ASP9726, A Unique 2nd Generation Echinocandin (5) -In Vitro and in vivo Activity of Combination Therapy with Voriconazole against Aspergillus fumigatus.-

Ref ID: 18669

Author:

S. Akamatsu, MS – Pharmacologist, S. Matsumoto, MS – Pharmacologist, S. Uchida, BS – Pharmacologist, T. Nakai, PhD – Pharmacologist, S. Takeda, PhD – Pharmacologist, K. Maki, MS – Pharmacologist;

Author address:

Astellas Pharma Inc.,, Tsukuba, Ibaraki, Japan.

Full conference title:

52nd Annual ICAAC

Date: 9 September 2014

Abstract:

Background: Combination therapy with echinocandins and triazoles may be more effective against invasive pulmonary aspergillosis (IPA) than monotherapy, but has not been adequately clarified. The aim of this study was to assess the antifungal activity of ASP9726 (ASP) in combination with voriconazole (VRCZ) against A. fumigatus in vitro and in a murine model of IPA which was co-administrated with aminobenzotriazole (ABT) as a CYP inhibitor to maintain plasma levels of VRCZ. Methods: In vitro antifungal activities of combination of VRCZ with ASP against A. fumigatus were compared with those of VRCZ or ASP by using XTT assay in human serum. VRCZ plasma concentrations were measured by LC/MS/MS in mice administered with dose escalation resimen (10 mg/kg on day 1-2 and 15 mg/kg on day 3-6 PO BID) co-administered with ABT 30 mg/kg PO BID. Therapeutic activities against IPA caused by A. fumigatus were studied in an immunosupressed mice model. Combination therapy (VRCZ; dose escalation regimen, + ASP 3 mg/kg IV QD) and monotherapy were started 30 hrs after infection and continued for 6 days and survival was monitored for 10 days. Lung fungal burden and histopathology were also evaluated. Results: Significant growth reduction was observed in combination of VRCZ with ASP compared with VRCZ or ASP. AUC0-12 of VRCZ is 39, 124 and 114 μg·hr/mL on 2, 4 and 6 days, respectively, which is similar to the exposure in humans. In a murine model of IPA, combination therapy significantly prolonged survival compared with monotherapy (p<0.025). Combination therapy resulted in significant improvements in lung fungal burden and histopathological analysis, compared with monotherapy. Conclusions: These results suggest that combination therapy with ASP and VRCZ has a potential advantage for the treatment of IPA compared with monotherapy.

Abstract Number: F-821

Conference Poster: y

Conference Year: 2012

Link to conference website: NULL

New link: NULL

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