{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T18:29:52Z","timestamp":1787596192361,"version":"build-2736575974"},"reference-count":40,"publisher":"Public Library of Science (PLoS)","issue":"8","license":[{"start":{"date-parts":[[2022,8,17]],"date-time":"2022-08-17T00:00:00Z","timestamp":1660694400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"MIUR (Italian Minister for Education) under the initiative Departments of Excellence","award":["Law 232\/2016"],"award-info":[{"award-number":["Law 232\/2016"]}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>A computational approach involving mathematical modeling and <jats:italic>in silico<\/jats:italic> experiments was used to characterize the determinants of extent and duration of platelet cyclooxygenase (COX)-1 inhibition by aspirin and design precision dosing in patients with accelerated platelet turnover or reduced drug bioavailability. To this purpose, a recently developed physiologically-based pharmacokinetics (PK) and pharmacodynamics (PD) model of low-dose aspirin in regenerating platelets and megakaryocytes, was used to predict the main features and determinants of platelet COX-1 inhibition. The response to different aspirin regimens in healthy subjects and in pathological conditions associated with alterations in aspirin PK (i.e., severely obese subjects) or PD (i.e., essential thrombocytemya patients), were simulated. A model sensitivity analysis was performed to identify the main processes influencing COX-1 dynamics. <jats:italic>In silico<\/jats:italic> experiments and sensitivity analyses indicated a major role for megakaryocytes and platelet turnover in determining the extent and duration of COX-1 inhibition by once-daily, low-dose aspirin. They also showed the superiority of reducing the dosing interval <jats:italic>vs<\/jats:italic> increasing the once-daily dose in conditions of increased platelet turnover, while suggested specific dose adjustments in conditions of possible reduction in drug bioavailability. In conclusion, the consistency of our model-based findings with experimental data from studies in healthy subjects and patients with essential thrombocythemia supports the potential of our approach for describing the determinants of platelet inhibition by aspirin and informing precision dosing which may guide personalized antithrombotic therapy in different patient populations, especially in those under-represented in clinical trials or in those associated with poor feasibility.<\/jats:p>","DOI":"10.1371\/journal.pone.0268905","type":"journal-article","created":{"date-parts":[[2022,8,17]],"date-time":"2022-08-17T17:40:22Z","timestamp":1660758022000},"page":"e0268905","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":8,"title":["Physiologically based modelling of the antiplatelet effect of aspirin: A tool to characterize drug responsiveness and inform precision dosing"],"prefix":"10.1371","volume":"17","author":[{"given":"Alberto","family":"Giaretta","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanna","family":"Petrucci","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bianca","family":"Rocca","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gianna Maria","family":"Toffolo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2022,8,17]]},"reference":[{"issue":"4","key":"pone.0268905.ref001","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1111\/jphp.13070","article-title":"Application of the relationship between pharmacokinetics and pharmacodynamics in drug development and therapeutic equivalence: a PEARRL review","volume":"71","author":"I Loisios-Konstantinidis","year":"2019","journal-title":"J Pharm Pharmacol"},{"key":"pone.0268905.ref002","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1146\/annurev-pharmtox-010510-100540","article-title":"Physiologically-Based Pharmacokinetics in Drug Development and Regulatory Science","volume":"51","author":"M Rowland","year":"2011","journal-title":"Annu Rev Pharmacol Toxicol"},{"issue":"6","key":"pone.0268905.ref003","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1002\/psp4.52","article-title":"Physiologically Based Pharmacokinetics Is Impacting Drug Development and Regulatory Decision Making.","volume":"4","author":"M Rowland","year":"2015","journal-title":"CPT Pharmacometrics Syst Pharmacol"},{"issue":"3","key":"pone.0268905.ref004","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1002\/cpt.37","article-title":"Physiologically based pharmacokinetic modeling in drug discovery and development: a pharmaceutical industry perspective","volume":"97","author":"HM Jones","year":"2015","journal-title":"Clin Pharmacol Ther"},{"issue":"9","key":"pone.0268905.ref005","doi-asserted-by":"crossref","first-page":"2380","DOI":"10.1016\/j.xphs.2017.04.035","article-title":"Usefulness of PBPK Modeling in Incorporation of Clinical Conditions in Personalized Medicine","volume":"106","author":"N Marsousi","year":"2017","journal-title":"J Pharm Sci"},{"key":"pone.0268905.ref006","first-page":"226","article-title":"Application of Physiologically Based Pharmacokinetic (PBPK) Modeling to Support Dose Selection: Report of an FDA Public Workshop on PBPK.","author":"C Wagner","year":"2015"},{"issue":"5","key":"pone.0268905.ref007","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1002\/cpt.659","article-title":"Why has model-informed precision dosing not yet become common clinical reality? 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