Methods to Develop an in silico Clinical Trial: Computational Head-to-Head Comparison of Lisdexamfetamine and Methylphenidate

Regulatory agencies encourage computer modeling and simulation to reduce the time and cost of clinical trials. Although still not classified in formal guidelines, system biology-based models represent a powerful tool for generating hypotheses with great molecular detail. Herein, we have applied a me...

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Detalles Bibliográficos
Autores: Gutiérrez Casares, José Ramón, Quintero Gutiérrez Del Álamo, Francisco Javier, Montoto, Carmen
Tipo de recurso: artículo
Fecha de publicación:2021
País:España
Institución:Universidad Complutense de Madrid (UCM)
Repositorio:Docta Complutense
Idioma:inglés
OAI Identifier:oai:docta.ucm.es:20.500.14352/99000
Acceso en línea:https://hdl.handle.net/20.500.14352/99000
Access Level:acceso abierto
Palabra clave:616.831-053.2
616.89-008.43
616.89
attention-deficit/hyperactivity disorder
in silico clinical trial
lisdexamfetamine
mathematical modeling
methylphenidate
Ciencias Biomédicas
32 Ciencias Médicas
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oai_identifier_str oai:docta.ucm.es:20.500.14352/99000
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spelling Methods to Develop an in silico Clinical Trial: Computational Head-to-Head Comparison of Lisdexamfetamine and MethylphenidateMétodos para desarrollar un ensayo clínico in silico: Comparación computacional directa de lisdexanfetamina y metilfenidatoGutiérrez Casares, José RamónQuintero Gutiérrez Del Álamo, Francisco JavierMontoto, Carmen616.831-053.2616.89-008.43616.89attention-deficit/hyperactivity disorderin silico clinical triallisdexamfetaminemathematical modelingmethylphenidateCiencias Biomédicas32 Ciencias MédicasRegulatory agencies encourage computer modeling and simulation to reduce the time and cost of clinical trials. Although still not classified in formal guidelines, system biology-based models represent a powerful tool for generating hypotheses with great molecular detail. Herein, we have applied a mechanistic head-to-head in silico clinical trial (ISCT) between two treatments for attention-deficit/hyperactivity disorder, to wit lisdexamfetamine (LDX) and methylphenidate (MPH). The ISCT was generated through three phases comprising (i) the molecular characterization of drugs and pathologies, (ii) the generation of adult and children virtual populations (vPOPs) totaling 2,600 individuals and the creation of physiologically based pharmacokinetic (PBPK) and quantitative systems pharmacology (QSP) models, and (iii) data analysis with artificial intelligence methods. The characteristics of our vPOPs were in close agreement with real reference populations extracted from clinical trials, as did our PBPK models with in vivo parameters. The mechanisms of action of LDX and MPH were obtained from QSP models combining PBPK modeling of dosing schemes and systems biology-based modeling technology, i.e., therapeutic performance mapping system. The step-by-step process described here to undertake a head-to-head ISCT would allow obtaining mechanistic conclusions that could be extrapolated or used for predictions to a certain extent at the clinical level. Altogether, these computational techniques are proven an excellent tool for hypothesis-generation and would help reach a personalized medicine.FrontiersUniversidad Complutense de Madrid20212021-07-1420212021-07-14journal articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/20.500.14352/99000reponame:Docta Complutenseinstname:Universidad Complutense de Madrid (UCM)Inglésengopen accesshttp://purl.org/coar/access_right/c_abf2Attribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:docta.ucm.es:20.500.14352/990002026-06-02T12:44:21Z
dc.title.none.fl_str_mv Methods to Develop an in silico Clinical Trial: Computational Head-to-Head Comparison of Lisdexamfetamine and Methylphenidate
Métodos para desarrollar un ensayo clínico in silico: Comparación computacional directa de lisdexanfetamina y metilfenidato
title Methods to Develop an in silico Clinical Trial: Computational Head-to-Head Comparison of Lisdexamfetamine and Methylphenidate
spellingShingle Methods to Develop an in silico Clinical Trial: Computational Head-to-Head Comparison of Lisdexamfetamine and Methylphenidate
Gutiérrez Casares, José Ramón
616.831-053.2
616.89-008.43
616.89
attention-deficit/hyperactivity disorder
in silico clinical trial
lisdexamfetamine
mathematical modeling
methylphenidate
Ciencias Biomédicas
32 Ciencias Médicas
title_short Methods to Develop an in silico Clinical Trial: Computational Head-to-Head Comparison of Lisdexamfetamine and Methylphenidate
title_full Methods to Develop an in silico Clinical Trial: Computational Head-to-Head Comparison of Lisdexamfetamine and Methylphenidate
title_fullStr Methods to Develop an in silico Clinical Trial: Computational Head-to-Head Comparison of Lisdexamfetamine and Methylphenidate
title_full_unstemmed Methods to Develop an in silico Clinical Trial: Computational Head-to-Head Comparison of Lisdexamfetamine and Methylphenidate
title_sort Methods to Develop an in silico Clinical Trial: Computational Head-to-Head Comparison of Lisdexamfetamine and Methylphenidate
dc.creator.none.fl_str_mv Gutiérrez Casares, José Ramón
Quintero Gutiérrez Del Álamo, Francisco Javier
Montoto, Carmen
author Gutiérrez Casares, José Ramón
author_facet Gutiérrez Casares, José Ramón
Quintero Gutiérrez Del Álamo, Francisco Javier
Montoto, Carmen
author_role author
author2 Quintero Gutiérrez Del Álamo, Francisco Javier
Montoto, Carmen
author2_role author
author
dc.contributor.none.fl_str_mv Universidad Complutense de Madrid
dc.subject.none.fl_str_mv 616.831-053.2
616.89-008.43
616.89
attention-deficit/hyperactivity disorder
in silico clinical trial
lisdexamfetamine
mathematical modeling
methylphenidate
Ciencias Biomédicas
32 Ciencias Médicas
topic 616.831-053.2
616.89-008.43
616.89
attention-deficit/hyperactivity disorder
in silico clinical trial
lisdexamfetamine
mathematical modeling
methylphenidate
Ciencias Biomédicas
32 Ciencias Médicas
description Regulatory agencies encourage computer modeling and simulation to reduce the time and cost of clinical trials. Although still not classified in formal guidelines, system biology-based models represent a powerful tool for generating hypotheses with great molecular detail. Herein, we have applied a mechanistic head-to-head in silico clinical trial (ISCT) between two treatments for attention-deficit/hyperactivity disorder, to wit lisdexamfetamine (LDX) and methylphenidate (MPH). The ISCT was generated through three phases comprising (i) the molecular characterization of drugs and pathologies, (ii) the generation of adult and children virtual populations (vPOPs) totaling 2,600 individuals and the creation of physiologically based pharmacokinetic (PBPK) and quantitative systems pharmacology (QSP) models, and (iii) data analysis with artificial intelligence methods. The characteristics of our vPOPs were in close agreement with real reference populations extracted from clinical trials, as did our PBPK models with in vivo parameters. The mechanisms of action of LDX and MPH were obtained from QSP models combining PBPK modeling of dosing schemes and systems biology-based modeling technology, i.e., therapeutic performance mapping system. The step-by-step process described here to undertake a head-to-head ISCT would allow obtaining mechanistic conclusions that could be extrapolated or used for predictions to a certain extent at the clinical level. Altogether, these computational techniques are proven an excellent tool for hypothesis-generation and would help reach a personalized medicine.
publishDate 2021
dc.date.none.fl_str_mv 2021
2021-07-14
2021
2021-07-14
dc.type.none.fl_str_mv journal article
http://purl.org/coar/resource_type/c_6501
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://hdl.handle.net/20.500.14352/99000
url https://hdl.handle.net/20.500.14352/99000
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Frontiers
publisher.none.fl_str_mv Frontiers
dc.source.none.fl_str_mv reponame:Docta Complutense
instname:Universidad Complutense de Madrid (UCM)
instname_str Universidad Complutense de Madrid (UCM)
reponame_str Docta Complutense
collection Docta Complutense
repository.name.fl_str_mv
repository.mail.fl_str_mv
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