Tropically stable novel oral lipid formulation of amphotericin B (iCo-010): biodistribution and toxicity in a mouse model

Olena Sivak,Jinying Zhao,Kishor M Wasan,David Owen,Molly Lin,Ellen K Wasan,John G Clement,Pavel Gershkovich

doi:10.1186/1476-511x-10-135

Abstract

BackgroundThe purpose of this study was to evaluate the biodistribution and toxicity of amphotericin B (AmB) following multiple oral administrations of a novel tropically stable lipid-based formulation (iCo-010).MethodsBALB/c mice were allocated into six groups: oral iCo-010 twice daily for 5 days in the dose of 20, 10, 5 and 2.5 mg/kg; vehicle control; and intravenous boluses of Fungizone® 2 mg/kg once daily for 5 days. The animals were sacrificed 12 h following the last administration and blood and tissues were collected.ResultsThe plasma concentrations of AmB were similar to previously reported after administration of iCo-009. Somewhat lower concentrations of AmB were detected in reticulo-endothelial system in the case of iCo-010 when compared with iCo-009. The concentration in kidney was higher with iCo-010 than with iCo-009. The creatinine levels in all oral treatment groups were in a normal range as in the case of iCo-009. Administration of Fungizone® resulted in elevated plasma creatinine levels. Histopathology analysis detected no GI, liver or kidney toxicity following multiple dose oral administration of iCo-010. Fungizone® treatment induced necrotic changes in hepatic and kidney tissues.ConclusionsGiven the tropical stability of iCo-010, near identical activity against visceral leishmaniasis and significant concentrations in target organs this formulation has a potential to become a treatment of choice in tropical developing countries.

Highlights

The purpose of this study was to evaluate the biodistribution and toxicity of amphotericin B (AmB) following multiple oral administrations of a novel tropically stable lipid-based formulation
An additional novel aspect of this work was that tissue concentrations of AmB following multiple intravenous (IV) bolus administrations of Fungizone® were measured and compared to the concentrations obtained after multiple oral dosing, a head to head comparison that was not done in our previous works with multiple administrations of older formulations
This is consistent with slightly lower activity of iCo-010 in a murine model of visceral leishmaniasis [6,8]

Summary

Methods

The lipid-based oral formulation of AmB (iCo-10) was prepared as recently reported [8]. Following a one week acclimatization period animals were allocated into the following groups: oral gavages of iCo-010 twice daily for 5 days in the dose of 20 mg/kg (n = 7), 10 mg/kg (n = 6), 5 mg/kg (n = 6) and 2.5 mg/kg (n = 6); oral gavages of vehicle control of iCo-010 (n = 5); and intravenous (IV) boluses of Fungizone® once daily for 5 days in the dose that was shown to be nephrotoxic in a previously reported study (2 mg/kg, n = 16) [3]. Plasma and tissue samples were analyzed for concentrations of AmB by HPLC as previously reported [7]. Plasma samples were analyzed for creatinine concentrations using previously published validated HPLC method [10]. A portion of jejunum and a median lobe of liver were removed and fixated in 10% neutral buffered formalin for histopathological analysis

Results

Conclusions

Results and Discussion