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Abstract

Introduction: Oral voriconazole is recommended over intravenous (IV) voriconazole in patients with CrCl < 50 ml/min to avoid accumulation of SBECD; however, poor enteral absorption in ICU patients may lead to inadequate plasma concentrations and treatment failure. The purpose of this study was to evaluate the pharmacokinetics of SBECD and IV voriconazole in ICU patients undergoing CRRT. Hypothesis: CRRT is effective at removing SBECD and allows use of IV voriconazole without concern of SBECD accumulation. Methods: Patients > 18 years of age receiving IV voriconazole therapy for treatment or prophylaxis of systemic fungal infection while undergoing CRRT were eligible. Intensive pharmacokinetic sampling for determination of SBECD and voriconazole concentrations was completed on study days 1, 3, and 5; then sparse sampling every 3-5 days thereafter. Voriconazole and SBECD plasma and effluent concentrations were measured by LC MS/MS. Results: Six patients were enrolled. Patients were (mean ± SD) 56 ± 11 years old, 67% male, 83 ± 12 kg, and had APACHE II scores of 30.5 ± 3.3. All patients received CVVH with a median predilution replacement fluid rate of 36 (IQR 32-39) ml/kg/hr and effluent rate of 38 (IQR 35-40) ml/kg/hr. Mean ± SD voriconazole and SBECD dosages administered were 7.9 ± 2.6 mg/kg/day and 126 ± 42 mg/kg/day. Mean ± SD plasma voriconazole Cmax, Cmin, Vd, t1/2, AUC0-12, total systemic clearance, and CRRT clearance were 3.6 ± 1.6 mg/L, 1.6 ± 0.8 mg/L, 2.8 ± 0.6 L/kg, 15 ± 7 hrs, 29 ± 10 mg*hr/L, 0.15 ± 0.05 L/hr/kg, and 0.03 ± 0.03 L/hr/kg, respectively. Mean ± SD plasma SBECD Cmax, Cmin, Vd, t1/2, AUC0-12, total systemic clearance, and CRRT clearance were 276 ± 154 mg/L, 55 ± 47 mg/L, 0.5 ± 0.2 L/kg, 6.6 ± 2.4 hrs, 1600 ± 1000 mg*hr/L, 0.05 ± 0.02 L/hr/kg, and 0.03 ± 0.01 L/hr/kg, respectively. Minimal increases in SBECD Cmax (255 ± 143 to 331 ± 255 mg/L; p=0.54) and Cmin (64 ± 59 to 76 ± 64 mg/L; p=0.74) were observed after study day 1. Conclusions: CVVH effectively removed SBECD at a rate similar to the effluent rate. Voriconazole clearance by CVVH was not clinically significant. Standard dosages of IV voriconazole can be utilized in patients undergoing CVVH without significant risk of SBECD accumulation.