Methods to develop an in silico clinical trial: computational head-to-head comparison of lisdexamfetamine and methylphenidate

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• dc.contributor.author Gutiérrez-Casares, José Ramón
• dc.contributor.author Quintero, Javier
• dc.contributor.author Jorba Argemí, Guillem
• dc.contributor.author Junet, Valentin
• dc.contributor.author Martínez, Vicente
• dc.contributor.author Pozo-Rubio, Tamara
• dc.contributor.author Oliva Miguel, Baldomero
• dc.contributor.author Daura, Xavier
• dc.contributor.author Mas, José Manuel
• dc.contributor.author Montoto, Carmen
• dc.date.accessioned 2021-12-14T06:55:18Z
• dc.date.available 2021-12-14T06:55:18Z
• dc.date.issued 2021
• dc.description.abstract 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.
• dc.description.sponsorship This study was funded by Takeda. Public funders provided support for some of the authors' salaries: GJ has received funding from the European Union's Horizon 2020 research and innovation program under the Marie Skłodowska-Curie Grant Agreement No. 765912. VJ is part of a project (COSMIC; www.cosmic-h2020.eu) that has received funding from the European Union's Horizon 2020 research and innovation program under the Marie Skłodowska-Curie Grant Agreement No. 765158.
• dc.format.mimetype application/pdf
• dc.identifier.citation Gutiérrez-Casares JR, Quintero J, Jorba G, Junet V, Martínez V, Pozo-Rubio T, Oliva B, Daura X, Mas JM, Montoto C. Methods to develop an in silico clinical trial: computational head-to-head comparison of lisdexamfetamine and methylphenidate. Front Psychiatry. 2021;12:741170. DOI: 10.3389/fpsyt.2021.741170
• dc.identifier.doi http://dx.doi.org/10.3389/fpsyt.2021.741170
• dc.identifier.issn 1664-0640
• dc.identifier.uri http://hdl.handle.net/10230/49194
• dc.language.iso eng
• dc.publisher Frontiers
• dc.relation.ispartof Front Psychiatry. 2021;12:741170
• dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/765912
• dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/765158
• dc.rights © 2021 Gutiérrez-Casares, Quintero, Jorba, Junet, Martínez, Pozo-Rubio, Oliva, Daura, Mas and Montoto. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.keyword Attention-deficit/hyperactivity disorder
• dc.subject.keyword In silico clinical trial
• dc.subject.keyword Lisdexamfetamine
• dc.subject.keyword Mathematical modeling
• dc.subject.keyword Methylphenidate
• dc.title Methods to develop an in silico clinical trial: computational head-to-head comparison of lisdexamfetamine and methylphenidate
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion