GSTA1 genetic variants and conditioning regimen : missing key factors in dosing guidelines of busulfan in pediatric hematopoietic stem cell transplantation
Autor(a) principal: | |
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Data de Publicação: | 2017 |
Outros Autores: | , , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Institucional da UFRGS |
Texto Completo: | http://hdl.handle.net/10183/204380 |
Resumo: | Busulfan (Bu) is a key component of conditioning regimens used before hematopoietic stem cell transplantation (SCT) in children. Different predictive methods have been used to calculate the first dose of Bu. To evaluate the necessity of further improvements, we retrospectively analyzed the currently available weight- and age-based guidelines to calculate the first doses in 101 children who underwent allogenic SCT in CHU Sainte-Justine, Montreal, after an intravenous Bu-containing conditioning regimen according to genetic and clinical factors. The measured areas under the curve (AUCs) were within target (900 to 1500 µM/min) in 38.7% of patients after the administration of the first dose calculated based on age and weight, as locally recommended. GSTA1 diplotypes linked to poor Bu metabolism (G3) and fludarabine-containing regimens were the only factors associated with AUC within target (OR, 4.7 [95% CI, 1.1 to 19.8, P = .04]; and OR, 9.9 [95% CI, 1.6 to 61.7, P = .01], respectively). From the 11 methods selected for dose calculation, the percentage of AUCs within the target varied between 16% and 74%. In some models G3 was associated with AUCs within the therapeutic and the toxic range, whereas rapid metabolizers (G1) were correlated with subtherapeutic AUCs when different methods were used. These associations were confirmed by clearance-prediction analysis, in which GSTA1 diplotypes consistently influenced the prediction errors of the methods. These findings suggest that these factors should be considered in Bu dose prediction in addition to the anthropometric data from patients. Furthermore, our data indicated that GSTA1 diplotypes was a factor that should be included in future population pharmacokinetic models, including similar conditioning regiments, to improve the prediction of Bu exposure after its initial dose. |
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Nava, Tiago RodriguesRezgui, Mohammed AzizUppugunduri, Chakradhara Rao SatyanarayanaCurtis, Patricia Huezo DiazThéorêt, YvesDuval, MichelDaudt, Liane EstevesAnsari, Marc A.H.Krajinović, MajaBittencourt, Henrique Neves da Silva2020-01-16T04:10:27Z20171523-6536http://hdl.handle.net/10183/204380001107090Busulfan (Bu) is a key component of conditioning regimens used before hematopoietic stem cell transplantation (SCT) in children. Different predictive methods have been used to calculate the first dose of Bu. To evaluate the necessity of further improvements, we retrospectively analyzed the currently available weight- and age-based guidelines to calculate the first doses in 101 children who underwent allogenic SCT in CHU Sainte-Justine, Montreal, after an intravenous Bu-containing conditioning regimen according to genetic and clinical factors. The measured areas under the curve (AUCs) were within target (900 to 1500 µM/min) in 38.7% of patients after the administration of the first dose calculated based on age and weight, as locally recommended. GSTA1 diplotypes linked to poor Bu metabolism (G3) and fludarabine-containing regimens were the only factors associated with AUC within target (OR, 4.7 [95% CI, 1.1 to 19.8, P = .04]; and OR, 9.9 [95% CI, 1.6 to 61.7, P = .01], respectively). From the 11 methods selected for dose calculation, the percentage of AUCs within the target varied between 16% and 74%. In some models G3 was associated with AUCs within the therapeutic and the toxic range, whereas rapid metabolizers (G1) were correlated with subtherapeutic AUCs when different methods were used. These associations were confirmed by clearance-prediction analysis, in which GSTA1 diplotypes consistently influenced the prediction errors of the methods. These findings suggest that these factors should be considered in Bu dose prediction in addition to the anthropometric data from patients. Furthermore, our data indicated that GSTA1 diplotypes was a factor that should be included in future population pharmacokinetic models, including similar conditioning regiments, to improve the prediction of Bu exposure after its initial dose.application/pdfengBiology of blood and marrow transplantation. Charlottesville. vol. 23, no. 11 (Nov. 2017), p. 1918-1924BussulfanoDosagemFarmacogenéticaFarmacocinéticaCriançaBusulfanDosing guidelinesPharmacogeneticsPharmacokineticsGSTA1ChildrenGSTA1 genetic variants and conditioning regimen : missing key factors in dosing guidelines of busulfan in pediatric hematopoietic stem cell transplantationEstrangeiroinfo:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/openAccessreponame:Repositório Institucional da UFRGSinstname:Universidade Federal do Rio Grande do Sul (UFRGS)instacron:UFRGSTEXT001107090.pdf.txt001107090.pdf.txtExtracted Texttext/plain46852http://www.lume.ufrgs.br/bitstream/10183/204380/2/001107090.pdf.txtf8390bc92d18edb6f8e7cc5580b8375cMD52ORIGINAL001107090.pdfTexto completo (inglês)application/pdf387304http://www.lume.ufrgs.br/bitstream/10183/204380/1/001107090.pdf3580cbbc5d3cbf34363173e6a67bf467MD5110183/2043802020-01-17 05:10:53.495158oai:www.lume.ufrgs.br:10183/204380Repositório de PublicaçõesPUBhttps://lume.ufrgs.br/oai/requestopendoar:2020-01-17T07:10:53Repositório Institucional da UFRGS - Universidade Federal do Rio Grande do Sul (UFRGS)false |
dc.title.pt_BR.fl_str_mv |
GSTA1 genetic variants and conditioning regimen : missing key factors in dosing guidelines of busulfan in pediatric hematopoietic stem cell transplantation |
title |
GSTA1 genetic variants and conditioning regimen : missing key factors in dosing guidelines of busulfan in pediatric hematopoietic stem cell transplantation |
spellingShingle |
GSTA1 genetic variants and conditioning regimen : missing key factors in dosing guidelines of busulfan in pediatric hematopoietic stem cell transplantation Nava, Tiago Rodrigues Bussulfano Dosagem Farmacogenética Farmacocinética Criança Busulfan Dosing guidelines Pharmacogenetics Pharmacokinetics GSTA1 Children |
title_short |
GSTA1 genetic variants and conditioning regimen : missing key factors in dosing guidelines of busulfan in pediatric hematopoietic stem cell transplantation |
title_full |
GSTA1 genetic variants and conditioning regimen : missing key factors in dosing guidelines of busulfan in pediatric hematopoietic stem cell transplantation |
title_fullStr |
GSTA1 genetic variants and conditioning regimen : missing key factors in dosing guidelines of busulfan in pediatric hematopoietic stem cell transplantation |
title_full_unstemmed |
GSTA1 genetic variants and conditioning regimen : missing key factors in dosing guidelines of busulfan in pediatric hematopoietic stem cell transplantation |
title_sort |
GSTA1 genetic variants and conditioning regimen : missing key factors in dosing guidelines of busulfan in pediatric hematopoietic stem cell transplantation |
author |
Nava, Tiago Rodrigues |
author_facet |
Nava, Tiago Rodrigues Rezgui, Mohammed Aziz Uppugunduri, Chakradhara Rao Satyanarayana Curtis, Patricia Huezo Diaz Théorêt, Yves Duval, Michel Daudt, Liane Esteves Ansari, Marc A.H. Krajinović, Maja Bittencourt, Henrique Neves da Silva |
author_role |
author |
author2 |
Rezgui, Mohammed Aziz Uppugunduri, Chakradhara Rao Satyanarayana Curtis, Patricia Huezo Diaz Théorêt, Yves Duval, Michel Daudt, Liane Esteves Ansari, Marc A.H. Krajinović, Maja Bittencourt, Henrique Neves da Silva |
author2_role |
author author author author author author author author author |
dc.contributor.author.fl_str_mv |
Nava, Tiago Rodrigues Rezgui, Mohammed Aziz Uppugunduri, Chakradhara Rao Satyanarayana Curtis, Patricia Huezo Diaz Théorêt, Yves Duval, Michel Daudt, Liane Esteves Ansari, Marc A.H. Krajinović, Maja Bittencourt, Henrique Neves da Silva |
dc.subject.por.fl_str_mv |
Bussulfano Dosagem Farmacogenética Farmacocinética Criança |
topic |
Bussulfano Dosagem Farmacogenética Farmacocinética Criança Busulfan Dosing guidelines Pharmacogenetics Pharmacokinetics GSTA1 Children |
dc.subject.eng.fl_str_mv |
Busulfan Dosing guidelines Pharmacogenetics Pharmacokinetics GSTA1 Children |
description |
Busulfan (Bu) is a key component of conditioning regimens used before hematopoietic stem cell transplantation (SCT) in children. Different predictive methods have been used to calculate the first dose of Bu. To evaluate the necessity of further improvements, we retrospectively analyzed the currently available weight- and age-based guidelines to calculate the first doses in 101 children who underwent allogenic SCT in CHU Sainte-Justine, Montreal, after an intravenous Bu-containing conditioning regimen according to genetic and clinical factors. The measured areas under the curve (AUCs) were within target (900 to 1500 µM/min) in 38.7% of patients after the administration of the first dose calculated based on age and weight, as locally recommended. GSTA1 diplotypes linked to poor Bu metabolism (G3) and fludarabine-containing regimens were the only factors associated with AUC within target (OR, 4.7 [95% CI, 1.1 to 19.8, P = .04]; and OR, 9.9 [95% CI, 1.6 to 61.7, P = .01], respectively). From the 11 methods selected for dose calculation, the percentage of AUCs within the target varied between 16% and 74%. In some models G3 was associated with AUCs within the therapeutic and the toxic range, whereas rapid metabolizers (G1) were correlated with subtherapeutic AUCs when different methods were used. These associations were confirmed by clearance-prediction analysis, in which GSTA1 diplotypes consistently influenced the prediction errors of the methods. These findings suggest that these factors should be considered in Bu dose prediction in addition to the anthropometric data from patients. Furthermore, our data indicated that GSTA1 diplotypes was a factor that should be included in future population pharmacokinetic models, including similar conditioning regiments, to improve the prediction of Bu exposure after its initial dose. |
publishDate |
2017 |
dc.date.issued.fl_str_mv |
2017 |
dc.date.accessioned.fl_str_mv |
2020-01-16T04:10:27Z |
dc.type.driver.fl_str_mv |
Estrangeiro info:eu-repo/semantics/article |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://hdl.handle.net/10183/204380 |
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1523-6536 |
dc.identifier.nrb.pt_BR.fl_str_mv |
001107090 |
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1523-6536 001107090 |
url |
http://hdl.handle.net/10183/204380 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.ispartof.pt_BR.fl_str_mv |
Biology of blood and marrow transplantation. Charlottesville. vol. 23, no. 11 (Nov. 2017), p. 1918-1924 |
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info:eu-repo/semantics/openAccess |
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openAccess |
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