Prophylactic Dosing of NKTR-024 (Formerly Amphotericin B Inhalation Powder, ABIP) in a Guinea Pig Model of Invasive Pulmonary Aspergillosis (IPA).

W. R. KIRKPATRICK1, L. K. NAJVAR 1, A. C. VALLOR 1, R. BOCANEGRA 1, J. PFEIFFER 2, K. PERKINS 2, A. R. KUGLER 2, T. D. SWEENEY 2, J. R. GRAYBILL 1, T. F. PATTERSON 1;

Author address: 

1Univ. of Texas Hlth. Sci. Ctr., San Antonio, TX, 2Nektar Therapeutics, San Carlos, CA.

Abstract: 

Background: NKTR-024 is a novel dry-powder formulation of amphotericin B (AmB), and is directly delivered to the lung to produce lung AmB concentrations with potential to prevent fungal disease and eliminate systemic AmB toxicity. Prophylactic efficacy of NKTR-024 was evaluated in a guinea pig model of IPA and compared to untreated controls and animals treated with voriconazole (VRC). Methods: Guinea pigs were immunosuppressed with cortisone acetate and made temporarily neutropenic with cyclophosphamide d -2 pre, and d +3 post aerosolized challenge with 12 mL 109 CFU/mL Aspergillus fumigatus AF293 in an acrylic chamber. Groups of guinea pigs received prophylaxis with one dose of inhaled NKTR-024 (NKTR) at 0.05, 0.5, 4, or 10 mg/kg, given 24 h prior to infection, or treatment with oral VRC at 5 or 10 mg/kg/bid begun 24 h post challenge and continued for 8 d. Results: NKTR 4 (p=.02) and VRC 5 (p=.03) showed significantly improved survival vs controls. Decreased mortality (mean day of death), was also shown in a dose-dependent manner with NKTR 0.05, 0.5 and 4. Semi-quantitative assessment of lung tissue burden by colony forming units (CFU) revealed that NKTR 4 prophylaxis and therapy with either VRC dose yielded significantly reduced over controls. Similarly, assessment of lung burden by q-PCR (Conidial Equivalents; CE) showed NKTR 4 prophylaxis or VRC 5 or 10 therapy, vs controls, yielded significant reductions in counts. Galactomannan (GM) levels in lung homogenates showed that NKTR 4 prophylaxis or VRC 5 or10 therapy yielded significant reductions over controls or NKTR 0.05. Conclusions: NKTR-024 prophylaxis shows significant activity against A. fumigatus in this lethal model of IPA. Optimization of the dosing frequency and NKTR-024 dose should define the anti-Aspergillus efficacy in this stringent model of IPA.
2007

abstract No: 

M-1849

Full conference title: 

47th Interscience Conference on Antimicrobial agents and Chemotherapy
    • ICAAC 47th