Gutiérrez-Casares, José RamónQuintero, JavierJorba Argemí, GuillemJunet, ValentinMartínez, VicentePozo-Rubio, TamaraOliva Miguel, BaldomeroDaura, XavierMas, José ManuelMontoto, Carmen2021-12-142021-12-142021Gutiérrez-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.2021.7411701664-0640http://hdl.handle.net/10230/49194Regulatory 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.application/pdfeng© 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.info:eu-repo/semantics/articlehttp://dx.doi.org/10.3389/fpsyt.2021.741170Attention-deficit/hyperactivity disorderIn silico clinical trialLisdexamfetamineMathematical modelingMethylphenidateinfo:eu-repo/semantics/openAccess