Abstract
ABSTRACTAmBisome (LAmB), a liposomal formulation of amphotericin B (AmB), is a second-line treatment for the parasitic skin disease cutaneous leishmaniasis (CL). Little is known about its tissue distribution and pharmacodynamics to inform clinical use in CL. Here, we compared the skin pharmacokinetics of LAmB with those of the deoxycholate form of AmB (DAmB; trade name Fungizone) in murine models of Leishmania major CL. Drug levels at the target site (the localized lesion) 48 h after single intravenous (i.v.) dosing of the individual AmB formulations (1 mg/kg of body weight) were similar but were 3-fold higher for LAmB than for DAmB on day 10 after multiple administrations (1 mg/kg on days 0, 2, 4, 6, and 8). After single and multiple dosing, intralesional concentrations were 5- and 20-fold, respectively, higher than those in the healthy control skin of the same infected mice. We then evaluated how drug levels in the lesion after LAmB treatment relate to therapeutic outcomes. After five administrations of the drug at 0, 6.25, or 12.5 mg/kg (i.v.), there was a clear correlation between dose level, intralesional AmB concentration, and relative reduction in parasite load and lesion size (R2 values of >0.9). This study confirms the improved efficacy of the liposomal over the deoxycholate AmB formulation in experimental CL, which is related to higher intralesional drug accumulation.
Highlights
AmBisome (LAmB), a liposomal formulation of amphotericin B (AmB), is a second-line treatment for the parasitic skin disease cutaneous leishmaniasis (CL)
No standard dose regimens have been established for liposome AmBisome (LAmB) in the treatment of CL, as published data are limited to small case series or individual case reports [4], but clinical success has been achieved with a daily course of 3 mg/kg of body weight for a total dose of 18 to 21 mg/kg
The pharmacokinetics and pharmacodynamics of many drugs currently used in the treatment of CL, including different formulations of AmB, are poorly understood [12]
Summary
AmBisome (LAmB), a liposomal formulation of amphotericin B (AmB), is a second-line treatment for the parasitic skin disease cutaneous leishmaniasis (CL). Due to the need for intravenous administration of LAmB and the related risk of systemic adverse effects, it is typically reserved as a 2nd-line treatment for complex CL This includes patients with (or at risk of) MCL, DCL, or CCL, as well as cases where lesions are large, numerous, potentially disfiguring, unresponsive to earlier therapeutic attempts, and esthetically or practically infeasible to cure locally. We report (i) the single-dose pharmacokinetics of LAmB and DAmB in both healthy and Leishmania major-infected BALB/c mice, (ii) skin distribution after multiple dosing of LAmB and DamB in murine CL, and (iii) the relationship between dose, intralesional AmB concentrations, and response after LAmB treatment at three dose levels
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