Pharmacokinetics and Efficacy of Isavuconazole for Treatment of Experimental Invasive Pulmonary Aspergillosis

Ref ID: 19581

Author:

R Petraitiene1, V Petraitis1, PW Moradi1, GE Strauss1, BT Huertas1, A Katragkou1, E Petraityte1,
LL Kovanda2, J Smart2, WW Hope2, TJ Walsh1*

Author address:

1Transplantation-Oncology Infectious Diseases Program, Division of Infectious Diseases, Weill Cornell
Medical Center of Cornell University, New York, USA
2Astellas Pharma Global Development, Inc., Northbrook, USA
3University of Liverpool, Liverpoo

Full conference title:

6th Advances Against Aspergillosis 2014

Abstract:

Purpose:
New antifungal agents are needed to improve outcome in immunocompromised patients with
invasive pulmonary aspergillosis (IPA). The third-generation triazole isavuconazole (ISA) in vitro
demonstrated superior hyphal growth inhibition and lower MICs against A. fumigatus in comparison
to that of voriconazole (VRC). We therefore studied the pharmacokinetics, efficacy, and safety of
ISA in treatment of experimental IPA in persistently neutropenic rabbits.
Methods:
Treatment groups included rabbits receiving orally administered BAL8557 prodrug equivalent
to active compound (ISA or BAL4815) of 20 (ISA20), 40 (ISA40), and 60 (ISA60) mg/kg/day.
Control groups consisted of untreated controls (UC) and VRC-treated animals at 15 (VRC) mg/kg
Q12 PO. ISA treated rabbits received loading dose of BAL8557 prodrug equivalent to isavuconazole
90 mg/kg PO 24 h after endotracheal inoculation of A. fumigatus. Isavuconazole treatment was
administered once daily thereafter for up to 12 days.
Results:
There was a significant reduction of residual fungal burden (CFU/g) in ISA40 and ISA60 treated
rabbits vs that of VRC or UC (p<0.001). As measures of organism-mediated pulmonary injury, lung weights, and pulmonary infarct score were significantly lower in ISA40 and ISA60 treated rabbits in comparison to that of VRC and UC (p<0.001). Rabbits treated with ISA40, ISA60 significantly prolonged survival in comparison to that of UC (p<0.001). In addition, rabbits treated with ISA40 and ISA60 demonstrated significantly prolonged survival in comparison to that of VRC treated (p<0.05). ISA20 and VRC treated rabbits showed prolonged survival vs untreated controls (p<0.05). ISA40 and ISA60 treated animals demonstrated a significant decline of galactomannan antigenemia (GMI) during therapy following day 4 in comparison to progressive GMI of VRC treated rabbits, and untreated controls (p<0.01). There was significantly lower GMI in bronchoalveolar lavage (BAL) from rabbits treated with ISA40 and ISA60 in comparison to that of VRC or untreated controls rabbits (p<0.001). There also was significant decrease of plasma (18594;3)-β -D-glucan concentrations ISA40 and ISA60 treated rabbits in comparison to that of VRC or untreated controls rabbits (p<0.05). These outcome variables correlated directly with ISA exposure measured by AUC08209;24. within individual rabbits. Conclusion: In summary, rabbits treated with ISA40 and ISA60 demonstrated significant dose-dependent reduction of CFU/g, decreased pulmonary injury, prolonged survival, lower GMI in serum and BAL, lower plasma (18594;3)-β -D-glucan concentrations in comparison to that of VRC and untreated controls with a direct pharmacodynamic relation between exposure and outcome.

Abstract Number: 106

Conference Year: 2014

Link to conference website: http://www.AAA2014.org

New link: NULL

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