Pharmacodynamics of amphotericin B deoxycholate, amphotericin B lipid complex, and liposomal amphotericin B against Aspergillus fumigatus.

Abstract

Amphotericin B is a first-line agent for the treatment of invasive aspergillosis. However, relatively little is known about the pharmacodynamics of amphotericin B for invasive pulmonary aspergillosis. We studied the pharmacokinetics (PK) and pharmacodynamics (PD) of amphotericin B deoxycholate (DAMB), amphotericin B lipid complex (ABLC), and liposomal amphotericin B (LAMB) by using a neutropenic-rabbit model of invasive pulmonary aspergillosis. The study endpoints were lung weight, infarct score, and levels of circulating galactomannan and (1 → 3)-β-D-glucan. Mathematical models were used to describe PK-PD relationships. The experimental findings were bridged to humans by Monte Carlo simulation. Each amphotericin B formulation induced a dose-dependent decline in study endpoints. Near-maximal antifungal activity was evident with DAMB at 1 mg/kg/day and ABLC and LAMB at 5 mg/kg/day. The bridging study suggested that the "average" patient receiving LAMB at 3 mg/kg/day was predicted to have complete suppression of galactomannan and (1 → 3)-β-D-glucan levels, but 20 to 30% of the patients still had a galactomannan index of >1 and (1 → 3)-β-D-glucan levels of >60 pg/ml. All formulations of amphotericin B induce a dose-dependent reduction in markers of lung injury and circulating fungus-related biomarkers. A clinical dosage of liposomal amphotericin B of 3 mg/kg/day is predicted to cause complete suppression of galactomannan and (1 → 3)-β-D-glucan levels in the majority of patients.

• Authors: Zaid Al-Nakeeb, Vidmantas Petraitis, Joanne Goodwin, Ruta Petraitiene, Thomas J Walsh, William W Hope
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 59 Issue 5 Pg. 2735-45 (May 2015) ISSN: 1098-6596 [Electronic] United States
• PMID: 25712363 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Chemical References

• Antifungal Agents
• Drug Combinations
• Deoxycholic Acid
• Amphotericin B
• amphotericin B, deoxycholate drug combination

Topics

• Amphotericin B (therapeutic use)
• Animals
• Antifungal Agents (therapeutic use)
• Aspergillus fumigatus (drug effects, pathogenicity)
• Deoxycholic Acid (therapeutic use)
• Drug Combinations
• Invasive Pulmonary Aspergillosis (drug therapy)
• Models, Theoretical
• Monte Carlo Method
• Rabbits