Comparative Pharmacodynamics (PD) of a Triazole and Echinocandin for Invasive Pulmonary Aspergillosis (IPA)

Ref ID: 15138

Author:

A. LEPAK, H. SANCHEZ, K. MARCHILLO,D. R. ANDES;

Author address:

Univ. of Wisconsin, Madison, WI.

Full conference title:

50th Annual ICAAC

Date: 12 September 2014

Abstract:

Background:Aspergillosis is a devastating cause of infection in immunocompromised hosts. Despite therapeutic advances outcomes remain poor. PD approaches have been useful for design of optimal dosing strategies for many infections but is underexplored for aspergillosis. We compared the PD target for two commonly utilized antifungal drug classes using a persistently neutropenic and corticosteroid suppressed murine IPA model.Methods:In vitro testing revealed a posaconazole (P) MIC and caspofungin (C) MEC of 0.5 ug/ml. Mice had 0.15 ng/ml of lungA. fumigatus293 DNA when a 7 d regimen of either P (0.625-160 mg/kg/d) or C (0.3125-80 mg/kg/d) were started. A sigmoid Emax model was used to estimate doses and AUC/MIC or MEC needed to achieve a variety of treatment endpoints based upon the quantity of lungAspergillusat the end of therapy (static dose [SD], 1 log reduction [1log], ED25, 50, and 75). Mann-Whitney test was used to compare the PD targets for P and C.Results:The lung burden ofAspergillusincreased nearly 2 log10 in control mice. The exposure response relationships were well described using the Emax model (R2=0.63-0.84). The maximal reduction in burden was greater (p=0.007) for P (2.4±0.29log10) than C (1.7±0.46 log10). For each treatment endpoint, C required more drug whether expressed on a mg/kg or AUC/MIC or MEC basis (2.8- to 36-fold, p=0.03). ED50 was similar to the SD and ED75 was similar to 1log endpoint. Total drug AUC/MIC or MEC relationships were similar.

Conclusion:The Emax model is useful to characterize the PD relationship for these antifungals using a quantitativeAspergillusDNA endpoint. The PD target was markedly different for the triazole and echinocandin in this model.

Abstract Number: A1-040

Conference Year: 2010

Link to conference website: NULL

New link:

Conference abstracts, posters & presentations

Showing 10 posts of 17325 posts found.

  • Title

    Author

    Year

    Number

    Poster