Format

Send to

Choose Destination
J Infect Dis. 2004 Oct 15;190(8):1464-71. Epub 2004 Sep 10.

Pharmacodynamics of caspofungin in a murine model of invasive pulmonary aspergillosis: evidence of concentration-dependent activity.

Author information

1
The University of Houston College of Pharmacy and The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.

Abstract

BACKGROUND:

A paucity of data exists regarding the pharmacodynamics of caspofungin (CAS) during invasive pulmonary aspergillosis (IPA). We conducted a dosage-fractionation study to characterize the in vivo pharmacodynamics of CAS activity during IPA, using immunosuppressed mice inoculated intranasally with Aspergillus fumigatus.

METHODS:

After single intraperitoneal doses (0.25, 1.0, and 4.0 mg/kg), plasma CAS concentrations were assayed by high-performance liquid chromatography. The pharmacokinetic data were analyzed by nonparametric population pharmacokinetic analysis. Three dosage groups (0.25, 1.0, and 4.0 mg/kg) fractionated into 3 different dosing intervals (q6, q24, or q48 h) were then used to evaluate the pharmacokinetic/pharmacodynamic effects (percentage of time greater than the minimum effective concentration [MEC], 96-h area under the plasma concentration curve:MEC ratio, and peak concentration in plasma [Cmax]:MEC ratio) at clinically achievable exposures. Mice were treated for 96 h and were then euthanized, and their lungs were harvested for analysis of pulmonary fungal burden by real-time quantitative polymerase chain reaction.

RESULTS:

A concentration-dependent reduction in mean pulmonary fungal burden was evident in mice in the 1 mg/kg dosage-fractionation group, with significantly lower mean pulmonary fungal burden in mice dosed q48 h versus q6 h (P < .01). A paradoxical increase in pulmonary fungal burden was observed in the highest dosage-fractionation group.

CONCLUSIONS:

CAS demonstrates concentration-dependent pharmacodynamics in the treatment of IPA. The Cmax : MEC ratio appears to be the parameter most closely associated with the reduction of pulmonary fungal burden.

PMID:
15378439
DOI:
10.1086/424465
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Silverchair Information Systems
Loading ...
Support Center