Pharmacodynamics of Caspofungin in a Murine Model of Invasive Pulmonary Aspergillosis: Evidence of Concentration-Dependent Activity

J Infect Dis. 2004 Oct 15;190(8):1464-71. doi: 10.1086/424465. Epub 2004 Sep 10.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

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

Substances

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