Compartmental pharmacokinetics of the antifungal echinocandin caspofungin (MK-0991) in rabbits

Antimicrob Agents Chemother. 2001 Feb;45(2):596-600. doi: 10.1128/AAC.45.2.596-600.2001.

Abstract

The pharmacokinetics of the antifungal echinocandin-lipopeptide caspofungin (MK-0991) in plasma were studied in groups of three healthy rabbits after single and multiple daily intravenous administration of doses of 1, 3, and 6 mg/kg of body weight. Concentrations were measured by a validated high-performance liquid chromatography method and fitted into a three-compartment open pharmacokinetic model. Across the investigated dosage range, caspofungin displayed dose-independent pharmacokinetics. Following administration over 7 days, the mean peak concentration in plasma (C(max)) +/- standard error of the mean increased from 16.01 +/- 0.61 microg/ml at the 1-mg/kg dose to 105.52 +/- 8.92 microg/ml at the 6-mg/kg dose; the mean area under the curve from 0 h to infinity rose from 13.15 +/- 2.37 to 158.43 +/- 15.58 microg. h/ml, respectively. The mean apparent volume of distribution at steady state (Vd(ss)) was 0.299 +/- 0.011 liter/kg at the 1-mg/kg dose and 0.351 +/- 0.016 liter/kg at the 6-mg/kg dose (not significant [NS]). Clearance (CL) ranged from 0.086 +/- 0.017 liter/kg/h at the 1-mg/kg dose to 0.043 +/- 0.004 liter/kg/h at the 6-mg/kg dose (NS), and the mean terminal half-life was between 30 and 34 h (NS). Except for a trend towards an increased Vd(ss), there were no significant differences in pharmacokinetic parameters in comparison to those after single-dose administration. Caspofungin was well tolerated, displayed linear pharmacokinetics that fit into a three-compartment pharmacokinetic model, and achieved sustained concentrations in plasma that were multiple times in excess of reported MICs for susceptible opportunistic fungi.

MeSH terms

  • Analysis of Variance
  • Animals
  • Anti-Bacterial Agents / administration & dosage
  • Anti-Bacterial Agents / blood
  • Anti-Bacterial Agents / pharmacokinetics*
  • Antifungal Agents / administration & dosage
  • Antifungal Agents / blood
  • Antifungal Agents / pharmacokinetics*
  • Area Under Curve
  • Caspofungin
  • Echinocandins
  • Female
  • Kidney Function Tests
  • Lipopeptides
  • Peptides*
  • Peptides, Cyclic*
  • Protein Binding
  • Rabbits

Substances

  • Anti-Bacterial Agents
  • Antifungal Agents
  • Echinocandins
  • Lipopeptides
  • Peptides
  • Peptides, Cyclic
  • Caspofungin