Artículo
Development of a Minimal Physiologically-Based Pharmacokinetic Model to Simulate Lung Exposure in Humans Following Oral Administration of Ivermectin for COVID-19 Drug Repurposing
Jermain, Brian; Hanafin, Patrick O.; Cao, Yanguang; Lifschitz, Adrian Luis
; Lanusse, Carlos Edmundo
; Rao, Gauri G.
Fecha de publicación:
01/12/2020
Editorial:
Elsevier
Revista:
Journal of Pharmaceutical Sciences
ISSN:
0022-3549
Idioma:
Inglés
Tipo de recurso:
Artículo publicado
Clasificación temática:
Resumen
SARS-CoV-2 utilizes the IMPα/β1 heterodimer to enter host cell nuclei after gaining cellular access through the ACE2 receptor. Ivermectin has shown antiviral activity by inhibiting the formation of the importin-α (IMPα) and IMPβ1 subunits as well as dissociating the IMPα/β1 heterodimer and has in vitro efficacy against SARS-CoV-2. Plasma and lung ivermectin concentrations vs. time profiles in cattle were used to determine the apparent plasma to lung tissue partition coefficient of ivermectin. This coefficient, together with a simulated geometric mean plasma profile of ivermectin from a published population pharmacokinetic model, was utilized to develop a minimal physiologically-based pharmacokinetic (mPBPK) model. The mPBPK model accurately described the simulated ivermectin plasma concentration profile in humans. The mPBPK model was also used to simulate human lung exposure to ivermectin after 12, 30, and 120 mg oral doses. The simulated ivermectin lung exposures reached a maximum concentration of 772 ng/mL, far less than the estimated 1750 ng/mL IC50 reported for ivermectin against SARS-CoV-2 in vitro. Further studies of ivermectin either reformulated for inhaled delivery or in combination with other antivirals with differing mechanisms of action is needed to assess its therapeutic potential.
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Colecciones
Articulos(CIVETAN)
Articulos de CENTRO DE INVESTIGACION VETERINARIA DE TANDIL
Articulos de CENTRO DE INVESTIGACION VETERINARIA DE TANDIL
Citación
Jermain, Brian; Hanafin, Patrick O.; Cao, Yanguang; Lifschitz, Adrian Luis; Lanusse, Carlos Edmundo; et al.; Development of a Minimal Physiologically-Based Pharmacokinetic Model to Simulate Lung Exposure in Humans Following Oral Administration of Ivermectin for COVID-19 Drug Repurposing; Elsevier; Journal of Pharmaceutical Sciences; 109; 12; 1-12-2020; 3574-3578
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