Serum pharmacology of amphotericin B applied in lipid emulsions

Abstract

Application of amphotericin B in lipid emulsions (AmB/L) reduced membrane toxicity in vitro and decreased amphotericin B-associated toxic side effects in vivo when compared to that of amphotericin B applied in 5% glucose (AmB/G). Therefore, a comparative analysis of the pharmacological parameters of AmB/L and AmB/G was performed. Thirteen patients were analyzed, and nine of these patients received a subsequent treatment with AmB/G and AmB/L. In patients in both treatment groups amphotericin B showed a biphasic elimination from serum, with a prolonged terminal half-life of approximately 27 h. Patients treated with AmB/L showed significantly lower peak concentrations (44.2%; P = 0.008) and correspondingly lower area under the drug concentration-time curve (AUC) values (64.3%; P = 0.015) compared to the values for the same patients treated with AmB/G at a dose range of 0.6 to 1.5 mg/kg of body weight. The enhanced clearance of AmB/L may be due to a faster initial elimination of amphotericin B-lipid aggregates by the reticuloendothelial system. Lower peak concentrations and AUC values in serum and a correspondingly faster deposition of AmB/L in tissues may at least partly explain the lower toxicity of AmB/L. A comparative pharmacokinetic analysis with data for a single patient treated with AmB/L demonstrated that hemodialysis did not significantly affect the disposition of amphotericin B.

Amphotericin B/Emulsion Admixture Interactions: An Approach Concerning the Reduction of Amphotericin B Toxicity

“…An alternative delivery system, based on the lipid emulsions used for parenteral nutrition in clinical practice (Intralipid™ or Lipofundin™), has been shown to reduce the AmB toxicity with little compromise in efficacy 8–16…”

“…At least three reports have shown that FImix was responsible for a reduction in fever and chills in neutropenic patients,9,17,18 whereas its effectiveness in the treatment of systemic candidiasis was maintained 10. In a pharmacokinetic study, Heinemann et al14 found an important decrease in both maximum concentration of AmB in serum (Cmax) value and area under the concentration‐time curve value when FImix was used. In addition, a recent study with critically ill patients showed that FImix compared with Fungizone™ was not only effective in eradicating Candida infections but also better tolerated in that the frequency rate and severity of immediate side effects (hypotension, chills, fever, anaphylaxis, renal impairment) were diminished 13.…”

Case‐Control Study of Amphotericin B in a Triglyceride Fat Emulsion versus Conventional Amphotericin B in Patients with AIDS

“…3 7 Other authors reported lower trough concentrations compared with the conventional f~rmulation. '~~ 21 On the other hand, in an animal model of cryptococcosis investigators found a relevant increase in drug diffusion17* 299 37 and an enhanced concentration of comparable.l, 5, 9,12,13,17,19,20,[22][23][24], 2 6 2 9 , 31, [35][36][37] active drug in infected sites related to better in vivo therapeutic activity compared with conventionally administered drug. 19 In fact, effective tissue drug concentrations with parallel decrease of toxicity are expected to be of significance i n the clinical outcome of opportunistic visceral mycoses, as evaluated in laboratory and animal models.…”

Lipid-based Antifungal Agents Current Status

“…During follow-up of a patient with liver transplant failure and pulmonary aspergillosis, it was observed that peak and trough serum concentrations of amphotericin B were increased, as were pulmonary concentrations of the drug [89]. The authors hypothesized that, in absence of a normally functioning liver tissue as a component of RES, the clearance function of the liver was diminished and that the clearance by the lung began to be important.…”