Comparison of different pharmacodynamic models for PK-PD modeling of verapamil in renovascular hypertension

Autores
Bertera, Facundo Martin; Mayer, Marcos Alejandro; Opezzo, Javier A. W.; Taira, Carlos Alberto; Höcht, Christian
Año de publicación
2008
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Introduction: The aim of this work was to compare the suitability of different pharmacodynamic models for PK-PD modeling of verapamil cardiovascular effects in aortic coarctated rats (ACo), a model of renovascular hypertension. Methods: A "shunt" microdialysis probe was inserted in a carotid artery of anaesthetized sham-operated (SO) and ACo rats for determination of verapamil plasma concentrations and their effects on blood pressure and heart rate after intravenous application (1 and 3 mg kg- 1). Correlation between verapamil plasma levels and their cardiovascular effects was established by fitting data to a linear, and a conventional and modified Emax model. Results: No differences in verapamil volume of distribution were observed between experimental groups. Whilst clearance increased with dose in SO rats, no differences were found in verapamil clearance in ACo comparing both dose levels. A good correlation between verapamil plasma unbound concentrations and their hypotensive and chronotropic effects was found in both experimental groups using the tested PK-PD models. Although all pharmacodynamic models allowed a precise estimation of verapamil PK-PD parameters, linear and Emax model did not permit an accurate PK-PD parameter estimation for the hypotensive and chronotropic effect, respectively. Conversely, the modified Emax model allows both a precise and accurate estimation of PK-PD parameters for verapamil effects. Although, absolute verapamil blood pressure lowering effect was greater in ACo rats compared with SO rats, no differences were found in verapamil PK-PD parameters estimated for the hypotensive response. Discussion: Side-by-side comparison of the tested pharmacodynamic models showed that accuracy of PK-PD parameters estimation by using the linear and classical Emax model depends on the magnitude of concentration-effect curve covered in the study. Conversely, the modified Emax model allowed both a precise and accurate estimation of PK-PD parameters, suggesting that the modified Emax pharmacodynamic model is the most suitable for verapamil PK-PD modeling.
Fil: Bertera, Facundo Martin. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología. Cátedra de Farmacología; Argentina
Fil: Mayer, Marcos Alejandro. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología. Cátedra de Farmacología; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Fisiopatología y Bioquímica Clínica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; Argentina
Fil: Opezzo, Javier A. W.. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Fisiopatología y Bioquímica Clínica; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología. Cátedra de Farmacología; Argentina
Fil: Taira, Carlos Alberto. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología. Cátedra de Farmacología; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Fisiopatología y Bioquímica Clínica; Argentina
Fil: Höcht, Christian. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Fisiopatología y Bioquímica Clínica; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología. Cátedra de Farmacología; Argentina
Materia
AORTIC COARCTATION
CHRONOTROPIC EFFECT
HYPOTENSIVE EFFECT
MICRODIALYSIS
PHARMACOKINETIC-PHARMACODYNAMIC MODELING
PLASMA PHARMACOKINETICS
VERAPAMIL
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:11336/160513
Acceder
id CONICETDig_eb446abe4a2d67ea197f226945d5dd52
oai_identifier_str oai:ri.conicet.gov.ar:11336/160513
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Comparison of different pharmacodynamic models for PK-PD modeling of verapamil in renovascular hypertensionBertera, Facundo MartinMayer, Marcos AlejandroOpezzo, Javier A. W.Taira, Carlos AlbertoHöcht, ChristianAORTIC COARCTATIONCHRONOTROPIC EFFECTHYPOTENSIVE EFFECTMICRODIALYSISPHARMACOKINETIC-PHARMACODYNAMIC MODELINGPLASMA PHARMACOKINETICSVERAPAMILIntroduction: The aim of this work was to compare the suitability of different pharmacodynamic models for PK-PD modeling of verapamil cardiovascular effects in aortic coarctated rats (ACo), a model of renovascular hypertension. Methods: A "shunt" microdialysis probe was inserted in a carotid artery of anaesthetized sham-operated (SO) and ACo rats for determination of verapamil plasma concentrations and their effects on blood pressure and heart rate after intravenous application (1 and 3 mg kg- 1). Correlation between verapamil plasma levels and their cardiovascular effects was established by fitting data to a linear, and a conventional and modified Emax model. Results: No differences in verapamil volume of distribution were observed between experimental groups. Whilst clearance increased with dose in SO rats, no differences were found in verapamil clearance in ACo comparing both dose levels. A good correlation between verapamil plasma unbound concentrations and their hypotensive and chronotropic effects was found in both experimental groups using the tested PK-PD models. Although all pharmacodynamic models allowed a precise estimation of verapamil PK-PD parameters, linear and Emax model did not permit an accurate PK-PD parameter estimation for the hypotensive and chronotropic effect, respectively. Conversely, the modified Emax model allows both a precise and accurate estimation of PK-PD parameters for verapamil effects. Although, absolute verapamil blood pressure lowering effect was greater in ACo rats compared with SO rats, no differences were found in verapamil PK-PD parameters estimated for the hypotensive response. Discussion: Side-by-side comparison of the tested pharmacodynamic models showed that accuracy of PK-PD parameters estimation by using the linear and classical Emax model depends on the magnitude of concentration-effect curve covered in the study. Conversely, the modified Emax model allowed both a precise and accurate estimation of PK-PD parameters, suggesting that the modified Emax pharmacodynamic model is the most suitable for verapamil PK-PD modeling.Fil: Bertera, Facundo Martin. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología. Cátedra de Farmacología; ArgentinaFil: Mayer, Marcos Alejandro. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología. Cátedra de Farmacología; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Fisiopatología y Bioquímica Clínica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; ArgentinaFil: Opezzo, Javier A. W.. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Fisiopatología y Bioquímica Clínica; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología. Cátedra de Farmacología; ArgentinaFil: Taira, Carlos Alberto. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología. Cátedra de Farmacología; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Fisiopatología y Bioquímica Clínica; ArgentinaFil: Höcht, Christian. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Fisiopatología y Bioquímica Clínica; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología. Cátedra de Farmacología; ArgentinaElsevier2008-05info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/160513Bertera, Facundo Martin; Mayer, Marcos Alejandro; Opezzo, Javier A. W.; Taira, Carlos Alberto; Höcht, Christian; Comparison of different pharmacodynamic models for PK-PD modeling of verapamil in renovascular hypertension; Elsevier; Journal Of Pharmacological And Toxicological Methods.; 57; 3; 5-2008; 212-2191056-8719CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.sciencedirect.com/science/article/abs/pii/S1056871908000233info:eu-repo/semantics/altIdentifier/doi/10.1016/j.vascn.2008.03.002info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T10:31:54Zoai:ri.conicet.gov.ar:11336/160513instacron: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:34982025-09-29 10:31:54.646CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Comparison of different pharmacodynamic models for PK-PD modeling of verapamil in renovascular hypertension
title Comparison of different pharmacodynamic models for PK-PD modeling of verapamil in renovascular hypertension
spellingShingle Comparison of different pharmacodynamic models for PK-PD modeling of verapamil in renovascular hypertension
Bertera, Facundo Martin
AORTIC COARCTATION
CHRONOTROPIC EFFECT
HYPOTENSIVE EFFECT
MICRODIALYSIS
PHARMACOKINETIC-PHARMACODYNAMIC MODELING
PLASMA PHARMACOKINETICS
VERAPAMIL
title_short Comparison of different pharmacodynamic models for PK-PD modeling of verapamil in renovascular hypertension
title_full Comparison of different pharmacodynamic models for PK-PD modeling of verapamil in renovascular hypertension
title_fullStr Comparison of different pharmacodynamic models for PK-PD modeling of verapamil in renovascular hypertension
title_full_unstemmed Comparison of different pharmacodynamic models for PK-PD modeling of verapamil in renovascular hypertension
title_sort Comparison of different pharmacodynamic models for PK-PD modeling of verapamil in renovascular hypertension
dc.creator.none.fl_str_mv Bertera, Facundo Martin
Mayer, Marcos Alejandro
Opezzo, Javier A. W.
Taira, Carlos Alberto
Höcht, Christian
author Bertera, Facundo Martin
author_facet Bertera, Facundo Martin
Mayer, Marcos Alejandro
Opezzo, Javier A. W.
Taira, Carlos Alberto
Höcht, Christian
author_role author
author2 Mayer, Marcos Alejandro
Opezzo, Javier A. W.
Taira, Carlos Alberto
Höcht, Christian
author2_role author
author
author
author
dc.subject.none.fl_str_mv AORTIC COARCTATION
CHRONOTROPIC EFFECT
HYPOTENSIVE EFFECT
MICRODIALYSIS
PHARMACOKINETIC-PHARMACODYNAMIC MODELING
PLASMA PHARMACOKINETICS
VERAPAMIL
topic AORTIC COARCTATION
CHRONOTROPIC EFFECT
HYPOTENSIVE EFFECT
MICRODIALYSIS
PHARMACOKINETIC-PHARMACODYNAMIC MODELING
PLASMA PHARMACOKINETICS
VERAPAMIL
dc.description.none.fl_txt_mv Introduction: The aim of this work was to compare the suitability of different pharmacodynamic models for PK-PD modeling of verapamil cardiovascular effects in aortic coarctated rats (ACo), a model of renovascular hypertension. Methods: A "shunt" microdialysis probe was inserted in a carotid artery of anaesthetized sham-operated (SO) and ACo rats for determination of verapamil plasma concentrations and their effects on blood pressure and heart rate after intravenous application (1 and 3 mg kg- 1). Correlation between verapamil plasma levels and their cardiovascular effects was established by fitting data to a linear, and a conventional and modified Emax model. Results: No differences in verapamil volume of distribution were observed between experimental groups. Whilst clearance increased with dose in SO rats, no differences were found in verapamil clearance in ACo comparing both dose levels. A good correlation between verapamil plasma unbound concentrations and their hypotensive and chronotropic effects was found in both experimental groups using the tested PK-PD models. Although all pharmacodynamic models allowed a precise estimation of verapamil PK-PD parameters, linear and Emax model did not permit an accurate PK-PD parameter estimation for the hypotensive and chronotropic effect, respectively. Conversely, the modified Emax model allows both a precise and accurate estimation of PK-PD parameters for verapamil effects. Although, absolute verapamil blood pressure lowering effect was greater in ACo rats compared with SO rats, no differences were found in verapamil PK-PD parameters estimated for the hypotensive response. Discussion: Side-by-side comparison of the tested pharmacodynamic models showed that accuracy of PK-PD parameters estimation by using the linear and classical Emax model depends on the magnitude of concentration-effect curve covered in the study. Conversely, the modified Emax model allowed both a precise and accurate estimation of PK-PD parameters, suggesting that the modified Emax pharmacodynamic model is the most suitable for verapamil PK-PD modeling.
Fil: Bertera, Facundo Martin. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología. Cátedra de Farmacología; Argentina
Fil: Mayer, Marcos Alejandro. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología. Cátedra de Farmacología; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Fisiopatología y Bioquímica Clínica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; Argentina
Fil: Opezzo, Javier A. W.. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Fisiopatología y Bioquímica Clínica; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología. Cátedra de Farmacología; Argentina
Fil: Taira, Carlos Alberto. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología. Cátedra de Farmacología; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Fisiopatología y Bioquímica Clínica; Argentina
Fil: Höcht, Christian. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Fisiopatología y Bioquímica Clínica; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología. Cátedra de Farmacología; Argentina
description Introduction: The aim of this work was to compare the suitability of different pharmacodynamic models for PK-PD modeling of verapamil cardiovascular effects in aortic coarctated rats (ACo), a model of renovascular hypertension. Methods: A "shunt" microdialysis probe was inserted in a carotid artery of anaesthetized sham-operated (SO) and ACo rats for determination of verapamil plasma concentrations and their effects on blood pressure and heart rate after intravenous application (1 and 3 mg kg- 1). Correlation between verapamil plasma levels and their cardiovascular effects was established by fitting data to a linear, and a conventional and modified Emax model. Results: No differences in verapamil volume of distribution were observed between experimental groups. Whilst clearance increased with dose in SO rats, no differences were found in verapamil clearance in ACo comparing both dose levels. A good correlation between verapamil plasma unbound concentrations and their hypotensive and chronotropic effects was found in both experimental groups using the tested PK-PD models. Although all pharmacodynamic models allowed a precise estimation of verapamil PK-PD parameters, linear and Emax model did not permit an accurate PK-PD parameter estimation for the hypotensive and chronotropic effect, respectively. Conversely, the modified Emax model allows both a precise and accurate estimation of PK-PD parameters for verapamil effects. Although, absolute verapamil blood pressure lowering effect was greater in ACo rats compared with SO rats, no differences were found in verapamil PK-PD parameters estimated for the hypotensive response. Discussion: Side-by-side comparison of the tested pharmacodynamic models showed that accuracy of PK-PD parameters estimation by using the linear and classical Emax model depends on the magnitude of concentration-effect curve covered in the study. Conversely, the modified Emax model allowed both a precise and accurate estimation of PK-PD parameters, suggesting that the modified Emax pharmacodynamic model is the most suitable for verapamil PK-PD modeling.
publishDate 2008
dc.date.none.fl_str_mv 2008-05
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/11336/160513
Bertera, Facundo Martin; Mayer, Marcos Alejandro; Opezzo, Javier A. W.; Taira, Carlos Alberto; Höcht, Christian; Comparison of different pharmacodynamic models for PK-PD modeling of verapamil in renovascular hypertension; Elsevier; Journal Of Pharmacological And Toxicological Methods.; 57; 3; 5-2008; 212-219
1056-8719
CONICET Digital
CONICET
url http://hdl.handle.net/11336/160513
identifier_str_mv Bertera, Facundo Martin; Mayer, Marcos Alejandro; Opezzo, Javier A. W.; Taira, Carlos Alberto; Höcht, Christian; Comparison of different pharmacodynamic models for PK-PD modeling of verapamil in renovascular hypertension; Elsevier; Journal Of Pharmacological And Toxicological Methods.; 57; 3; 5-2008; 212-219
1056-8719
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://www.sciencedirect.com/science/article/abs/pii/S1056871908000233
info:eu-repo/semantics/altIdentifier/doi/10.1016/j.vascn.2008.03.002
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
dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
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 13.070432

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