Insights from a pharmacometric analysis of HDMTX in adults with cancer: Clinically relevant covariates for application in precision dosing

Autores
Ibarra Viñales, Manuel; Combs, Ryan; Taylor, Zachary L.; Ramsey, Laura B.; Mikkelsen, Torben; Buddington, Randal K.; Heldrup, Jesper; Barreto, Jason N.; Guscott, Martin; Lowe, Jennifer; Hurmiz, Charles; Marada. Suresh; Howard, Scott C.; Schaiquevich, Paula Susana
Año de publicación
2023
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Aims: High-dose methotrexate (HDMTX) is an essential part of the treatment of several adult and paediatric malignancies. Despite meticulous supportive care during HDMTX administration, severe toxicities, including acute kidney injury (AKI), may occur contributing to patient morbidity. Population pharmacokinetics provide a powerful tool to predict time to clear HDMTX and adjust subsequent doses. We sought to develop and validate pharmacokinetic models for HDMTX in adults with diverse malignancies and to relate systemic exposure with the occurrence of severe toxicity.Methods: Anonymized, de-identified data were provided from 101 US oncology practices that participate in the Guardian Research Network, a non-profit clinical research consortium. Modelled variables included clinical, laboratory, demographic and pharmacological data. Population pharmacokinetic analysis was performed by means of nonlinear mixed effects modelling using MonolixSuite.Results: A total of 693 HDMTX courses from 243 adults were analysed, of which 62 courses (8.8%) were associated with stage 2/3 acute kidney injury (43 stage 2, 19 stage 3). A three-compartment model adequately fitted the data. Time-dependent serum creatinine, baseline serum albumin and allometrically scaled bodyweight were clinically significant covariates related to methotrexate clearance. External evaluation confirmed a satisfactory predictive performance of the model in adults receiving HDMTX. Dose-normalized methotrexate concentration at 24 and 48 hours correlated with AKI incidence.Conclusion: We developed a population pharmacometric model that considers weight, albumin and time-dependent creatinine that can be used to guide supportive care in adult patients with delayed HDMTX elimination.
Fil: Ibarra Viñales, Manuel. Universidad de la República; Uruguay
Fil: Combs, Ryan. No especifíca;
Fil: Taylor, Zachary L.. Cincinnati Children's Hospital Medical Center; Estados Unidos
Fil: Ramsey, Laura B.. Cincinnati Children's Hospital Medical Center; Estados Unidos
Fil: Mikkelsen, Torben. University Aarhus; Dinamarca
Fil: Buddington, Randal K.. No especifíca;
Fil: Heldrup, Jesper. University Children's Hospital; Suecia
Fil: Barreto, Jason N.. No especifíca;
Fil: Guscott, Martin. Cincinnati Children's Hospital Medical Center; Estados Unidos
Fil: Lowe, Jennifer. Cincinnati Children's Hospital Medical Center; Estados Unidos
Fil: Hurmiz, Charles. No especifíca;
Fil: Marada. Suresh. No especifíca;
Fil: Howard, Scott C.. University of Tennessee; Estados Unidos
Fil: Schaiquevich, Paula Susana. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Materia
ONCOLOGY
PHARMACOMETRICS
METHOTREXATE
ADULTS
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:11336/232235
Acceder
id CONICETDig_bd1702f808cace359b58c7b03802e45a
oai_identifier_str oai:ri.conicet.gov.ar:11336/232235
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Insights from a pharmacometric analysis of HDMTX in adults with cancer: Clinically relevant covariates for application in precision dosingIbarra Viñales, ManuelCombs, RyanTaylor, Zachary L.Ramsey, Laura B.Mikkelsen, TorbenBuddington, Randal K.Heldrup, JesperBarreto, Jason N.Guscott, MartinLowe, JenniferHurmiz, CharlesMarada. SureshHoward, Scott C.Schaiquevich, Paula SusanaONCOLOGYPHARMACOMETRICSMETHOTREXATEADULTShttps://purl.org/becyt/ford/3.2https://purl.org/becyt/ford/3Aims: High-dose methotrexate (HDMTX) is an essential part of the treatment of several adult and paediatric malignancies. Despite meticulous supportive care during HDMTX administration, severe toxicities, including acute kidney injury (AKI), may occur contributing to patient morbidity. Population pharmacokinetics provide a powerful tool to predict time to clear HDMTX and adjust subsequent doses. We sought to develop and validate pharmacokinetic models for HDMTX in adults with diverse malignancies and to relate systemic exposure with the occurrence of severe toxicity.Methods: Anonymized, de-identified data were provided from 101 US oncology practices that participate in the Guardian Research Network, a non-profit clinical research consortium. Modelled variables included clinical, laboratory, demographic and pharmacological data. Population pharmacokinetic analysis was performed by means of nonlinear mixed effects modelling using MonolixSuite.Results: A total of 693 HDMTX courses from 243 adults were analysed, of which 62 courses (8.8%) were associated with stage 2/3 acute kidney injury (43 stage 2, 19 stage 3). A three-compartment model adequately fitted the data. Time-dependent serum creatinine, baseline serum albumin and allometrically scaled bodyweight were clinically significant covariates related to methotrexate clearance. External evaluation confirmed a satisfactory predictive performance of the model in adults receiving HDMTX. Dose-normalized methotrexate concentration at 24 and 48 hours correlated with AKI incidence.Conclusion: We developed a population pharmacometric model that considers weight, albumin and time-dependent creatinine that can be used to guide supportive care in adult patients with delayed HDMTX elimination.Fil: Ibarra Viñales, Manuel. Universidad de la República; UruguayFil: Combs, Ryan. No especifíca;Fil: Taylor, Zachary L.. Cincinnati Children's Hospital Medical Center; Estados UnidosFil: Ramsey, Laura B.. Cincinnati Children's Hospital Medical Center; Estados UnidosFil: Mikkelsen, Torben. University Aarhus; DinamarcaFil: Buddington, Randal K.. No especifíca;Fil: Heldrup, Jesper. University Children's Hospital; SueciaFil: Barreto, Jason N.. No especifíca;Fil: Guscott, Martin. Cincinnati Children's Hospital Medical Center; Estados UnidosFil: Lowe, Jennifer. Cincinnati Children's Hospital Medical Center; Estados UnidosFil: Hurmiz, Charles. No especifíca;Fil: Marada. Suresh. No especifíca;Fil: Howard, Scott C.. University of Tennessee; Estados UnidosFil: Schaiquevich, Paula Susana. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaWiley Blackwell Publishing, Inc2023-02info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/232235Ibarra Viñales, Manuel; Combs, Ryan; Taylor, Zachary L.; Ramsey, Laura B.; Mikkelsen, Torben; et al.; Insights from a pharmacometric analysis of HDMTX in adults with cancer: Clinically relevant covariates for application in precision dosing; Wiley Blackwell Publishing, Inc; British Journal Of Clinical Pharmacology; 89; 2; 2-2023; 660-6710306-5251CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://bpspubs.onlinelibrary.wiley.com/doi/full/10.1111/bcp.15506info:eu-repo/semantics/altIdentifier/doi/10.1111/bcp.15506info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-22T11:24:49Zoai:ri.conicet.gov.ar:11336/232235instacron: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:34982025-10-22 11:24:49.446CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Insights from a pharmacometric analysis of HDMTX in adults with cancer: Clinically relevant covariates for application in precision dosing
title Insights from a pharmacometric analysis of HDMTX in adults with cancer: Clinically relevant covariates for application in precision dosing
spellingShingle Insights from a pharmacometric analysis of HDMTX in adults with cancer: Clinically relevant covariates for application in precision dosing
Ibarra Viñales, Manuel
ONCOLOGY
PHARMACOMETRICS
METHOTREXATE
ADULTS
title_short Insights from a pharmacometric analysis of HDMTX in adults with cancer: Clinically relevant covariates for application in precision dosing
title_full Insights from a pharmacometric analysis of HDMTX in adults with cancer: Clinically relevant covariates for application in precision dosing
title_fullStr Insights from a pharmacometric analysis of HDMTX in adults with cancer: Clinically relevant covariates for application in precision dosing
title_full_unstemmed Insights from a pharmacometric analysis of HDMTX in adults with cancer: Clinically relevant covariates for application in precision dosing
title_sort Insights from a pharmacometric analysis of HDMTX in adults with cancer: Clinically relevant covariates for application in precision dosing
dc.creator.none.fl_str_mv Ibarra Viñales, Manuel
Combs, Ryan
Taylor, Zachary L.
Ramsey, Laura B.
Mikkelsen, Torben
Buddington, Randal K.
Heldrup, Jesper
Barreto, Jason N.
Guscott, Martin
Lowe, Jennifer
Hurmiz, Charles
Marada. Suresh
Howard, Scott C.
Schaiquevich, Paula Susana
author Ibarra Viñales, Manuel
author_facet Ibarra Viñales, Manuel
Combs, Ryan
Taylor, Zachary L.
Ramsey, Laura B.
Mikkelsen, Torben
Buddington, Randal K.
Heldrup, Jesper
Barreto, Jason N.
Guscott, Martin
Lowe, Jennifer
Hurmiz, Charles
Marada. Suresh
Howard, Scott C.
Schaiquevich, Paula Susana
author_role author
author2 Combs, Ryan
Taylor, Zachary L.
Ramsey, Laura B.
Mikkelsen, Torben
Buddington, Randal K.
Heldrup, Jesper
Barreto, Jason N.
Guscott, Martin
Lowe, Jennifer
Hurmiz, Charles
Marada. Suresh
Howard, Scott C.
Schaiquevich, Paula Susana
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv ONCOLOGY
PHARMACOMETRICS
METHOTREXATE
ADULTS
topic ONCOLOGY
PHARMACOMETRICS
METHOTREXATE
ADULTS
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.2
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Aims: High-dose methotrexate (HDMTX) is an essential part of the treatment of several adult and paediatric malignancies. Despite meticulous supportive care during HDMTX administration, severe toxicities, including acute kidney injury (AKI), may occur contributing to patient morbidity. Population pharmacokinetics provide a powerful tool to predict time to clear HDMTX and adjust subsequent doses. We sought to develop and validate pharmacokinetic models for HDMTX in adults with diverse malignancies and to relate systemic exposure with the occurrence of severe toxicity.Methods: Anonymized, de-identified data were provided from 101 US oncology practices that participate in the Guardian Research Network, a non-profit clinical research consortium. Modelled variables included clinical, laboratory, demographic and pharmacological data. Population pharmacokinetic analysis was performed by means of nonlinear mixed effects modelling using MonolixSuite.Results: A total of 693 HDMTX courses from 243 adults were analysed, of which 62 courses (8.8%) were associated with stage 2/3 acute kidney injury (43 stage 2, 19 stage 3). A three-compartment model adequately fitted the data. Time-dependent serum creatinine, baseline serum albumin and allometrically scaled bodyweight were clinically significant covariates related to methotrexate clearance. External evaluation confirmed a satisfactory predictive performance of the model in adults receiving HDMTX. Dose-normalized methotrexate concentration at 24 and 48 hours correlated with AKI incidence.Conclusion: We developed a population pharmacometric model that considers weight, albumin and time-dependent creatinine that can be used to guide supportive care in adult patients with delayed HDMTX elimination.
Fil: Ibarra Viñales, Manuel. Universidad de la República; Uruguay
Fil: Combs, Ryan. No especifíca;
Fil: Taylor, Zachary L.. Cincinnati Children's Hospital Medical Center; Estados Unidos
Fil: Ramsey, Laura B.. Cincinnati Children's Hospital Medical Center; Estados Unidos
Fil: Mikkelsen, Torben. University Aarhus; Dinamarca
Fil: Buddington, Randal K.. No especifíca;
Fil: Heldrup, Jesper. University Children's Hospital; Suecia
Fil: Barreto, Jason N.. No especifíca;
Fil: Guscott, Martin. Cincinnati Children's Hospital Medical Center; Estados Unidos
Fil: Lowe, Jennifer. Cincinnati Children's Hospital Medical Center; Estados Unidos
Fil: Hurmiz, Charles. No especifíca;
Fil: Marada. Suresh. No especifíca;
Fil: Howard, Scott C.. University of Tennessee; Estados Unidos
Fil: Schaiquevich, Paula Susana. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
description Aims: High-dose methotrexate (HDMTX) is an essential part of the treatment of several adult and paediatric malignancies. Despite meticulous supportive care during HDMTX administration, severe toxicities, including acute kidney injury (AKI), may occur contributing to patient morbidity. Population pharmacokinetics provide a powerful tool to predict time to clear HDMTX and adjust subsequent doses. We sought to develop and validate pharmacokinetic models for HDMTX in adults with diverse malignancies and to relate systemic exposure with the occurrence of severe toxicity.Methods: Anonymized, de-identified data were provided from 101 US oncology practices that participate in the Guardian Research Network, a non-profit clinical research consortium. Modelled variables included clinical, laboratory, demographic and pharmacological data. Population pharmacokinetic analysis was performed by means of nonlinear mixed effects modelling using MonolixSuite.Results: A total of 693 HDMTX courses from 243 adults were analysed, of which 62 courses (8.8%) were associated with stage 2/3 acute kidney injury (43 stage 2, 19 stage 3). A three-compartment model adequately fitted the data. Time-dependent serum creatinine, baseline serum albumin and allometrically scaled bodyweight were clinically significant covariates related to methotrexate clearance. External evaluation confirmed a satisfactory predictive performance of the model in adults receiving HDMTX. Dose-normalized methotrexate concentration at 24 and 48 hours correlated with AKI incidence.Conclusion: We developed a population pharmacometric model that considers weight, albumin and time-dependent creatinine that can be used to guide supportive care in adult patients with delayed HDMTX elimination.
publishDate 2023
dc.date.none.fl_str_mv 2023-02
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/11336/232235
Ibarra Viñales, Manuel; Combs, Ryan; Taylor, Zachary L.; Ramsey, Laura B.; Mikkelsen, Torben; et al.; Insights from a pharmacometric analysis of HDMTX in adults with cancer: Clinically relevant covariates for application in precision dosing; Wiley Blackwell Publishing, Inc; British Journal Of Clinical Pharmacology; 89; 2; 2-2023; 660-671
0306-5251
CONICET Digital
CONICET
url http://hdl.handle.net/11336/232235
identifier_str_mv Ibarra Viñales, Manuel; Combs, Ryan; Taylor, Zachary L.; Ramsey, Laura B.; Mikkelsen, Torben; et al.; Insights from a pharmacometric analysis of HDMTX in adults with cancer: Clinically relevant covariates for application in precision dosing; Wiley Blackwell Publishing, Inc; British Journal Of Clinical Pharmacology; 89; 2; 2-2023; 660-671
0306-5251
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://bpspubs.onlinelibrary.wiley.com/doi/full/10.1111/bcp.15506
info:eu-repo/semantics/altIdentifier/doi/10.1111/bcp.15506
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
dc.publisher.none.fl_str_mv Wiley Blackwell Publishing, Inc
publisher.none.fl_str_mv Wiley Blackwell Publishing, Inc
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_ 1846781790477352960
score 12.982451

Publicaciones similares