Pharmacokinetics and target attainment of intravenous posaconazole in critically ill patients during extracorporeal membrane oxygenation

Background: Posaconazole is an antifungal drug used for prophylaxis and treatment of invasive fungal infections. Severe influenza has been identified as a risk factor for invasive pulmonary aspergillosis in critically ill patients. In this population, extracorporeal membrane oxygenation (ECMO) is used as rescue therapy, although little is known about the pharmacokinetics (PK) of posaconazole during ECMO. Objectives: To determine the PK and target attainment of six patients treated with IV posaconazole under ECMO and to develop a population PK model that can be used to simulate the PTA. Methods: Critically ill patients treated with posaconazole and ECMO were included in this study. Plasma samples were collected at several timepoints within one dosing interval on two occasions: an early (Day 2-3) and a late (Day 4-7) sampling day. Daily trough concentrations were measured. Results: The median (IQR) AUC0-24, CL and Vd were 34.3 (28.3-37.7) mg·h/L, 8.7 (8.0-10.6) L/h and 389 (314-740) L, if calculated with non-compartmental analysis based on the observed concentrations. All measured trough concentrations were ≥0.7 mg/L and 11/16 were ≥1 mg/L, which are the haematological thresholds for prophylaxis and treatment of invasive aspergillosis, respectively. The targeted PTA (>90%) was attained for prophylaxis but not for treatment. Conclusions: ECMO does not appear to influence posaconazole exposure compared with haematology patients. However, some trough levels were below the lower limit for treatment. An a priori dose adjustment does not appear to be necessary but drug monitoring is recommended.