Background: Amphotericin B (AmB) is used to treat fungal infections and a neglected parasitic disease called visceral leishmaniasis (VL). Although AmB is very effective with little resistance reported, it has a narrow therapeutic window. Several AmB formulations are available with liposomal AmB (AmBisome® ) being the most efficacious against VL, with the best safety profile. However, requirement for cold chain supply in areas where VL is most prevalent can be cost prohibitive. AmB complexed with a polymer (PolyAmpâ„¢) has been developed as a cost effective alternative to AmBisome® . PolyAmpâ„¢ comprises AmB complexed to a low-cost, biodegradable polymer. This new formulation is heat stable and is expected to tolerate the high temperatures in countries where VL is most prevalent, allowing for distribution without cooling. Methods: PolyAmpâ„¢ was prepared as a freeze dried solid using a proprietary process where AmB was mixed with a polymer solution to enable complexation. The haemolytic activity of PolyAmpâ„¢ was determined in human red blood cells (RBCs) at 100 μg/mL of AmB and compared to Fungizone® at the same AmB concentration. The efficacy of PolyAmpâ„¢ was determined in a mouse model of VL (L. donovani HU3). PolyAmpâ„¢ was administered intravenously as three injections at 0.3, 1, 3 and 10 mg/kg doses per injection, based on AmB loading. AmBisome® was used as a control at the same dosing schedule. Results: PolyAmpâ„¢ showed similar physicochemical properties to AmBisome® . PolyAmpâ„¢ did not haemolyse RBCs; less than 5% lysis was observed after 24 h incubation. Fungizone® displayed > 60% haemolysis under the same conditions. The low haemolytic activity of PolyAmpâ„¢ translated into good in vivo tolerability with no adverse effects observed in the mice after a cumulative dose of 30 mg/kg of AmB. The ED50 of PolyAmpâ„¢ was 0.32 mg/kg, comparable to that of AmBisome® of 0.26 mg/kg. Conclusions: PolyAmpâ„¢ was produced with similar physicochemical properties to AmBisome® . PolyAmpâ„¢ was not haemolytic in vitro and was well-tolerated in mice. The in vivo activity of PolyAmpâ„¢ in a model of VL was similar to that of AmBisome® . PolyAmpâ„¢ is therefore a promising candidate for development as a new AmB formulation to treat VL.
Full conference title:
53rd Interscience Conference on Antimicrobial Agents and Chemotherapy
- ICAAC, 53rd (2013)