Reappraisal of the clinical pharmacology of low‐dose aspirin by comparing novel direct and traditional indirect biomarkers of drug action

• DOI: 10.1111/jth.12637
• Publication Date: 2014-06-18T14:02:37Z
• Authors: P. Patrignani; S. Tacconelli; E. Piazuelo; L. Di Francesco; M. Dovizio; C. Sostres; E. Marcantoni; P. Guillem‐Llobat; P. Del Boccio; M. Zucchelli; C. Patrono; A. Lanas
• Keywords: Aspirin; Dose-Response Relationship, Drug; thromboxane A2; Acetylation; antiplatelet drugs; Acetylsalicylic acid; Antiplatelet drugs; Cyclooxygenase-1; Proteomics; acetylsalicylic acid; 3. Good health; Thromboxane B2; 03 medical and health sciences; 11-dehydro-thromboxane B2; proteomics; 0302 clinical medicine; cyclooxygenase-1; Area Under Curve; Cyclooxygenase 1; Biomarkers

Even though the acetylation of platelet cyclooxygenase (COX)-1 at serine-529 is the direct mechanism of action of low-dose aspirin, its antiplatelet effect has been characterized using indirect indexes of COX-1 activity.We performed a clinical study with enteric-coated low-dose aspirin (EC-aspirin), in healthy subjects, to evaluate the effects on the extent and duration of platelet COX-1 acetylation, using a novel proteomic strategy for absolute protein quantification (termed AQUA), as compared with traditional pharmacokinetic and pharmacodynamic parameters.In a phase I, single-arm, open-label study of EC aspirin (100 mg day(-1) ) administered to 24 healthy subjects, we compared, over a 24 h-period on day 1 and 7, % platelet acetylated COX-1 (AceCOX-1) with traditional pharmacokinetic and pharmacodynamics [i.e. serum thromboxane (TX) B2 , platelet function by monitoring CEPI(collagen/epinephrine) closure time (CT) using whole-blood PFA-100 and urinary excretion of 11-dehydro-TXB2 ] parameters.Acetylation of platelet COX-1 was measurable before detection of aspirin levels in the systemic circulation and increased in a cumulative fashion upon repeated dosing. After the last dose of EC-aspirin, %AceCOX-1, serum TXB2 and CEPI-CT values were maximally and persistently modified throughout 24 h; they averaged 76 ± 2%, 99.0 ± 0.4% and 271 ± 5 s, respectively. EC-aspirin caused 75% reduction in urinary 11-dehydro-TXB2 excretion. After chronic dosing with aspirin, the pharmacokinetics of acetylsalicylic acid was completely dissociated from pharmacodynamics.The demonstrated feasibility of quantifying the extent and duration of platelet COX-1 acetylation will allow characterizing the genetic, pharmacokinetic and pharmacodynamic determinants of the inter-individual variability in the antiplatelet response to low-dose aspirin as well as identifying extra-platelet sites of drug action.