6; C6h: 1.61; C12h: 1.06 µg/mL. AUCisa was 36.8 µg/hour/mL. It was considered infra-therapeutic, so the isavuconazol dosage was increased to 200 mg/12 hours. On day 10, IsaPlasmConc were: C0h: 2.16, 2.17 and 2.09; C1h: 3.17, 2.99 and 2.96; C2h: 3.10; C4h: 2.67; C6h: 2.41; C12h: 2.24. AUCisa was 144.3µg/hour/mL. The patient achieved negative cultures and clinical improvement.

Patient 2: male, 65 years, 84 kg. Pulmonary aspergillosis treated with isavuconazole 200 mg/12 hours IV. On day 4, IsaPlasmConc (arterial, pre-oxygenator and post-oxygenatore) were: C0h: 2.00, 1.95 and 1.86, respectively, C1h: 3.01, 3.34 and 3.21; C2h: 3.00; C4h: 2.44; C6h: 2.34; C12h: 3.09. AUCisa was 125.2 µg/hour/mL. The patient died due to external causes.

Conclusion and relevance In our patients there was not a significant sequestration of isavuconazole in the ECMO circuit. However, patients required higher isavuconazole doses to achieve IsaPlasmConc therapeutic goals. Therapeutic drug monitoring during ECMO is appropriate to assure therapeutic efficacy and security.

Conflict of interest No conflict of interest