title: 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.affiliation: Antimicrobial Pharmacodynamics and Therapeutics, Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Zaid
authors.initials: Z
authors.lastname: Al-Nakeeb
authors.affiliation: Transplantation-Oncology Infectious Diseases Program, Division of Infectious Diseases, Department of Medicine, Weill Cornell Medical College of Cornell University, New York, New York, USA.
authors.forename: Vidmantas
authors.initials: V
authors.lastname: Petraitis
authors.affiliation: Antimicrobial Pharmacodynamics and Therapeutics, Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Joanne
authors.initials: J
authors.lastname: Goodwin
authors.affiliation: Transplantation-Oncology Infectious Diseases Program, Division of Infectious Diseases, Department of Medicine, Weill Cornell Medical College of Cornell University, New York, New York, USA.
authors.forename: Ruta
authors.initials: R
authors.lastname: Petraitiene
authors.affiliation: Transplantation-Oncology Infectious Diseases Program, Division of Infectious Diseases, Department of Medicine, Weill Cornell Medical College of Cornell University, New York, New York, USA Departments of Pediatrics and Microbiology & Immunology, Weill Cornell Medical College of Cornell University, New York, New York, USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Walsh
authors.affiliation: Antimicrobial Pharmacodynamics and Therapeutics, Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, United Kingdom william.hope@liverpool.ac.uk.
authors.forename: William W
authors.initials: WW
authors.lastname: Hope
mesh_terms: D000666:Amphotericin B / Q000627:therapeutic use*; D000818:Animals; D000935:Antifungal Agents / Q000627:therapeutic use*; D001232:Aspergillus fumigatus / Q000187:drug effects* / Q000472:pathogenicity*; D003840:Deoxycholic Acid / Q000627:therapeutic use*; D004338:Drug Combinations; D055744:Invasive Pulmonary Aspergillosis / Q000188:drug therapy*; D008962:Models, Theoretical; D009010:Monte Carlo Method; D011817:Rabbits
chemical_list: D000935:Antifungal Agents; D004338:Drug Combinations; D003840:Deoxycholic Acid; D000666:Amphotericin B; C059765:amphotericin B, deoxycholate drug combination