Efficacy and Pharmacokinetics of ASP9726 in a Guinea Pig Model of Invasive Pulmonary Aspergillosis (IPA)

Ref ID: 18708

Author:

W. R. Kirkpatrick, MS – Project Coordinator1,2, N. P. Wiederhold, Pharm.D. – Associate Professor 3,1, L. K. Najvar, BS – Laboratory Director 1,2, S. Matsumoto, PhD – Research Scientist 4, R. A. Bocanegra, BA – Research Associate 1,2, T. F. Patterson,

Author address:

1UTHSCSA, San Antonio, TX, 2STVHCS, San Antonio, TX, 3UT Austin, Austin, TX, 4Astellas, Tsubuka, Japan.

Full conference title:

52nd Annual ICAAC

Date: 9 September 2014

Abstract:

Background: Current treatment options for IPA may be limited by toxicities and drug interactions. ASP9726 is an investigational echinocandin with improved in vitro activity against Aspergillus species. Our objective was to evaluate the pharmacokinetics and efficacy of this agent in a guinea pig model of IPA.
Methods: ASP9726 plasma concentrations were measured by LC/MS/MS in guinea pigs administered doses of 2.5, 5, & 10 mg/kg SC QD for 5 days. Immunosuppressed guinea pigs were inoculated with A. fumigatus AF293 using an aerosol chamber. For treatment (N = 8 – 16 per group), placebo (4% hydroxypropyl-β -cyclodextrin SC QD), ASP9726 (2.5, 5, & 10 mg/kg SC QD), Voriconazole (VRC, 10 mg/kg PO BID), or caspofungin (CSF, 3 mg/kg IP QD) were given on days 1 – 8, and animals were monitored off therapy until day 12. Lung fungal burden (CFU & qPCR), serum beta-glucan (BG) & galactomannan (GM), and histopathology were also evaluated.
Results: ASP9726 plasma concentrations increased in a dose-proportional manner and were well tolerated. Each dose of ASP9726, VRC, and CSF significantly reduced pulmonary fungal burden as measured by qPCR, BG and GM, but only VRC significantly reduced CFUs. ASP9726 5 mg/kg also significantly improved survival. Histopathology demonstrated morphologic changes in hyphae in animals exposed to ASP9726 and CSF consistent with the activity of the echinocandins.
Conclusions: ASP9726 was well tolerated and resulted in significant improvements in fungal burden and serum biomarkers. A survival advantage was also observed with ASP9726 5 mg/kg. These results suggest that ASP9726 may be efficacious for the treatment of IPA.

Abstract Number: F-823

Conference Year: 2012

Link to conference website: NULL

New link: NULL

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