TY - JOUR
T1 - Pharmacodynamics of caspofungin in a murine model of invasive pulmonary aspergillosis
T2 - Evidence of concentration-dependent activity
AU - Wiederhold, Nathan P.
AU - Kontoyiannis, Dimitrios P.
AU - Chi, Jingduan
AU - Prince, Randall A.
AU - Tam, Vincent H.
AU - Lewis, Russell E.
N1 - Funding Information:
Financial support: Merck (to R.E.L. and D.P.K.); National Cancer Institute,National Institutes of Health (core grant 16672 to The University of Texas M. D. Anderson Cancer Center Animal Care Unit).
PY - 2004/10/15
Y1 - 2004/10/15
N2 - 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 C max:MEC ratio appears to be the parameter most closely associated with the reduction of pulmonary fungal burden.
AB - 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 C max:MEC ratio appears to be the parameter most closely associated with the reduction of pulmonary fungal burden.
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U2 - 10.1086/424465
DO - 10.1086/424465
M3 - Article
C2 - 15378439
AN - SCOPUS:4944230721
SN - 0022-1899
VL - 190
SP - 1464
EP - 1471
JO - Journal of Infectious Diseases
JF - Journal of Infectious Diseases
IS - 8
ER -