Population Pharmacokinetic Study of Benznidazole in Pediatric Chagas Disease Suggests Efficacy despite Lower Plasma Concentrations than in Adults

Autores
Altcheh, Jaime Marcelo; Moscatelli, Guillermo; Mastrantonio Garrido, Guido Enrique; Moroni, Samanta; Giglio, Norberto; Marson, María Elena; Ballering, Griselda; Bisio, Margarita María Catalina; Koren, Gideon; García Bournissen, Facundo
Año de publicación
2014
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Introduction:Chagas disease, caused by the parasite Trypanosoma cruzi, can lead to long term cardiac morbidity. Treatment of children with benznidazole is effective, but no pediatric pharmacokinetics data are available and clinical pharmacology information on the drug is scarce.Patients and Methods:Prospective population pharmacokinetic (PK) cohort study in children 2-12 years old with Chagas disease treated with oral benznidazole 5-8 mg/kg/day BID for 60 days. (clinicaltrials.gov #NCT00699387).Results:Forty children were enrolled in the study. Mean age was 7.3 years. A total of 117 samples were obtained from 38 patients for PK analysis. A one compartment model best fit the data. Weight-corrected clearance rate (CL/F) showed a good correlation with age, with younger patients having a significantly higher CL/F than older children and adults. Simulated median steady-state benznidazole concentrations, based on model parameters, were lower for children in our study than for adults and lowest for children under 7 years of age. Treatment was efficacious in the 37 patients who completed the treatment course, and well tolerated, with few, and mild, adverse drug reactions (ADRs).Discussion:Observed benznidazole plasma concentrations in children were markedly lower than those previously reported in adults (treated with comparable mg/kg doses), possibly due to a higher CL/F in smaller children. These lower blood concentrations were nevertheless associated to a high therapeutic response in our cohort. Unlike adults, children have few adverse reactions to the drug, suggesting that there may be a direct correlation between drug concentrations and incidence of ADRs. Our results suggest that studies with lower doses in adults may be warranted.Trial Registration:ClinicalTrails.gov NCT00699387.
Fil: Altcheh, Jaime Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez". Servicio de Parasitología y Chagas; Argentina
Fil: Moscatelli, Guillermo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez". Servicio de Parasitología y Chagas; Argentina
Fil: Mastrantonio Garrido, Guido Enrique. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; Argentina. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Departamento de Ciencias Biológicas. Área de Toxicología; Argentina
Fil: Moroni, Samanta. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez". Servicio de Parasitología y Chagas; Argentina
Fil: Giglio, Norberto. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez". Servicio de Parasitología y Chagas; Argentina
Fil: Marson, María Elena. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; Argentina. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Departamento de Ciencias Biológicas. Área de Toxicología; Argentina
Fil: Ballering, Griselda. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez". Servicio de Parasitología y Chagas; Argentina
Fil: Bisio, Margarita María Catalina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez". Servicio de Parasitología y Chagas; Argentina
Fil: Koren, Gideon. University of Toronto. Hospital for Sick Children. División of Clinical Pharmacology & Toxicology; Canadá
Fil: García Bournissen, Facundo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez". Servicio de Parasitología y Chagas; Argentina. University of Toronto. Hospital for Sick Children. División of Clinical Pharmacology & Toxicology; Canadá
Materia
pharmacokinetics
benznidazole
chagas disease
pediatrics
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/80541
Acceder
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network_name_str CONICET Digital (CONICET)
spelling Population Pharmacokinetic Study of Benznidazole in Pediatric Chagas Disease Suggests Efficacy despite Lower Plasma Concentrations than in AdultsAltcheh, Jaime MarceloMoscatelli, GuillermoMastrantonio Garrido, Guido EnriqueMoroni, SamantaGiglio, NorbertoMarson, María ElenaBallering, GriseldaBisio, Margarita María CatalinaKoren, GideonGarcía Bournissen, Facundopharmacokineticsbenznidazolechagas diseasepediatricshttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3https://purl.org/becyt/ford/3.2https://purl.org/becyt/ford/3Introduction:Chagas disease, caused by the parasite Trypanosoma cruzi, can lead to long term cardiac morbidity. Treatment of children with benznidazole is effective, but no pediatric pharmacokinetics data are available and clinical pharmacology information on the drug is scarce.Patients and Methods:Prospective population pharmacokinetic (PK) cohort study in children 2-12 years old with Chagas disease treated with oral benznidazole 5-8 mg/kg/day BID for 60 days. (clinicaltrials.gov #NCT00699387).Results:Forty children were enrolled in the study. Mean age was 7.3 years. A total of 117 samples were obtained from 38 patients for PK analysis. A one compartment model best fit the data. Weight-corrected clearance rate (CL/F) showed a good correlation with age, with younger patients having a significantly higher CL/F than older children and adults. Simulated median steady-state benznidazole concentrations, based on model parameters, were lower for children in our study than for adults and lowest for children under 7 years of age. Treatment was efficacious in the 37 patients who completed the treatment course, and well tolerated, with few, and mild, adverse drug reactions (ADRs).Discussion:Observed benznidazole plasma concentrations in children were markedly lower than those previously reported in adults (treated with comparable mg/kg doses), possibly due to a higher CL/F in smaller children. These lower blood concentrations were nevertheless associated to a high therapeutic response in our cohort. Unlike adults, children have few adverse reactions to the drug, suggesting that there may be a direct correlation between drug concentrations and incidence of ADRs. Our results suggest that studies with lower doses in adults may be warranted.Trial Registration:ClinicalTrails.gov NCT00699387.Fil: Altcheh, Jaime Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez". Servicio de Parasitología y Chagas; ArgentinaFil: Moscatelli, Guillermo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez". Servicio de Parasitología y Chagas; ArgentinaFil: Mastrantonio Garrido, Guido Enrique. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; Argentina. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Departamento de Ciencias Biológicas. Área de Toxicología; ArgentinaFil: Moroni, Samanta. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez". Servicio de Parasitología y Chagas; ArgentinaFil: Giglio, Norberto. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez". Servicio de Parasitología y Chagas; ArgentinaFil: Marson, María Elena. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; Argentina. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Departamento de Ciencias Biológicas. Área de Toxicología; ArgentinaFil: Ballering, Griselda. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez". Servicio de Parasitología y Chagas; ArgentinaFil: Bisio, Margarita María Catalina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez". Servicio de Parasitología y Chagas; ArgentinaFil: Koren, Gideon. University of Toronto. Hospital for Sick Children. División of Clinical Pharmacology & Toxicology; CanadáFil: García Bournissen, Facundo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez". Servicio de Parasitología y Chagas; Argentina. University of Toronto. Hospital for Sick Children. División of Clinical Pharmacology & Toxicology; CanadáPublic Library of Science2014-05info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/80541Altcheh, Jaime Marcelo; Moscatelli, Guillermo; Mastrantonio Garrido, Guido Enrique; Moroni, Samanta; Giglio, Norberto; et al.; Population Pharmacokinetic Study of Benznidazole in Pediatric Chagas Disease Suggests Efficacy despite Lower Plasma Concentrations than in Adults; Public Library of Science; Neglected Tropical Diseases; 8; 5; 5-2014; 1-91935-2735CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0002907info:eu-repo/semantics/altIdentifier/doi/10.1371/journal.pntd.0002907info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T10:08:10Zoai:ri.conicet.gov.ar:11336/80541instacron: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 10:08:11.079CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Population Pharmacokinetic Study of Benznidazole in Pediatric Chagas Disease Suggests Efficacy despite Lower Plasma Concentrations than in Adults
title Population Pharmacokinetic Study of Benznidazole in Pediatric Chagas Disease Suggests Efficacy despite Lower Plasma Concentrations than in Adults
spellingShingle Population Pharmacokinetic Study of Benznidazole in Pediatric Chagas Disease Suggests Efficacy despite Lower Plasma Concentrations than in Adults
Altcheh, Jaime Marcelo
pharmacokinetics
benznidazole
chagas disease
pediatrics
title_short Population Pharmacokinetic Study of Benznidazole in Pediatric Chagas Disease Suggests Efficacy despite Lower Plasma Concentrations than in Adults
title_full Population Pharmacokinetic Study of Benznidazole in Pediatric Chagas Disease Suggests Efficacy despite Lower Plasma Concentrations than in Adults
title_fullStr Population Pharmacokinetic Study of Benznidazole in Pediatric Chagas Disease Suggests Efficacy despite Lower Plasma Concentrations than in Adults
title_full_unstemmed Population Pharmacokinetic Study of Benznidazole in Pediatric Chagas Disease Suggests Efficacy despite Lower Plasma Concentrations than in Adults
title_sort Population Pharmacokinetic Study of Benznidazole in Pediatric Chagas Disease Suggests Efficacy despite Lower Plasma Concentrations than in Adults
dc.creator.none.fl_str_mv Altcheh, Jaime Marcelo
Moscatelli, Guillermo
Mastrantonio Garrido, Guido Enrique
Moroni, Samanta
Giglio, Norberto
Marson, María Elena
Ballering, Griselda
Bisio, Margarita María Catalina
Koren, Gideon
García Bournissen, Facundo
author Altcheh, Jaime Marcelo
author_facet Altcheh, Jaime Marcelo
Moscatelli, Guillermo
Mastrantonio Garrido, Guido Enrique
Moroni, Samanta
Giglio, Norberto
Marson, María Elena
Ballering, Griselda
Bisio, Margarita María Catalina
Koren, Gideon
García Bournissen, Facundo
author_role author
author2 Moscatelli, Guillermo
Mastrantonio Garrido, Guido Enrique
Moroni, Samanta
Giglio, Norberto
Marson, María Elena
Ballering, Griselda
Bisio, Margarita María Catalina
Koren, Gideon
García Bournissen, Facundo
author2_role author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv pharmacokinetics
benznidazole
chagas disease
pediatrics
topic pharmacokinetics
benznidazole
chagas disease
pediatrics
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
https://purl.org/becyt/ford/3.2
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Introduction:Chagas disease, caused by the parasite Trypanosoma cruzi, can lead to long term cardiac morbidity. Treatment of children with benznidazole is effective, but no pediatric pharmacokinetics data are available and clinical pharmacology information on the drug is scarce.Patients and Methods:Prospective population pharmacokinetic (PK) cohort study in children 2-12 years old with Chagas disease treated with oral benznidazole 5-8 mg/kg/day BID for 60 days. (clinicaltrials.gov #NCT00699387).Results:Forty children were enrolled in the study. Mean age was 7.3 years. A total of 117 samples were obtained from 38 patients for PK analysis. A one compartment model best fit the data. Weight-corrected clearance rate (CL/F) showed a good correlation with age, with younger patients having a significantly higher CL/F than older children and adults. Simulated median steady-state benznidazole concentrations, based on model parameters, were lower for children in our study than for adults and lowest for children under 7 years of age. Treatment was efficacious in the 37 patients who completed the treatment course, and well tolerated, with few, and mild, adverse drug reactions (ADRs).Discussion:Observed benznidazole plasma concentrations in children were markedly lower than those previously reported in adults (treated with comparable mg/kg doses), possibly due to a higher CL/F in smaller children. These lower blood concentrations were nevertheless associated to a high therapeutic response in our cohort. Unlike adults, children have few adverse reactions to the drug, suggesting that there may be a direct correlation between drug concentrations and incidence of ADRs. Our results suggest that studies with lower doses in adults may be warranted.Trial Registration:ClinicalTrails.gov NCT00699387.
Fil: Altcheh, Jaime Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez". Servicio de Parasitología y Chagas; Argentina
Fil: Moscatelli, Guillermo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez". Servicio de Parasitología y Chagas; Argentina
Fil: Mastrantonio Garrido, Guido Enrique. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; Argentina. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Departamento de Ciencias Biológicas. Área de Toxicología; Argentina
Fil: Moroni, Samanta. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez". Servicio de Parasitología y Chagas; Argentina
Fil: Giglio, Norberto. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez". Servicio de Parasitología y Chagas; Argentina
Fil: Marson, María Elena. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; Argentina. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Departamento de Ciencias Biológicas. Área de Toxicología; Argentina
Fil: Ballering, Griselda. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez". Servicio de Parasitología y Chagas; Argentina
Fil: Bisio, Margarita María Catalina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez". Servicio de Parasitología y Chagas; Argentina
Fil: Koren, Gideon. University of Toronto. Hospital for Sick Children. División of Clinical Pharmacology & Toxicology; Canadá
Fil: García Bournissen, Facundo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez". Servicio de Parasitología y Chagas; Argentina. University of Toronto. Hospital for Sick Children. División of Clinical Pharmacology & Toxicology; Canadá
description Introduction:Chagas disease, caused by the parasite Trypanosoma cruzi, can lead to long term cardiac morbidity. Treatment of children with benznidazole is effective, but no pediatric pharmacokinetics data are available and clinical pharmacology information on the drug is scarce.Patients and Methods:Prospective population pharmacokinetic (PK) cohort study in children 2-12 years old with Chagas disease treated with oral benznidazole 5-8 mg/kg/day BID for 60 days. (clinicaltrials.gov #NCT00699387).Results:Forty children were enrolled in the study. Mean age was 7.3 years. A total of 117 samples were obtained from 38 patients for PK analysis. A one compartment model best fit the data. Weight-corrected clearance rate (CL/F) showed a good correlation with age, with younger patients having a significantly higher CL/F than older children and adults. Simulated median steady-state benznidazole concentrations, based on model parameters, were lower for children in our study than for adults and lowest for children under 7 years of age. Treatment was efficacious in the 37 patients who completed the treatment course, and well tolerated, with few, and mild, adverse drug reactions (ADRs).Discussion:Observed benznidazole plasma concentrations in children were markedly lower than those previously reported in adults (treated with comparable mg/kg doses), possibly due to a higher CL/F in smaller children. These lower blood concentrations were nevertheless associated to a high therapeutic response in our cohort. Unlike adults, children have few adverse reactions to the drug, suggesting that there may be a direct correlation between drug concentrations and incidence of ADRs. Our results suggest that studies with lower doses in adults may be warranted.Trial Registration:ClinicalTrails.gov NCT00699387.
publishDate 2014
dc.date.none.fl_str_mv 2014-05
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
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info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/80541
Altcheh, Jaime Marcelo; Moscatelli, Guillermo; Mastrantonio Garrido, Guido Enrique; Moroni, Samanta; Giglio, Norberto; et al.; Population Pharmacokinetic Study of Benznidazole in Pediatric Chagas Disease Suggests Efficacy despite Lower Plasma Concentrations than in Adults; Public Library of Science; Neglected Tropical Diseases; 8; 5; 5-2014; 1-9
1935-2735
CONICET Digital
CONICET
url http://hdl.handle.net/11336/80541
identifier_str_mv Altcheh, Jaime Marcelo; Moscatelli, Guillermo; Mastrantonio Garrido, Guido Enrique; Moroni, Samanta; Giglio, Norberto; et al.; Population Pharmacokinetic Study of Benznidazole in Pediatric Chagas Disease Suggests Efficacy despite Lower Plasma Concentrations than in Adults; Public Library of Science; Neglected Tropical Diseases; 8; 5; 5-2014; 1-9
1935-2735
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
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info:eu-repo/semantics/altIdentifier/doi/10.1371/journal.pntd.0002907
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
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publisher.none.fl_str_mv Public Library of Science
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repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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