Precision antiplatelet therapy

Abstract

A State of the Art lecture titled "Personalizing Antiplatelet Therapy Based on Platelet Turnover and Metabolic Phenotype" was presented by Bianca Rocca at the International Society on Thrombosis and Haemostasis (ISTH) Congress in 2022. Increased variability in drug response may be associated with serious, mechanism-based and off-target side effects, especially in the case of drugs that do not routinely undergo therapeutic drug monitoring, such as antiplatelet drugs or direct oral anticoagulants. Precision pharmacology can be defined as the identification of a drug regimen that maximizes the benefit/risk balance at the level of an individual patient. Key tools for identifying relevant sources of variability and developing precision drug dosing are represented by genetic, biochemical, and pharmacological biomarkers recognized as a valid surrogate or strong predictor of major clinical complications. Pharmacodynamic, pharmacokinetic, and/or disease-related biomarkers are central to identifying the right population to be targeted, characterizing the sources of variability in drug response, guiding precision treatments that maximize benefits and minimize risks, and designing precision dosing trials. Another valuable tool for guiding precision pharmacology is represented by in silico pharmacokinetic/pharmacodynamic models and simulations instructed by real-world data of validated biomarkers. This review critically analyzes the tools for precision dosing and exemplifies conditions in which precision dosing can considerably optimize the efficacy and safety of antiplatelet drugs, namely aspirin and P2Y₁₂ receptor blockers, used alone and in combination. Finally, we summarize relevant new data on this topic presented during the 2022 ISTH Congress.

Keywords: arterial occlusive diseases; aspirin; platelet aggregation inhibitors; precision medicine; purinergic P2Y receptor antagonists.

Figure 1

Pathophysiological mechanisms affecting aspirin pharmacodynamics after cardiopulmonary bypass surgery. Cardiac surgery and on-pump cardiopulmonary bypass in atherothrombotic disorders trigger platelet destruction and regeneration, acute inflammatory response, and in vivo platelet and endothelial activation. Platelet regeneration with accelerated cyclooxygenase-1 renewal over the 24-hour dosing interval impairs the pharmacodynamics of a conventional low-dose aspirin regimen, which is unable to restrain the enhanced platelet activation associated with cardiac surgery. The increased vascular biosynthesis of the antithrombotic prostanoid, prostacyclin, represents a homeostatic response to inflammation and platelet activation. Reproduced from reference [50] with permission from Wiley.

Figure 2

Mechanisms of altered aspirin pharmacodynamics in conditions associated with high platelet turnover. Central part of the figure: Under conditions of normal megakaryopoiesis, low-dose aspirin acetylated cyclooxygenase (COX)-isozymes in both circulating platelets and bone marrow megakaryocytes, and negligible amounts of unacetylated enzymes are re-synthesized within the 24-hour dosing interval. This pharmacodynamic pattern is associated with virtually complete suppression of platelet TXA₂/TXB₂ production in clotted peripheral blood throughout the dosing interval. Under conditions of abnormal megakaryopoiesis such as in essential thrombocythemia (ET), an accelerated rate of cyclooxygenase-isozyme resynthesis occurs in bone marrow megakaryocytes and platelet precursors, accompanied by faster peripheral release of immature platelets with unacetylated enzyme(s) during the aspirin dosing interval, and in particular between 12 and 24 hours after dosing. This pharmacodynamic pattern is associated with incomplete suppression of platelet TXA₂ production in peripheral blood and time-dependent recovery of TXA₂-dependent platelet function during the 24-hour dosing interval. When low-dose aspirin is administered more frequently, (ie, twice daily) the daily platelet TXA₂ production in peripheral blood is steadily inhibited. Immunohistochemistry panels on the left represent megakaryocytes from a patient with ET stained for cyclooxygenase-1 (A), from a normal subject stained for cyclooxygenase-2 (B), and peripheral washed platelets from a patient with ET stained for cyclooxygenase-2 (C). Reproduced from reference [32] with permission from the American Society of Hematology.

Figure 3

Serum TXB₂ at 24 hours post-aspirin (100 mg once daily) vs body mass index (BMI) or body weight. Serum TXB₂ data measured 24 hours after a witnessed aspirin intake are represented in relationship with BMI in panel A and with body weight in panel B. Green triangles represent patients on primary/secondary aspirin prevention (n = 71); green circles represent healthy control (n = 25). Green line and area: predicted serum TXB₂ and 95% CIs, respectively, in all 96 subjects. Dotted lines indicate the values of 3 (blue), 6 (gold), and 9 (red) ng/mL of serum TXB₂, corresponding to the 99%, 98%, and 97% inhibition levels of serum TXB₂, respectively, measured in healthy subjects. Reproduced modified from reference [57] with permission from Wiley.

Figure 4

The pharmacokinetics of oral P2Y₁₂ inhibitors. The figure depicts the major pharmacokinetic characteristics of clopidogrel (A), prasugrel (B), and ticagrelor (C), including biotransformation enzymes and excretion routes. Red arrows and characters indicate sites of possible drug-drug interactions. CES, carboxylesterases; CYP, cytochrome; P-gp, P-glycoprotein.

Figure 5

Allelic disposition and metabolizer phenotype of CYP2C19. Different alleles of the CYP2C19 are associated with gain, normal, or loss of function of the enzyme (left side of the figure). Their various combinations generate diplotypes with different phenotypic expressions that include ultrarapid and rapid metabolizers and normal, intermediate, and poor metabolizers (central part of the figure). The frequency of each phenotype in African Americans, Asians, and Caucasians are given on the right part of the figure, according to reference [69].

Figure 6

Determinants of variability for each antiplatelet drug and strategies for precision dosing. Variability in response to each antiplatelet agent may depend on body size, drug-drug interactions, genetics, diabetes, platelet turnover and/or kidney and/or liver function. Precision pharmacology by means of diverse and possibly integrated strategies, is aimed at identifying a drug regimen that maximizes the benefit/risk balance at the level of an individual patient. Key tools for identifying relevant sources of variability and developing precision drug dosing are genetic, biochemical, and pharmacological biomarkers recognized as valid surrogates or strong predictors of major clinical complications. In silico pharmacokinetic/pharmacodynamic models and simulations, generated by using real-world data of validated biomarkers, are precious tools for mimicking complex clinical scenarios.