Methods to Develop an in silico Clinical Trial : Computational Head-to-Head Comparison of Lisdexamfetamine and Methylphenidate
Gutiérrez-Casares, José Ramón (Hospital Perpetuo Socorro (Badajoz))
Quintero, Javier (Universidad Complutense de Madrid)
Jorba, Guillem (Universitat Pompeu Fabra. Departament de Ciències Experimentals i de la Salut)
Junet, Valentin (Universitat Autònoma de Barcelona. Institut de Biotecnologia i de Biomedicina "Vicent Villar Palasí")
Martínez Perea, Vicente (Takeda Farmacéutica España)
Pozo-Rubio, Tamara (Takeda Farmacéutica España)
Oliva Miguel, Baldomero (Universitat Pompeu Fabra. Departament de Ciències Experimentals i de la Salut)
Daura i Ribera, Xavier (Universitat Autònoma de Barcelona. Institut de Biotecnologia i de Biomedicina "Vicent Villar Palasí")
Mas, José Manuel (Anaxomics Biotech)
Montoto, Carmen (Takeda Farmacéutica España)

Date:	2021
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.
Grants:	European Commission 765912 European Commission 765158
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Attention-deficit/hyperactivity disorder ; Lisdexamfetamine ; Methylphenidate ; Mathematical modeling ; In silico clinical trial
Published in:	Frontiers in psychiatry, Vol. 12 (November 2021) , ISSN 1664-0640

DOI: 10.3389/fpsyt.2021.741170
PMID: 34803764

21 p, 4.3 MB

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Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Institut de Biotecnologia i de Biomedicina (IBB)
Articles > Research articles
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