In silico modeling of the antiplatelet pharmacodynamics of low-dose aspirin in health and disease

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 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 well reproduced the average time-course of sTXB2 inhibition in healthy (accuracy = 10.4%), the reduced inhibition of sTXB2 observed 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. This article is protected by copyright. All rights reserved.