Efficacy, plasma pharmacokinetics, and safety of icofungipen, an inhibitor of Candida isoleucyl-tRNA synthetase, in treatment of experimental disseminated candidiasis in persistently neutropenic rabbits. Academic Article uri icon

Overview

MeSH

  • Animals
  • Culture Media
  • Female
  • Immunosuppression
  • Kidney
  • Liver
  • Rabbits
  • Spleen

MeSH Major

  • Antifungal Agents
  • Candida albicans
  • Candidiasis
  • Cycloleucine
  • Isoleucine-tRNA Ligase
  • Neutropenia

abstract

  • Icofungipen (formerly PLD-118) is a synthetic derivative of the naturally occurring beta-amino acid cispentacin that blocks isoleucyl-tRNA synthetase, resulting in the inhibition of protein synthesis and growth of fungal cells. We investigated the efficacy, plasma pharmacokinetics, and safety of icofungipen in escalating dosages for the treatment of experimental subacute disseminated candidiasis in persistently neutropenic rabbits. Icofungipen was administered for 10 days starting 24 h after the intravenous inoculation of 10(3) Candida albicans blastoconidia. Study groups consisted of rabbits treated with icofungipen at 4 (ICO-4), 10 (ICO-10), and 25 (ICO-25) mg/kg of body weight/day in two divided dosages, rabbits treated with fluconazole at 10 mg/kg/day, rabbits treated with amphotericin B at 1 mg/kg/day, and untreated controls. Levels of icofungipen in plasma were derivatized by phthaldialdehyde and quantified by high-performance liquid chromatography with fluorescence detection. Rabbits treated with ICO-10 (P < 0.01) and ICO-25 (P < 0.001) showed significant dosage-dependent tissue clearance of C. albicans from the liver, spleen, kidney, brain, vitreous, vena cava, and lung in comparison to untreated controls. ICO-25 cleared C. albicans from all tissues and had activity comparable to that of amphotericin B versus untreated controls (P < 0.001). Pharmacokinetics of icofungipen in plasma approximated a dose-dependent relationship of the maximum concentration of drug in serum and the area under the concentration-time curve. There was no significant elevation of the levels of hepatic transaminases, alkaline phosphatase, bilirubin, urea nitrogen, or creatinine in icofungipen-treated rabbits. Icofungipen followed dose-dependent pharmacokinetics and was effective in the treatment of experimental disseminated candidiasis, including central nervous system infection, in persistently neutropenic rabbits.

publication date

  • May 2005

has subject area

  • Animals
  • Antifungal Agents
  • Candida albicans
  • Candidiasis
  • Culture Media
  • Cycloleucine
  • Female
  • Immunosuppression
  • Isoleucine-tRNA Ligase
  • Kidney
  • Liver
  • Neutropenia
  • Rabbits
  • Spleen

Research

keywords

  • Journal Article

Identity

Language

  • eng

PubMed Central ID

  • PMC1087633

Digital Object Identifier (DOI)

  • 10.1128/AAC.49.5.2084-2092.2005

PubMed ID

  • 15855534

Additional Document Info

start page

  • 2084

end page

  • 2092

volume

  • 49

number

  • 5