Pharmacokinetic Analysis of Melphalan after Superselective Ophthalmic Artery Infusion in Preclinical Models and Retinoblastoma Patients

Autores
Schaiquevich, Paula Susana; Buitrago, Emiliano; Taich, Paula Juliana; Torbidoni, Ana Vanesa; Ceciliano, Alejandro; Fandino, Adriana; Asprea, Marcelo; Requejo, Flavio; Abramson, David H.; Bramuglia, Guillermo Federico; Chantada, Guillermo Luis
Año de publicación
2012
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Purpose: To characterize melphalan pharmacokinetics after super-selective ophthalmic artery infusion (SSOAI) in animals and children with retinoblastoma. Methods: Vitreous and plasma samples of 5 Landrace pigs were obtained over a 4-hour period after SSOAI of melphalan (7 mg). Melphalan 50 % inhibitory concentration (IC50) was evaluated in retinoblastoma cell lines. Plasma samples were obtained from 17 retinoblastoma patients after SSOAI of 3 to 6 mg of melphalan to one (n=14) or two eyes (n=3). Correlation between plasma pharmacokinetics and age, dosage and systemic toxicity was studied in patients. Results: In animals, melphalan peak vitreous levels were greater than its IC50 and resulted in 3-fold vitreous-to-plasma exposure. In patients, large variability in pharmacokinetic parameters was observed and it was explained mainly by body weight (p< 0.05). A significantly higher systemic area under the curve was obtained in children receiving more than 0.48 mg/kg for bilateral tandem infusions (p< 0.05). These children had 50 % probability of grade 3-4 neutropenia. Plasma concentrations after 2 and 4 hours of SSOAI were significantly higher in these children (p< 0.05). A synergistic cytotoxic effect of melphalan and topotecan was evident in cell lines (p<0.001). Conclusions. Potentially active levels of melphalan after SSOAI were achieved in the vitreous of animals. Low systemic exposure was found in animals and children. Doses greater than 0.48 mg/kg, given for bilateral tandem infusions, were associated with significantly higher plasma levels and increased risk of neutropenia. Synergistic in vitro cytotoxicity between melphalan and topotecan favors combination treatment.
Fil: Schaiquevich, Paula Susana. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina
Fil: Buitrago, Emiliano. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; Argentina
Fil: Taich, Paula Juliana. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina
Fil: Torbidoni, Ana Vanesa. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina
Fil: Ceciliano, Alejandro. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina
Fil: Fandino, Adriana. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina
Fil: Asprea, Marcelo. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina
Fil: Requejo, Flavio. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina
Fil: Abramson, David H.. Memorial Sloan-Kettering Cancer Center; Estados Unidos
Fil: Bramuglia, Guillermo Federico. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; Argentina
Fil: Chantada, Guillermo Luis. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina
Materia
Pharmacokinetics
Super-selective ophthalmic artery nfusion
Retinoblastoma
Melphalan
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:11336/272858
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/272858
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Pharmacokinetic Analysis of Melphalan after Superselective Ophthalmic Artery Infusion in Preclinical Models and Retinoblastoma PatientsSchaiquevich, Paula SusanaBuitrago, EmilianoTaich, Paula JulianaTorbidoni, Ana VanesaCeciliano, AlejandroFandino, AdrianaAsprea, MarceloRequejo, FlavioAbramson, David H.Bramuglia, Guillermo FedericoChantada, Guillermo LuisPharmacokineticsSuper-selective ophthalmic artery nfusionRetinoblastomaMelphalanhttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Purpose: To characterize melphalan pharmacokinetics after super-selective ophthalmic artery infusion (SSOAI) in animals and children with retinoblastoma. Methods: Vitreous and plasma samples of 5 Landrace pigs were obtained over a 4-hour period after SSOAI of melphalan (7 mg). Melphalan 50 % inhibitory concentration (IC50) was evaluated in retinoblastoma cell lines. Plasma samples were obtained from 17 retinoblastoma patients after SSOAI of 3 to 6 mg of melphalan to one (n=14) or two eyes (n=3). Correlation between plasma pharmacokinetics and age, dosage and systemic toxicity was studied in patients. Results: In animals, melphalan peak vitreous levels were greater than its IC50 and resulted in 3-fold vitreous-to-plasma exposure. In patients, large variability in pharmacokinetic parameters was observed and it was explained mainly by body weight (p< 0.05). A significantly higher systemic area under the curve was obtained in children receiving more than 0.48 mg/kg for bilateral tandem infusions (p< 0.05). These children had 50 % probability of grade 3-4 neutropenia. Plasma concentrations after 2 and 4 hours of SSOAI were significantly higher in these children (p< 0.05). A synergistic cytotoxic effect of melphalan and topotecan was evident in cell lines (p<0.001). Conclusions. Potentially active levels of melphalan after SSOAI were achieved in the vitreous of animals. Low systemic exposure was found in animals and children. Doses greater than 0.48 mg/kg, given for bilateral tandem infusions, were associated with significantly higher plasma levels and increased risk of neutropenia. Synergistic in vitro cytotoxicity between melphalan and topotecan favors combination treatment.Fil: Schaiquevich, Paula Susana. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Buitrago, Emiliano. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; ArgentinaFil: Taich, Paula Juliana. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Torbidoni, Ana Vanesa. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Ceciliano, Alejandro. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Fandino, Adriana. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Asprea, Marcelo. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Requejo, Flavio. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Abramson, David H.. Memorial Sloan-Kettering Cancer Center; Estados UnidosFil: Bramuglia, Guillermo Federico. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; ArgentinaFil: Chantada, Guillermo Luis. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaAssociation for Research in Vision and Ophthalmology2012-05info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/272858Schaiquevich, Paula Susana; Buitrago, Emiliano; Taich, Paula Juliana; Torbidoni, Ana Vanesa; Ceciliano, Alejandro; et al.; Pharmacokinetic Analysis of Melphalan after Superselective Ophthalmic Artery Infusion in Preclinical Models and Retinoblastoma Patients; Association for Research in Vision and Ophthalmology; Investigative Opthalmology & Visual Science; 53; 7; 5-2012; 4205-42120146-04041552-5783CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://iovs.arvojournals.org/article.aspx?articleid=2129657info:eu-repo/semantics/altIdentifier/doi/10.1167/iovs.12-9501info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-15T15:31:05Zoai:ri.conicet.gov.ar:11336/272858instacron: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:34982025-10-15 15:31:05.599CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Pharmacokinetic Analysis of Melphalan after Superselective Ophthalmic Artery Infusion in Preclinical Models and Retinoblastoma Patients
title Pharmacokinetic Analysis of Melphalan after Superselective Ophthalmic Artery Infusion in Preclinical Models and Retinoblastoma Patients
spellingShingle Pharmacokinetic Analysis of Melphalan after Superselective Ophthalmic Artery Infusion in Preclinical Models and Retinoblastoma Patients
Schaiquevich, Paula Susana
Pharmacokinetics
Super-selective ophthalmic artery nfusion
Retinoblastoma
Melphalan
title_short Pharmacokinetic Analysis of Melphalan after Superselective Ophthalmic Artery Infusion in Preclinical Models and Retinoblastoma Patients
title_full Pharmacokinetic Analysis of Melphalan after Superselective Ophthalmic Artery Infusion in Preclinical Models and Retinoblastoma Patients
title_fullStr Pharmacokinetic Analysis of Melphalan after Superselective Ophthalmic Artery Infusion in Preclinical Models and Retinoblastoma Patients
title_full_unstemmed Pharmacokinetic Analysis of Melphalan after Superselective Ophthalmic Artery Infusion in Preclinical Models and Retinoblastoma Patients
title_sort Pharmacokinetic Analysis of Melphalan after Superselective Ophthalmic Artery Infusion in Preclinical Models and Retinoblastoma Patients
dc.creator.none.fl_str_mv Schaiquevich, Paula Susana
Buitrago, Emiliano
Taich, Paula Juliana
Torbidoni, Ana Vanesa
Ceciliano, Alejandro
Fandino, Adriana
Asprea, Marcelo
Requejo, Flavio
Abramson, David H.
Bramuglia, Guillermo Federico
Chantada, Guillermo Luis
author Schaiquevich, Paula Susana
author_facet Schaiquevich, Paula Susana
Buitrago, Emiliano
Taich, Paula Juliana
Torbidoni, Ana Vanesa
Ceciliano, Alejandro
Fandino, Adriana
Asprea, Marcelo
Requejo, Flavio
Abramson, David H.
Bramuglia, Guillermo Federico
Chantada, Guillermo Luis
author_role author
author2 Buitrago, Emiliano
Taich, Paula Juliana
Torbidoni, Ana Vanesa
Ceciliano, Alejandro
Fandino, Adriana
Asprea, Marcelo
Requejo, Flavio
Abramson, David H.
Bramuglia, Guillermo Federico
Chantada, Guillermo Luis
author2_role author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Pharmacokinetics
Super-selective ophthalmic artery nfusion
Retinoblastoma
Melphalan
topic Pharmacokinetics
Super-selective ophthalmic artery nfusion
Retinoblastoma
Melphalan
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Purpose: To characterize melphalan pharmacokinetics after super-selective ophthalmic artery infusion (SSOAI) in animals and children with retinoblastoma. Methods: Vitreous and plasma samples of 5 Landrace pigs were obtained over a 4-hour period after SSOAI of melphalan (7 mg). Melphalan 50 % inhibitory concentration (IC50) was evaluated in retinoblastoma cell lines. Plasma samples were obtained from 17 retinoblastoma patients after SSOAI of 3 to 6 mg of melphalan to one (n=14) or two eyes (n=3). Correlation between plasma pharmacokinetics and age, dosage and systemic toxicity was studied in patients. Results: In animals, melphalan peak vitreous levels were greater than its IC50 and resulted in 3-fold vitreous-to-plasma exposure. In patients, large variability in pharmacokinetic parameters was observed and it was explained mainly by body weight (p< 0.05). A significantly higher systemic area under the curve was obtained in children receiving more than 0.48 mg/kg for bilateral tandem infusions (p< 0.05). These children had 50 % probability of grade 3-4 neutropenia. Plasma concentrations after 2 and 4 hours of SSOAI were significantly higher in these children (p< 0.05). A synergistic cytotoxic effect of melphalan and topotecan was evident in cell lines (p<0.001). Conclusions. Potentially active levels of melphalan after SSOAI were achieved in the vitreous of animals. Low systemic exposure was found in animals and children. Doses greater than 0.48 mg/kg, given for bilateral tandem infusions, were associated with significantly higher plasma levels and increased risk of neutropenia. Synergistic in vitro cytotoxicity between melphalan and topotecan favors combination treatment.
Fil: Schaiquevich, Paula Susana. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina
Fil: Buitrago, Emiliano. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; Argentina
Fil: Taich, Paula Juliana. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina
Fil: Torbidoni, Ana Vanesa. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina
Fil: Ceciliano, Alejandro. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina
Fil: Fandino, Adriana. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina
Fil: Asprea, Marcelo. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina
Fil: Requejo, Flavio. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina
Fil: Abramson, David H.. Memorial Sloan-Kettering Cancer Center; Estados Unidos
Fil: Bramuglia, Guillermo Federico. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; Argentina
Fil: Chantada, Guillermo Luis. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina
description Purpose: To characterize melphalan pharmacokinetics after super-selective ophthalmic artery infusion (SSOAI) in animals and children with retinoblastoma. Methods: Vitreous and plasma samples of 5 Landrace pigs were obtained over a 4-hour period after SSOAI of melphalan (7 mg). Melphalan 50 % inhibitory concentration (IC50) was evaluated in retinoblastoma cell lines. Plasma samples were obtained from 17 retinoblastoma patients after SSOAI of 3 to 6 mg of melphalan to one (n=14) or two eyes (n=3). Correlation between plasma pharmacokinetics and age, dosage and systemic toxicity was studied in patients. Results: In animals, melphalan peak vitreous levels were greater than its IC50 and resulted in 3-fold vitreous-to-plasma exposure. In patients, large variability in pharmacokinetic parameters was observed and it was explained mainly by body weight (p< 0.05). A significantly higher systemic area under the curve was obtained in children receiving more than 0.48 mg/kg for bilateral tandem infusions (p< 0.05). These children had 50 % probability of grade 3-4 neutropenia. Plasma concentrations after 2 and 4 hours of SSOAI were significantly higher in these children (p< 0.05). A synergistic cytotoxic effect of melphalan and topotecan was evident in cell lines (p<0.001). Conclusions. Potentially active levels of melphalan after SSOAI were achieved in the vitreous of animals. Low systemic exposure was found in animals and children. Doses greater than 0.48 mg/kg, given for bilateral tandem infusions, were associated with significantly higher plasma levels and increased risk of neutropenia. Synergistic in vitro cytotoxicity between melphalan and topotecan favors combination treatment.
publishDate 2012
dc.date.none.fl_str_mv 2012-05
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/11336/272858
Schaiquevich, Paula Susana; Buitrago, Emiliano; Taich, Paula Juliana; Torbidoni, Ana Vanesa; Ceciliano, Alejandro; et al.; Pharmacokinetic Analysis of Melphalan after Superselective Ophthalmic Artery Infusion in Preclinical Models and Retinoblastoma Patients; Association for Research in Vision and Ophthalmology; Investigative Opthalmology & Visual Science; 53; 7; 5-2012; 4205-4212
0146-0404
1552-5783
CONICET Digital
CONICET
url http://hdl.handle.net/11336/272858
identifier_str_mv Schaiquevich, Paula Susana; Buitrago, Emiliano; Taich, Paula Juliana; Torbidoni, Ana Vanesa; Ceciliano, Alejandro; et al.; Pharmacokinetic Analysis of Melphalan after Superselective Ophthalmic Artery Infusion in Preclinical Models and Retinoblastoma Patients; Association for Research in Vision and Ophthalmology; Investigative Opthalmology & Visual Science; 53; 7; 5-2012; 4205-4212
0146-0404
1552-5783
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://iovs.arvojournals.org/article.aspx?articleid=2129657
info:eu-repo/semantics/altIdentifier/doi/10.1167/iovs.12-9501
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
application/pdf
application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Association for Research in Vision and Ophthalmology
publisher.none.fl_str_mv Association for Research in Vision and Ophthalmology
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 13.22299

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