The pharmacokinetics of lipid-bound and liberated amphotericin B (AMB) was assessed in 11 critically ill patients with cholestatic liver disease (CSLD) and in 9 subjects with normal liver function treated with AMB colloidal dispersion (ABCD). Exposure to lipid-bound AMB was higher in patients with CSLD. Levels of liberated AMB were elevated by CSLD only after the first dose, whereas its pharmacokinetics was unaffected at steady state. The standard dosage of ABCD is probably adequate for patients with CSLD. Liver disease has been identified as a risk factor for invasive fungal infections (IFIs) such as invasive aspergillosis in critically ill patients (15,16). Amphotericin B (AMB) has a broad antimycotic spectrum and is therefore a cornerstone in the treatment of IFIs. Because of its renal toxicity, however, conventional AMB is frequently replaced by less toxic lipid formulations such as AMB colloidal dispersion (ABCD; Amphocil, Amphotec). ABCD contains AMB as a cholesteryl sulfate complex forming disc-like structures of 74 to 170 nm in diameter (5). AMB does not undergo hepatic metabolism, but it is eliminated in part via the bile. ABCD is rapidly taken up by liver macrophages (11,25). Clinical studies on the influence of hepatic impairment on AMB pharmacokinetics are lacking so far. Therefore, the pharmacokinetics of lipidbound (colloidal) AMB and of AMB liberated from its lipid binding was assessed under single-dose and steady-state conditions in critically ill patients with and without cholestatic liver disease (CSLD) treated with ABCD.The study was approved by the local ethics committee. Time-AMB concentration profiles were determined in critically ill patients with CSLD (defined as plasma bilirubin of Ͼ10 mg/dl due to CSLD) and in a control group comprising critically ill patients with approximately normal hepatic function (bilirubin of Ͻ1.28 mg/dl). Patients with a plasma bilirubin level between 1.28 and 10 mg/dl and patients with a plasma bilirubin level of Ͼ10 mg/dl caused by disorders other than CSLD (e.g., hemolysis) were excluded from the study. ABCD was administered for suspected or proven IFIs over 4 h at a dose of ϳ4 mg/kg of body weight. In order to avoid infusion-related toxicity, ϳ2 mg/kg was given on day 1. In all patients enrolled, conventional AMB deoxycholate was contraindicated because of its renal toxicity. Blood samples of 2 ml were taken from an arterial line on day 1 of ABCD therapy (single dose) and on day 5 or later (steady state) before ABCD administration as well as 4,6,8,12, and 24 h after the start of infusion. Lipid-bound (colloidal) AMB and AMB that had been liberated from its lipid binding in the plasma were separated by solid-phase extraction and quantified by high-performance liquid chromatography as described previously (10). The pharmacokinetics of lipid-bound, liberated, and total AMB was calculated by Kinetica 2000 (InnaPhase Corporation, Champs-sur-Marne, France) using a noncompartmental model. The area under the concentration-time curve from time zero to 24 h (AUC 0 -24...
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