title: In Silico Modeling of the Antiplatelet Pharmacodynamics of Low-dose Aspirin in Health and Disease.
abstract: The influence of platelet turnover on cyclooxygenase (COX-1) inhibition by low-dose aspirin remains largely uncharacterized due to limited feasibility of studying aspirin pharmacodynamics in bone marrow precursors. We developed an in silico compartmental model describing the aspirin effects on COX-1 activity in a population of megakaryocytes (MK) and in peripheral platelets. Model parameters were inferred from the literature and calibrated using measurements of serum thromboxane B2(sTXB2), as proxy of COX-1 activity in peripheral platelets, in 17 healthy subjects and 24 patients with essential thrombocythemia (ET). The model reproduced well the average time-course of sTXB2inhibition in healthy (accuracy = 10.4%), the reduced inhibition of sTXB2observed in ET, and the effect of different dosing regimens. In conclusion, the in silico model accurately describes COX-1 inactivation by low-dose aspirin in MK and platelets in different clinical settings, and might help personalize aspirin regimens in conditions of altered megakaryopoiesis.
authors.affiliation: Department of Information Engineering, University of Padova, Padova, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Giaretta
authors.affiliation: Department of Pharmacology, Catholic University School of Medicine, Rome, Italy.
authors.forename: B
authors.initials: B
authors.lastname: Rocca
authors.affiliation: Department of Information Engineering, University of Padova, Padova, Italy.
authors.forename: B
authors.initials: B
authors.lastname: Di Camillo
authors.affiliation: Department of Information Engineering, University of Padova, Padova, Italy.
authors.forename: G M
authors.initials: GM
authors.lastname: Toffolo
authors.affiliation: Department of Pharmacology, Catholic University School of Medicine, Rome, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Patrono
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001241:Aspirin / Q000494:pharmacology*; D003198:Computer Simulation; D051545:Cyclooxygenase 1 / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D016208:Databases, Factual; D004305:Dose-Response Relationship, Drug; D006304:Health Status; D006801:Humans; D008962:Models, Theoretical; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D010975:Platelet Aggregation Inhibitors; D051545:Cyclooxygenase 1; C496511:PTGS1 protein, human; D001241:Aspirin