Comparative efficacy, toxicity and biodistribution of the liposomal amphotericin B formulations Fungisome® and AmBisome® in murine cutaneous leishmaniasis

Abstract

Fungisome® (F), a liposomal amphotericin B (AmB) product, is marketed in India as a safe and effective therapeutic for the parasitic infection visceral leishmaniasis. Its potential in the treatment of cutaneous leishmaniasis (CL), a disfiguring form of the disease affecting the skin, is currently unknown. Here, we report the evaluation of the efficacy of F in the Leishmania major BALB/c murine model of CL, including a head-to-head comparison with the standard liposomal AmB formulation AmBisome® (A). Upon intravenous administration at dose levels of 5, 10 and 15 mg/kg of body weight (on days 0, 2, 4, 6 and 8), F showed clear signs of toxicity (at 15 mg/kg), while A did not. After complete treatment (day 10), the tolerated doses of 5 and 10 mg/kg F had significant antileishmanial activity (ED50 = 4.0 and 12.8 mg/kg for qPCR-based parasite load and lesion size, respectively), although less than that of A at identical doses (ED50 = 3.0 and 8.8 mg/kg). The efficacy of F was inferior compared to A because lower levels of the active agent AmB accumulated within the infected lesion. In conclusion, despite possibly being less safe and efficacious than A at equivalent doses, the moderate in vivo activity of F could indicate a role in the systemic pharmacotherapy of CL.

Local Skin Inflammation in Cutaneous Leishmaniasis as a Source of Variable Pharmacokinetics and Therapeutic Efficacy of Liposomal Amphotericin B

“…Third, the in vivo activity of LAmB was superior against L. major than against L. mexicana , likely due to inflammation-enhanced and relatively increased drug levels at the infection site. A clear correlation between drug levels of the leishmanicidal, concentration-dependent antibiotic AmB delivered to the lesion and the efficacy of LAmB in murine CL has already been reported ( 21 , 52 ). Apart from skin PK, there could also be differences in antileishmanial pharmacodynamics (PD) and the resulting PK/PD relationship.…”

Activity of Amphotericin B-Loaded Chitosan Nanoparticles against Experimental Cutaneous Leishmaniasis

“…Amphotericin B forms pores in cell membranes, via complexation with ergosterol in Leishmania membranes [ 22 ]. However, the use of this deoxycholate amphotericin B is clinically limited due to infusion-related and nephrotoxicity issues [ 23 , 24 ]. A liposomal formulation (AmBisome ® , diameter = 80 nm) [ 24 , 25 ] was developed to improve the tolerability and reduce the adverse events associated with conventional AmB administration.…”

“…However, the use of this deoxycholate amphotericin B is clinically limited due to infusion-related and nephrotoxicity issues [ 23 , 24 ]. A liposomal formulation (AmBisome ® , diameter = 80 nm) [ 24 , 25 ] was developed to improve the tolerability and reduce the adverse events associated with conventional AmB administration. AmBisome ® is approved by the FDA for the treatment of visceral leishmaniasis (VL) and has also shown clinical efficacy in CL patients [ 24 , 26 ].…”

“…A liposomal formulation (AmBisome ® , diameter = 80 nm) [ 24 , 25 ] was developed to improve the tolerability and reduce the adverse events associated with conventional AmB administration. AmBisome ® is approved by the FDA for the treatment of visceral leishmaniasis (VL) and has also shown clinical efficacy in CL patients [ 24 , 26 ]. AmBisome ® is used widely for the treatment of VL as it is donated by Gilead via WHO but is only available at high cost for CL.…”

Scalable solvent-free production of liposomes

“…[17] Liposomal amphotericin B formulations are thus less toxic than conventional formulations and more effective in treating fungal infections allowing for higher exposure and longer duration of therapy. [18][19][20] Currently, manufacturing steps of AmBisome â involve solubilisation of lipids in an organic Figure 6 Effect of pressure and number of passes on particle size, PDI and drug loading of the non-PEGylated liposome formulation. Empty non-PEGylated liposomes were manufactured as outlined in Table 4 at 5000, 8000, 10 000, 15 000 and 18 000 psi for three passes.…”