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

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.

• Authors: Nathan P Wiederhold, Dimitrios P Kontoyiannis, Jingduan Chi, Randall A Prince, Vincent H Tam, Russell E Lewis
• Journal: The Journal of infectious diseases (J Infect Dis) Vol. 190 Issue 8 Pg. 1464-71 (Oct 15 2004) ISSN: 0022-1899 [Print] United States
• PMID: 15378439 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
• Copyright: Copyright 2004 Infectious Diseases Society of America

Chemical References

• Antifungal Agents
• Echinocandins
• Lipopeptides
• Peptides, Cyclic
• Caspofungin

Topics

• Animals
• Antifungal Agents (administration & dosage, pharmacokinetics, pharmacology)
• Aspergillosis (blood, drug therapy, microbiology)
• Aspergillus fumigatus
• Caspofungin
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Echinocandins
• Female
• Immunocompromised Host
• Injections, Intraperitoneal
• Lipopeptides
• Lung (microbiology, pathology)
• Lung Diseases, Fungal (blood, drug therapy, microbiology)
• Mice
• Peptides, Cyclic (administration & dosage, pharmacokinetics, pharmacology)