Liposomal amphotericin B (AmBisome®) pharmacokinetics: Reaching the skin, review of the literature, and a case series of treated severe disfiguring post kala-azar dermal leishmaniasis

Abstract Post kala-azar dermal leishmaniasis (PKDL) that usually follows successfully treated visceral leishmaniasis (VL) can be severe and disfiguring. Treatment with sodium stibogluconate is prolonged, expensive with colossal cardiorenal toxicities. Early trials with liposomal amphotericin B (AMB) (AmBisome®) revolutionized PKDL treatment with increased safety and improved efficacy. AmBisome® pharmacokinetics and dynamics are poorly understood. This study aimed to show the efficacy of AmBisome® through its permeation within skin lesions. Following guardians’ written consent, ten PKDL patients with a history of parasitolgically confirmed VL, typical histopathological patterns, and presence of Leishmania antigens/parasites were enrolled. Blood samples were taken for DAT, hematological, and biochemical investigations. Leishmanin skin test (LST) was performed, and skin biopsies were taken for histopathology and electron microscopy. Patients received 14 daily injections of AmBisome® at 3 g/Kg/body weight. Skin biopsies revealed hyperkeratosis, loose epithelioid granulomas with dermis lymphocytic and histiocytic infiltrates, destruction of the basal layer, melanin incontinence, and loss of basal layer pigmentation. Leishmania antigens and scanty parasites were detected in the lesions. LST was non-reactive in all patients. DAT titers ranged from 6400 to 51,200. Patients responded markedly; healing continued for a few months after the stoppage of the drug. Electron micrographs showed skin lesion infiltration by T lymphocytes, macrophages loaded with parasites, and lipid droplets. Liposomal AMB was likely absorbed by circulating macrophages though their high-density lipoprotein receptors to be recruited to the skin, where the leishmanial parasites will be engulfed as well. Fusion of the phagosomes of the drug and that of the parasite leads to local release of the drug, which combined with the ergosterol of the parasite cell membrane led to its demise. Skin lesion healing continued after stoppage of the drug due to the drug persistence in macrophages. In conclusion, liposomal AMB enters the skin through recruited circulating macrophages with parasite phagocytosis and killing through binding with cell membrane ergosterol and pore formation.