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

• Published in: The Journal of infectious diseases 2004-10, Vol.190 (8), p.1464-1471
• Main Authors: Wiederhold, Nathan P., Kontoyiannis, Dimitrios P., Chi, Jingduan, Prince, Randall A., Tam, Vincent H., Lewis, Russell E.
• Format: Article
• Language: English
• Subjects: Animals; Antifungal Agents - administration & dosage; Antifungal Agents - pharmacokinetics; Antifungal Agents - pharmacology; Antifungals; Aspergillosis; Aspergillosis - blood; Aspergillosis - drug therapy; Aspergillosis - microbiology; Aspergillus fumigatus; Biological and medical sciences; Cell walls; Disease Models, Animal; Dosage; Dose-Response Relationship, Drug; Drug design; Echinocandins; Female; Fundamental and applied biological sciences. Psychology; Fungi; Immunocompromised Host; Immunosuppressants; Infectious diseases; Injections, Intraperitoneal; Lipopeptides; Lung - microbiology; Lung - pathology; Lung Diseases, Fungal - blood; Lung Diseases, Fungal - drug therapy; Lung Diseases, Fungal - microbiology; Medical sciences; Mice; Microbiology; Peptides, Cyclic - administration & dosage; Peptides, Cyclic - pharmacokinetics; Peptides, Cyclic - pharmacology; Pharmacokinetics; Viability
• ISSN: 0022-1899; 1537-6613
• DOI: 10.1086/424465

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.