Compartmental pharmacokinetics of the antifungal echinocandin caspofungin (MK-0991) in rabbits.
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.
Groll
A H
AH
Immunocompromised Host Section, Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Gullick
B M
BM
Petraitiene
R
R
Petraitis
V
V
Candelario
M
M
Piscitelli
S C
SC
Walsh
T J
TJ
D000704:Analysis of Variance; D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D000935:Antifungal Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D000077336:Caspofungin; D054714:Echinocandins; D005260:Female; D007677:Kidney Function Tests; D055666:Lipopeptides; D010455:Peptides; D010456:Peptides, Cyclic; D011485:Protein Binding; D011817:Rabbits
D000900:Anti-Bacterial Agents; D000935:Antifungal Agents; D054714:Echinocandins; D055666:Lipopeptides; D010455:Peptides; D010456:Peptides, Cyclic; D000077336:Caspofungin