Population Pharmacokinetics and Exposure–Response Analysis of a Fixed‐Dose Combination of Ivermectin and Albendazole in Children, Adolescents, and Adults

Autores
Algorta, Jaime; Kepha, Stella; Krolewiecki, Alejandro Javier; Li, Hanbin; Giang, Justin; Fleitas, Pedro; Mwandawiro, Charles; Muñoz, José
Año de publicación
2024
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Trichuris trichiura is a soil-transmitted helminth causing intestinal disease. Albendazole is the standard treatment despite its moderate efficacy, which is improved when co-administered with ivermectin. A fixeddose combination adds practical advantages mainly for mass drug administration. The aim of this article is to define the population pharmacokinetic models and exposure–response of an innovative albendazole/ivermectin combination. Data were obtained from a phase I clinical trial in healthy adults and from a phase II trial in children and adolescents infected with T.trichiura. Nonlinear mixed-effects models were built for albendazole and ivermectin using NONMEM®. Area under the curve was calculated using the empirical Bayes estimates of the pharmacokinetic parameters of each individual and used for evaluation of exposure–response between cure rate and pharmacokinetic exposure. The pharmacokinetics of albendazole was described using a two-compartmental model with first-order absorption and the pharmacokinetics of ivermectin was described using a twocompartmental model with zero-order followed by first-order absorption. Clearance and volume of distribution increased with body weight for both albendazole and ivermectin. Day 1 area under the curve of albendazole and ivermectin from the children and adolescents treated with the combination regimens were similar to the healthy adults treated with control drugs. A flat exposure–response relationship was observed between the cure rate and drug exposure. Population pharmacokinetic of a combination of albendazole and ivermectin in children, adolescents, and adults, either healthy or infected by T.trichiura was described. The dosage selected in the phase II trial was appropriate for the subsequent phase III.
Fil: Algorta, Jaime. Liconsa Sa; España
Fil: Kepha, Stella. Kenya Medical Research Institute; Kenia
Fil: Krolewiecki, Alejandro Javier. Universidad Nacional de Salta. Sede Regional Orán. Instituto de Investigación de Enfermedades Tropicales; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Salta; Argentina
Fil: Li, Hanbin. Quantx Consulting; Estados Unidos
Fil: Giang, Justin. Quantx Consulting; Estados Unidos
Fil: Fleitas, Pedro. Universidad de Barcelona; España
Fil: Mwandawiro, Charles. Kenya Medical Research Institute; Kenia
Fil: Muñoz, José. Universidad de Barcelona; España
Materia
ALBENDAZOLE
IVERMECTIN
POP-PK
SOIL TRANSMITTED HELMINTHS
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:11336/247200
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/247200
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Population Pharmacokinetics and Exposure–Response Analysis of a Fixed‐Dose Combination of Ivermectin and Albendazole in Children, Adolescents, and AdultsAlgorta, JaimeKepha, StellaKrolewiecki, Alejandro JavierLi, HanbinGiang, JustinFleitas, PedroMwandawiro, CharlesMuñoz, JoséALBENDAZOLEIVERMECTINPOP-PKSOIL TRANSMITTED HELMINTHShttps://purl.org/becyt/ford/3.3https://purl.org/becyt/ford/3Trichuris trichiura is a soil-transmitted helminth causing intestinal disease. Albendazole is the standard treatment despite its moderate efficacy, which is improved when co-administered with ivermectin. A fixeddose combination adds practical advantages mainly for mass drug administration. The aim of this article is to define the population pharmacokinetic models and exposure–response of an innovative albendazole/ivermectin combination. Data were obtained from a phase I clinical trial in healthy adults and from a phase II trial in children and adolescents infected with T.trichiura. Nonlinear mixed-effects models were built for albendazole and ivermectin using NONMEM®. Area under the curve was calculated using the empirical Bayes estimates of the pharmacokinetic parameters of each individual and used for evaluation of exposure–response between cure rate and pharmacokinetic exposure. The pharmacokinetics of albendazole was described using a two-compartmental model with first-order absorption and the pharmacokinetics of ivermectin was described using a twocompartmental model with zero-order followed by first-order absorption. Clearance and volume of distribution increased with body weight for both albendazole and ivermectin. Day 1 area under the curve of albendazole and ivermectin from the children and adolescents treated with the combination regimens were similar to the healthy adults treated with control drugs. A flat exposure–response relationship was observed between the cure rate and drug exposure. Population pharmacokinetic of a combination of albendazole and ivermectin in children, adolescents, and adults, either healthy or infected by T.trichiura was described. The dosage selected in the phase II trial was appropriate for the subsequent phase III.Fil: Algorta, Jaime. Liconsa Sa; EspañaFil: Kepha, Stella. Kenya Medical Research Institute; KeniaFil: Krolewiecki, Alejandro Javier. Universidad Nacional de Salta. Sede Regional Orán. Instituto de Investigación de Enfermedades Tropicales; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Salta; ArgentinaFil: Li, Hanbin. Quantx Consulting; Estados UnidosFil: Giang, Justin. Quantx Consulting; Estados UnidosFil: Fleitas, Pedro. Universidad de Barcelona; EspañaFil: Mwandawiro, Charles. Kenya Medical Research Institute; KeniaFil: Muñoz, José. Universidad de Barcelona; EspañaNature Publishing Group2024-09info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/247200Algorta, Jaime; Kepha, Stella; Krolewiecki, Alejandro Javier; Li, Hanbin; Giang, Justin; et al.; Population Pharmacokinetics and Exposure–Response Analysis of a Fixed‐Dose Combination of Ivermectin and Albendazole in Children, Adolescents, and Adults; Nature Publishing Group; Clinical Pharmacology & Therapeutics; 2024; 9-2024; 1-110009-9236CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://ascpt.onlinelibrary.wiley.com/doi/10.1002/cpt.3424info:eu-repo/semantics/altIdentifier/doi/10.1002/cpt.3424info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T09:59:29Zoai:ri.conicet.gov.ar:11336/247200instacron: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:34982025-09-03 09:59:29.391CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Population Pharmacokinetics and Exposure–Response Analysis of a Fixed‐Dose Combination of Ivermectin and Albendazole in Children, Adolescents, and Adults
title Population Pharmacokinetics and Exposure–Response Analysis of a Fixed‐Dose Combination of Ivermectin and Albendazole in Children, Adolescents, and Adults
spellingShingle Population Pharmacokinetics and Exposure–Response Analysis of a Fixed‐Dose Combination of Ivermectin and Albendazole in Children, Adolescents, and Adults
Algorta, Jaime
ALBENDAZOLE
IVERMECTIN
POP-PK
SOIL TRANSMITTED HELMINTHS
title_short Population Pharmacokinetics and Exposure–Response Analysis of a Fixed‐Dose Combination of Ivermectin and Albendazole in Children, Adolescents, and Adults
title_full Population Pharmacokinetics and Exposure–Response Analysis of a Fixed‐Dose Combination of Ivermectin and Albendazole in Children, Adolescents, and Adults
title_fullStr Population Pharmacokinetics and Exposure–Response Analysis of a Fixed‐Dose Combination of Ivermectin and Albendazole in Children, Adolescents, and Adults
title_full_unstemmed Population Pharmacokinetics and Exposure–Response Analysis of a Fixed‐Dose Combination of Ivermectin and Albendazole in Children, Adolescents, and Adults
title_sort Population Pharmacokinetics and Exposure–Response Analysis of a Fixed‐Dose Combination of Ivermectin and Albendazole in Children, Adolescents, and Adults
dc.creator.none.fl_str_mv Algorta, Jaime
Kepha, Stella
Krolewiecki, Alejandro Javier
Li, Hanbin
Giang, Justin
Fleitas, Pedro
Mwandawiro, Charles
Muñoz, José
author Algorta, Jaime
author_facet Algorta, Jaime
Kepha, Stella
Krolewiecki, Alejandro Javier
Li, Hanbin
Giang, Justin
Fleitas, Pedro
Mwandawiro, Charles
Muñoz, José
author_role author
author2 Kepha, Stella
Krolewiecki, Alejandro Javier
Li, Hanbin
Giang, Justin
Fleitas, Pedro
Mwandawiro, Charles
Muñoz, José
author2_role author
author
author
author
author
author
author
dc.subject.none.fl_str_mv ALBENDAZOLE
IVERMECTIN
POP-PK
SOIL TRANSMITTED HELMINTHS
topic ALBENDAZOLE
IVERMECTIN
POP-PK
SOIL TRANSMITTED HELMINTHS
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.3
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Trichuris trichiura is a soil-transmitted helminth causing intestinal disease. Albendazole is the standard treatment despite its moderate efficacy, which is improved when co-administered with ivermectin. A fixeddose combination adds practical advantages mainly for mass drug administration. The aim of this article is to define the population pharmacokinetic models and exposure–response of an innovative albendazole/ivermectin combination. Data were obtained from a phase I clinical trial in healthy adults and from a phase II trial in children and adolescents infected with T.trichiura. Nonlinear mixed-effects models were built for albendazole and ivermectin using NONMEM®. Area under the curve was calculated using the empirical Bayes estimates of the pharmacokinetic parameters of each individual and used for evaluation of exposure–response between cure rate and pharmacokinetic exposure. The pharmacokinetics of albendazole was described using a two-compartmental model with first-order absorption and the pharmacokinetics of ivermectin was described using a twocompartmental model with zero-order followed by first-order absorption. Clearance and volume of distribution increased with body weight for both albendazole and ivermectin. Day 1 area under the curve of albendazole and ivermectin from the children and adolescents treated with the combination regimens were similar to the healthy adults treated with control drugs. A flat exposure–response relationship was observed between the cure rate and drug exposure. Population pharmacokinetic of a combination of albendazole and ivermectin in children, adolescents, and adults, either healthy or infected by T.trichiura was described. The dosage selected in the phase II trial was appropriate for the subsequent phase III.
Fil: Algorta, Jaime. Liconsa Sa; España
Fil: Kepha, Stella. Kenya Medical Research Institute; Kenia
Fil: Krolewiecki, Alejandro Javier. Universidad Nacional de Salta. Sede Regional Orán. Instituto de Investigación de Enfermedades Tropicales; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Salta; Argentina
Fil: Li, Hanbin. Quantx Consulting; Estados Unidos
Fil: Giang, Justin. Quantx Consulting; Estados Unidos
Fil: Fleitas, Pedro. Universidad de Barcelona; España
Fil: Mwandawiro, Charles. Kenya Medical Research Institute; Kenia
Fil: Muñoz, José. Universidad de Barcelona; España
description Trichuris trichiura is a soil-transmitted helminth causing intestinal disease. Albendazole is the standard treatment despite its moderate efficacy, which is improved when co-administered with ivermectin. A fixeddose combination adds practical advantages mainly for mass drug administration. The aim of this article is to define the population pharmacokinetic models and exposure–response of an innovative albendazole/ivermectin combination. Data were obtained from a phase I clinical trial in healthy adults and from a phase II trial in children and adolescents infected with T.trichiura. Nonlinear mixed-effects models were built for albendazole and ivermectin using NONMEM®. Area under the curve was calculated using the empirical Bayes estimates of the pharmacokinetic parameters of each individual and used for evaluation of exposure–response between cure rate and pharmacokinetic exposure. The pharmacokinetics of albendazole was described using a two-compartmental model with first-order absorption and the pharmacokinetics of ivermectin was described using a twocompartmental model with zero-order followed by first-order absorption. Clearance and volume of distribution increased with body weight for both albendazole and ivermectin. Day 1 area under the curve of albendazole and ivermectin from the children and adolescents treated with the combination regimens were similar to the healthy adults treated with control drugs. A flat exposure–response relationship was observed between the cure rate and drug exposure. Population pharmacokinetic of a combination of albendazole and ivermectin in children, adolescents, and adults, either healthy or infected by T.trichiura was described. The dosage selected in the phase II trial was appropriate for the subsequent phase III.
publishDate 2024
dc.date.none.fl_str_mv 2024-09
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/11336/247200
Algorta, Jaime; Kepha, Stella; Krolewiecki, Alejandro Javier; Li, Hanbin; Giang, Justin; et al.; Population Pharmacokinetics and Exposure–Response Analysis of a Fixed‐Dose Combination of Ivermectin and Albendazole in Children, Adolescents, and Adults; Nature Publishing Group; Clinical Pharmacology & Therapeutics; 2024; 9-2024; 1-11
0009-9236
CONICET Digital
CONICET
url http://hdl.handle.net/11336/247200
identifier_str_mv Algorta, Jaime; Kepha, Stella; Krolewiecki, Alejandro Javier; Li, Hanbin; Giang, Justin; et al.; Population Pharmacokinetics and Exposure–Response Analysis of a Fixed‐Dose Combination of Ivermectin and Albendazole in Children, Adolescents, and Adults; Nature Publishing Group; Clinical Pharmacology & Therapeutics; 2024; 9-2024; 1-11
0009-9236
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://ascpt.onlinelibrary.wiley.com/doi/10.1002/cpt.3424
info:eu-repo/semantics/altIdentifier/doi/10.1002/cpt.3424
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 Nature Publishing Group
publisher.none.fl_str_mv Nature Publishing Group
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
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score 13.13397

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