Development of a Minimal Physiologically-Based Pharmacokinetic Model to Simulate Lung Exposure in Humans Following Oral Administration of Ivermectin for COVID-19 Drug Repurposing

Autores
Jermain, Brian; Hanafin, Patrick O.; Cao, Yanguang; Lifschitz, Adrian Luis; Lanusse, Carlos Edmundo; Rao, Gauri G.
Año de publicación
2020
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
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.
Fil: Jermain, Brian. University of North Carolina; Estados Unidos
Fil: Hanafin, Patrick O.. University of North Carolina; Estados Unidos
Fil: Cao, Yanguang. University of North Carolina; Estados Unidos
Fil: Lifschitz, Adrian Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil. Centro de Investigación Veterinaria de Tandil. Universidad Nacional del Centro de la Provincia de Buenos Aires. Centro de Investigación Veterinaria de Tandil. Provincia de Buenos Aires. Gobernación. Comision de Investigaciones Científicas. Centro de Investigación Veterinaria de Tandil; Argentina
Fil: Lanusse, Carlos Edmundo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil. Centro de Investigación Veterinaria de Tandil. Universidad Nacional del Centro de la Provincia de Buenos Aires. Centro de Investigación Veterinaria de Tandil. Provincia de Buenos Aires. Gobernación. Comision de Investigaciones Científicas. Centro de Investigación Veterinaria de Tandil; Argentina
Fil: Rao, Gauri G.. University of North Carolina; Estados Unidos
Materia
COVID-19
IMPORTINS
IVERMECTIN
KINETICS
MINIMAL PHYSIOLOGICALLY-BASED PHARMACOKINETIC MODEL
PHARMACOKINETIC/PHARMACODYNAMIC (PK/PD) MODELING
PHARMACOKINETICS
PHARMACOMETRICS
PHYSIOLOGICALLY BASED PHARMACOKINETIC MODELING
SARS-COV-2
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/127348
Acceder
id CONICETDig_27df8416b1f4d88aa244ece176231bbc
oai_identifier_str oai:ri.conicet.gov.ar:11336/127348
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Development of a Minimal Physiologically-Based Pharmacokinetic Model to Simulate Lung Exposure in Humans Following Oral Administration of Ivermectin for COVID-19 Drug RepurposingJermain, BrianHanafin, Patrick O.Cao, YanguangLifschitz, Adrian LuisLanusse, Carlos EdmundoRao, Gauri G.COVID-19IMPORTINSIVERMECTINKINETICSMINIMAL PHYSIOLOGICALLY-BASED PHARMACOKINETIC MODELPHARMACOKINETIC/PHARMACODYNAMIC (PK/PD) MODELINGPHARMACOKINETICSPHARMACOMETRICSPHYSIOLOGICALLY BASED PHARMACOKINETIC MODELINGSARS-COV-2https://purl.org/becyt/ford/3.3https://purl.org/becyt/ford/3SARS-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.Fil: Jermain, Brian. University of North Carolina; Estados UnidosFil: Hanafin, Patrick O.. University of North Carolina; Estados UnidosFil: Cao, Yanguang. University of North Carolina; Estados UnidosFil: Lifschitz, Adrian Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil. Centro de Investigación Veterinaria de Tandil. Universidad Nacional del Centro de la Provincia de Buenos Aires. Centro de Investigación Veterinaria de Tandil. Provincia de Buenos Aires. Gobernación. Comision de Investigaciones Científicas. Centro de Investigación Veterinaria de Tandil; ArgentinaFil: Lanusse, Carlos Edmundo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil. Centro de Investigación Veterinaria de Tandil. Universidad Nacional del Centro de la Provincia de Buenos Aires. Centro de Investigación Veterinaria de Tandil. Provincia de Buenos Aires. Gobernación. Comision de Investigaciones Científicas. Centro de Investigación Veterinaria de Tandil; ArgentinaFil: Rao, Gauri G.. University of North Carolina; Estados UnidosElsevier2020-12-01info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/127348Jermain, 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; 3574-35780022-3549CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1016/j.xphs.2020.08.024info:eu-repo/semantics/altIdentifier/url/https://jpharmsci.org/article/S0022-3549(20)30495-0/fulltextinfo:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T09:33:41Zoai:ri.conicet.gov.ar:11336/127348instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-29 09:33:42.013CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Development of a Minimal Physiologically-Based Pharmacokinetic Model to Simulate Lung Exposure in Humans Following Oral Administration of Ivermectin for COVID-19 Drug Repurposing
title Development of a Minimal Physiologically-Based Pharmacokinetic Model to Simulate Lung Exposure in Humans Following Oral Administration of Ivermectin for COVID-19 Drug Repurposing
spellingShingle 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
COVID-19
IMPORTINS
IVERMECTIN
KINETICS
MINIMAL PHYSIOLOGICALLY-BASED PHARMACOKINETIC MODEL
PHARMACOKINETIC/PHARMACODYNAMIC (PK/PD) MODELING
PHARMACOKINETICS
PHARMACOMETRICS
PHYSIOLOGICALLY BASED PHARMACOKINETIC MODELING
SARS-COV-2
title_short Development of a Minimal Physiologically-Based Pharmacokinetic Model to Simulate Lung Exposure in Humans Following Oral Administration of Ivermectin for COVID-19 Drug Repurposing
title_full Development of a Minimal Physiologically-Based Pharmacokinetic Model to Simulate Lung Exposure in Humans Following Oral Administration of Ivermectin for COVID-19 Drug Repurposing
title_fullStr Development of a Minimal Physiologically-Based Pharmacokinetic Model to Simulate Lung Exposure in Humans Following Oral Administration of Ivermectin for COVID-19 Drug Repurposing
title_full_unstemmed Development of a Minimal Physiologically-Based Pharmacokinetic Model to Simulate Lung Exposure in Humans Following Oral Administration of Ivermectin for COVID-19 Drug Repurposing
title_sort Development of a Minimal Physiologically-Based Pharmacokinetic Model to Simulate Lung Exposure in Humans Following Oral Administration of Ivermectin for COVID-19 Drug Repurposing
dc.creator.none.fl_str_mv Jermain, Brian
Hanafin, Patrick O.
Cao, Yanguang
Lifschitz, Adrian Luis
Lanusse, Carlos Edmundo
Rao, Gauri G.
author Jermain, Brian
author_facet Jermain, Brian
Hanafin, Patrick O.
Cao, Yanguang
Lifschitz, Adrian Luis
Lanusse, Carlos Edmundo
Rao, Gauri G.
author_role author
author2 Hanafin, Patrick O.
Cao, Yanguang
Lifschitz, Adrian Luis
Lanusse, Carlos Edmundo
Rao, Gauri G.
author2_role author
author
author
author
author
dc.subject.none.fl_str_mv COVID-19
IMPORTINS
IVERMECTIN
KINETICS
MINIMAL PHYSIOLOGICALLY-BASED PHARMACOKINETIC MODEL
PHARMACOKINETIC/PHARMACODYNAMIC (PK/PD) MODELING
PHARMACOKINETICS
PHARMACOMETRICS
PHYSIOLOGICALLY BASED PHARMACOKINETIC MODELING
SARS-COV-2
topic COVID-19
IMPORTINS
IVERMECTIN
KINETICS
MINIMAL PHYSIOLOGICALLY-BASED PHARMACOKINETIC MODEL
PHARMACOKINETIC/PHARMACODYNAMIC (PK/PD) MODELING
PHARMACOKINETICS
PHARMACOMETRICS
PHYSIOLOGICALLY BASED PHARMACOKINETIC MODELING
SARS-COV-2
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.3
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv 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.
Fil: Jermain, Brian. University of North Carolina; Estados Unidos
Fil: Hanafin, Patrick O.. University of North Carolina; Estados Unidos
Fil: Cao, Yanguang. University of North Carolina; Estados Unidos
Fil: Lifschitz, Adrian Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil. Centro de Investigación Veterinaria de Tandil. Universidad Nacional del Centro de la Provincia de Buenos Aires. Centro de Investigación Veterinaria de Tandil. Provincia de Buenos Aires. Gobernación. Comision de Investigaciones Científicas. Centro de Investigación Veterinaria de Tandil; Argentina
Fil: Lanusse, Carlos Edmundo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil. Centro de Investigación Veterinaria de Tandil. Universidad Nacional del Centro de la Provincia de Buenos Aires. Centro de Investigación Veterinaria de Tandil. Provincia de Buenos Aires. Gobernación. Comision de Investigaciones Científicas. Centro de Investigación Veterinaria de Tandil; Argentina
Fil: Rao, Gauri G.. University of North Carolina; Estados Unidos
description 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.
publishDate 2020
dc.date.none.fl_str_mv 2020-12-01
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/127348
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
0022-3549
CONICET Digital
CONICET
url http://hdl.handle.net/11336/127348
identifier_str_mv 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
0022-3549
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1016/j.xphs.2020.08.024
info:eu-repo/semantics/altIdentifier/url/https://jpharmsci.org/article/S0022-3549(20)30495-0/fulltext
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
_version_ 1844613036863651840
score 13.070432

Publicaciones similares