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

Ref ID: 19293

Author:

R. Petraitiene, V. Petraitis, P. W. Moradi, G. E. Strauss, B. T. Huertas, A. Katragkou, E. Petraityte, L. L. Kovanda, J. Smart, W. W. Hope, T. J. Walsh

Author address:

Weill Cornell Med. Ctr. of Cornell Univ., New York, NY, Weill Cornell Med. Ctr. of Cornell Univeristy, New York, NY, Astellas Pharma Global Dev., Inc, Northbrook, IL,Univ. of Liverpool, Liverpool, UNITED KINGDOM

Full conference title:

53rd Interscience Conference on Antimicrobial Agents and Chemotherapy

Date: 10 September 2014

Abstract:

Background: Invasive pulmonary aspergillosis (IPA) is a life-threatening infection in immunosuppressed patients. New antifungal agents are needed to improve outcome. 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 consisted of active compound (BAL4815) ISA at 20 (ISA20), 40 (ISA40), 60 (ISA60) mg/kg/day PO, VRC at 15 (VRC) mg/kg Q12 PO, and untreated controls (UC). ISA treated rabbits received loading dose of 90 mg/kg PO 24 h after endotracheal inoculation of A. fumigatus.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<0.05). As measures of organism-mediated pulmonary injury, lung weights and pulmonary infarct score were lower in ISA40 and ISA60 treated rabbits in comparison to that of VRC and UC (p<0.05). Rabbits treated with ISA40, ISA60 and VRC significantly prolonged survival in comparison to that of UC (p<0.05). ISA40 treated rabbits showed prolonged survival vs VRC treated (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 ISA20, VRC treated rabbits, and UC (p<0.01). Rabbits treated with ISA60 demonstrated a trend toward increased serum transaminase levels. Values of AUC0-24 after single dose in normal animals for ISA20, ISA40, and ISA60 were 3.3±0.4x103, 5.9±0.8x103, and 32.8x±6.7103 ng"¢h/mL, respectively, and for clearance were 15.7±3.1, 17.8±2.3, and 3.4±0.9 ml/h, consistent with non-linear saturation kinetics. Vd was relatively constant between 0.1-0.2 L across dosage groups. Conclusions: Rabbits treated with ISA40 and ISA60 demonstrated significant reduction of CFU/g, lower GMI, decreased pulmonary injury, and prolonged survival in comparison to that of VRC and UC.

Abstract Number: NULL

Conference Year: 2013

Link to conference website: NULL

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