Pharmacokinetics of liposomal amphotericin B (Ambisome) in critically ill patients

Abstract

The liposomal formulation of amphotericin B (AmBisome) greatly reduces the acute and chronic side effects of the parent drug. The present study describes the pharmacokinetic characteristics of AmBisome applied to 10 patients at a dose of 2.8 to 3.0 mg/kg of body weight and compares them to the pharmacokinetics observed in 6 patients treated with amphotericin B deoxycholate at the standard dose of 1.0 mg/kg. Interpatient variabilities of amphotericin B peak concentrations (C max ) and areas under concentration-time curves (AUC) were 8-to 10-fold greater for patients treated with AmBisome than for patients treated with amphotericin B deoxycholate. At the threefold greater dose of AmBisome, median C max s were 8.4-fold higher (14.4 versus 1.7 g/ml) and median AUCs exceeded those observed with amphotericin B deoxycholate by 9-fold. This was in part explained by a 5.7-fold lower volume of distribution (0.42 liters/kg) in AmBisome-treated patients. The elimination of amphotericin B from serum was biphasic for both formulations. However, the apparent half-life of elimination was twofold shorter for AmBisome (P ‫؍‬ 0.03). Neither hemodialysis nor hemofiltration had a significant impact on AmBisome pharmacokinetics as analyzed in one patient. In conclusion, the liposomal formulation of amphotericin B significantly (P ‫؍‬ 0.001) reduces the volume of drug distribution, thereby allowing for greater drug concentrations in serum. The low toxicity of AmBisome therefore cannot readily be explained by its serum pharmacokinetics.

Differential effects of amphotericin B and liposomal amphotericin B on inflammatory cells in vitro

“…1 A). It is worth noting that this concentration was 100 times higher than the maximal serum concentration (1.70 mg ml -1 ) measured in patients treated with AmB-deoxycholate and 10 times the maximal serum concentration found in patients treated with liposomal-AmB (14.4 mg ml -1 ) [16]. Consistently, LDH was retained, and only a release of about 10 % was observed when mast cells were incubated with AmB-DMSO at the concentration of 100 mg ml -1 (data not shown).…”

“…In fact, many reports claim that liposomal AmB is capable to reach higher serum concentrations in comparison to AmB-DC [16] without producing side effects as severe as those observed with AmB-DC. It is conceivable that the significantly greater C max and AUC values of L-AmB could translate into an equivalent greater antifungal activity.…”

“…Interestingly, AmB-DC released 30 % of mast cell histamine at the same of concentration (1 mg ml -1 , Fig. 2) found in serum of critically ill patients treated with AmB-DC, given intravenously at the dose of 1 mg kg -1 (1.74 mg ml -1 ) [16].…”

Mucormycosis Resulting in Gastric Perforation in a Patient with Acute Myelogenous Leukemia: Report of a Case

“…Renal toxicity and some symptoms of intolerance of conventional amphotericin B infusion can be avoided by using liposomal amphotericin B. 18,19 Our patient's recurrent postoperative intraabdominal bleeding was probably caused by a thromboembolic event resulting from remnant mucormycosis in the blood vessels. This finding suggests that the dose of amphotericin B should be determined in each individual patient according to their clinical condition.…”

Clinical consequences of resistant Candida infections in intensive care

“…In patients with end-stage renal failure or those requiring renal support, amphotericin B therapy no longer constitutes a problem. A standard dose of lipid-formulated amphotericin B has been proposed in patients treated by haemofiltration [28][29][30].…”