Estudo pré-clínico do perfil farmacocinético, biodistribuição e atividade antifúngica de formulação lipossomal de voriconazol para uso intravenoso em infecções sistêmicas
Carregando...
Data
2018-07-24
Título da Revista
ISSN da Revista
Título de Volume
Editor
Universidade Federal de Goiás
Resumo
Voriconazole, a second-generation triazole with a large spectrum of action is one of the most
recommended systemic antifungal agents as the first line therapy against several clinically
important fungal pathogens, among them Candida albicans. This antifungal has moderate water
solubility and exhibits a nonlinear pharmacokinetic profile due to metabolic clearance saturation.
By entrapping voriconazole into liposomes it is possible to circumvent its physico-chemical
limitations, avoid the high toxicity of the antimicrobial, caused by sulfobutyl ether-betacyclodextrin,
vehicle used to increase its solubility, present in its commercially available
formulation: VFEND®. Pharmacokinetics and biodistribution of voriconazole modified by
encapsulation in liposomes allowed its antifungal activity to be potentiated, leading to increased
specificity and tissue penetration, protection the drug from biological degradation and reduced
metabolism. Liposomes entrapping voriconazole (LVCZ) showed a particle size of 95.3 ± 1.27 nm,
PdI of 0.09 ± 0.01, zeta potential near to neutrality, as well as a high efficiency of encapsulation of
the antifungal and vesicles presenting spherical morphology uni and/or multilamellar. In vitro and
in vivo evaluations of the performance of the liposomal formulation containing voriconazole were
all performed in a comparative fashion with the commercially available formulation, VFEND®. In
the in vitro assays using different species of fungal isolates of Candida and Aspergillus sp. the
liposomal formulation was equivalent or superior to VFEND®. In a non-clinical pharmacokinetic
assay in Balb/c mice, using a dose of 10 mg/kg, the main pharmacokinetic parameters were
obtained: Cmax (μg/mL) = 1.23 ± 0.28 and 0.61 ± 0.15; AUC0-24 (μg/ml*h) = 4.86 ± 1.01 and 1.96 ±
0.30; Cl (mL/h) = 52.75 ± 8.88
and 100.91 ± 20.14; Vd (mL) = 230.18 ± 53.61 and 314.18 ± 106.24 for LVCZ and VFEND®,
respectively. In all calculated/observed parameters, the liposomal formulation presented superior
performance, using the same dose as the commercial formulation. Increases in antifungal
concentrations found in blood, liver and kidneys and lower amounts of the inactive metabolite
formed when using the liposomal formulation can be attributed to the ability of liposomes to alter
the pharmacokinetics and biodistribution of voriconazole in the body mainly because of their
capacity to protect the drug from accelerated metabolism. In vivo efficacy evaluation of
voriconazole was also performed in a systemic candidiasis model in immunosuppressed animals,
as well as parameters such as weight loss, fungal burden in the liver and kidneys and histological
alterations caused by infection and treatment. As a consequence of voriconazole pharmacokinetics
and biodistribution modified by the encapsulation in liposomes, the antifungal activity of drug was
potentiated, leading to greater specificity and tissue penetration. In conclusion, in order to provide
appropriate dose regimens for the treatment of systemic fungal infections, avoiding obstacles such
as toxicity and resistance mechanisms we developed na alternative therapeutic platform, able to
lead to safe and effective treatment.
Descrição
Citação
VELOSO, D. F. M. C. Estudo pré-clínico do perfil farmacocinético, biodistribuição e atividade antifúngica de formulação lipossomal de voriconazol para uso intravenoso em infecções sistêmicas. 2018.50 f. Tese (Doutorado em Ciências da Saúde) - Universidade Federal de Goiás, Goiânia, 2018.