Relation between Skin Pharmacokinetics and Efficacy in AmBisome Treatment of Murine Cutaneous Leishmaniasis

Abstract

AmBisome (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.

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

“…We have recently demonstrated that the efficacy of LAmB in murine CL relies on adequate exposure of the active compound AmB at the local site of infection, the skin lesion. Moreover, we also showed higher drug disposition in diseased than in healthy skin ( 21 ). Altered pharmacokinetics (PK) at sites of tissue inflammation have been reported previously for antimicrobials ( 22 ), anti-inflammatory agents ( 23 ), and cancer chemotherapeutics ( 24 ).…”

“…However, this difference was significant for L. major ( P < 0.0001) but not for L. mexicana ( P = 0.15). The L. major data have been reported earlier ( 21 ) but are included to enable a direct comparison with L. mexicana (novel data).…”

“…Here, we confirmed the existence of this phenomenon in experimental CL for the first time. It could facilitate extravasation of the liposomes (∼80 nm in size) through the dermal capillaries, which under normal physiological conditions have a pore cutoff size of 6 to 12 nm ( 21 ). However, it cannot explain a decrease in AmB disposition in lesions as CL progresses by itself, because we found comparable degrees of capillary leakage in papules, initial nodules, and established nodules.…”

Promising nanotherapy in treating leishmaniasis

“…Patients treated with 0.6 mg/kg of AMB (0.060 ± 0.01 µg/mL) presented significantly higher Cmax (mean ± SD) than patients treated with 2 mg/kg of L-AMB (0.016 ± 0.004 µg/mL) allowing reducing the side effects of AMB (Bekersky et al, 2002). For leishmaniases, Wijnant et al (2017) compared the skin pharmacokinetics of L-AMB with AMB, in murine models of Leishmania major. The study showed that after multiple administration, on day 10, the drug level in the lesion location was 3-fold higher for L-AMB than for AMB.…”

Activity of Chitosan and Its Derivatives against Leishmania major and Leishmania mexicana In Vitro

“…These drugs have several limitations, including difficulty of administration, toxicity of the drug, and varying sensitivities among Leishmania species (9). Second-line treatments include the polyene antifungal amphotericin B, which also suffers from toxicity, the oral phospholipid miltefosine, the use of which is limited by teratogenicity, and the aminoglycoside antibiotic paromomycin (PM), which has low cure rates for certain Leishmania species (10)(11)(12). Treatment with intravenous liposomal amphotericin B (AmBisome) is safe and has achieved clinical success against CL at a dose of 3 mg/kg of body weight daily for 7 days (13,14), but the high cost of this formulation limits its use (15).…”