PHARMACOKINETICS OF INTRAVENOUS POSACONAZOLE IN CRITICALLY ILL PATIENTS [PublishAheadOfPrint]

To date, there is no information on the IV posaconazole pharmacokinetics in ICU patients. This prospective observational study aimed to describe the pharmacokinetics of a single dose of IV posaconazole in critically ill patients. Patients with no history of allergy to triazole antifungals and requiring systemic antifungal therapy were enrolled if aged ≥ 18 years, central venous access was available, were not pregnant, and didn't receive prior posaconazole or drugs interacting with posaconazole. A single dose of 300 mg posaconazole was administered over 90 minutes. Total plasma concentrations were measured from serial plasma samples collected over 48 h, using a validated chromatographic method. The pharmacokinetic data set was analyzed by non-compartmental methods. Eight patients (7 male) were enrolled; median (interquartile range, IQR) age 46 years (40-51), weight 68 kg (65-82) and albumin concentration 20 g/L (18-24). Median (IQR) pharmacokinetic parameter estimates were Cmax, 1,702 ng/mL (1,352-2,141); AUC_0-, 17,932 ng*h/mL (13,823 — 27, 905); CL, 16.8 L/h (11.1-21.7); and Vd, 529.1 L (352.2 — 720.6). The Vd and CL were greater than two fold and AUC_0- was 39% of values reported for heathy volunteers. The AUC_0- was only 52% of the steady-state AUC_0-24 reported for hematology patients. The median of estimated average steady-steady state concentrations was 747 ng/mL (IQR, 576 -1,163), which is within but close to the lower end of previously recommended therapeutic range of 500 to 2,500 ng/mL. In conclusion, we observed different pharmacokinetics of intravenous posaconazole in this cohort of critically ill patients compared to healthy volunteers and hematology patients.

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