Early attainment of isavuconazole target concentration using an increased loading dose in critically ill patients with extracorporeal membrane oxygenation

Abstract

Abstract Background In critically ill patients with extracorporeal membrane oxygenation (ECMO) attainment of target concentration of isavuconazole is delayed using the routine loading dose. Objectives We investigated the influence of increasing the first loading dose of isavuconazole on plasma concentrations in critically ill patients treated with ECMO. Methods Fifteen patients were included in this study, and isavuconazole concentrations were measured at several timepoints starting 2 h after the first isavuconazole dose up to 168 h. By interim analysis of isavuconazole concentrations and meticulous screening for adverse events, the first loading dose was stepwise increased from 200 to 300 mg, and finally to 400 mg. Results Seven of 15 patients (47%) received standard isavuconazole loading dosage with 200 mg as the first dose, 3/15 (20%) received 300 mg, and 5/15 (33%) received 400 mg isavuconazole as the first dose, followed by subsequent standard dosing in all patients. In patients receiving 400 mg as the first dose all isavuconazole concentrations were significantly higher at timepoints up to the first 24 h, resulting in higher proportions of isavuconazole concentrations ≥1 mg/L compared with patients with other loading dosages. In timepoints ≥24 h after isavuconazole initiation all patient groups reached comparable plasma concentrations, regardless of the first loading dose regimen. We did not observe concentrations above ≥5 mg/L or any adverse events related to isavuconazole administration. Conclusions In critically ill patients with ECMO the 400 mg loading dose of isavuconazole resulted in immediate median isavuconazole plasma concentrations ≥1 mg/L and remained constant above this threshold after the first loading dose.