Individual Variability in Platelet Responsiveness To P2Y₁₂ Receptor Antagonists Reflects Status of Adenylate Cyclase Pathway

Although anti-aggregatory agents which block the effects of ADP on the platelet P2Y₁₂ receptor (for example clopidogrel of ticagrelor) vary markedly between individuals, the cause of this variability has never been adequately explained. In the case of clopidogrel, impaired CTP2C19-mediated bioactivation has been shown to play some part. Variability in patient responses, in turn, might result in risk of thrombotic or haemorrhagic complications, which in theory might be prevented by individualization of dosing.

ADP binding to P2Y₁₂ receptors exerts a number of “post-receptor” effects, including blocking the effects of ADP in initiating Gi-protein-mediated inhibition of platelet adenylate cyclases (AC). In turn, the main physiological activator of AC is prostacyclin (PGI₂ ). Therefore we have tested the hypothesis that pre-treatment responses to agents acting on PGI₂ receptors predict subsequent responses to clopidogrel, as measured by changes in ADP-induced aggregation and in platelet reactivity index (PRI).

It was found that both 4 hours and 7 days after initiation of clopidogrel therapy, pretreatment prostanoid responses were univariate and multivariate predictors of responses to clopidogrel. We have therefore continued these studies by showing that a similar relationship also applies to ticagrelor , and that at least part of the interindividual variability in AC signaling reflects the activity of AC.

Additional studies are now in progress to determine whether variability in activation of platelet AC activation is predictable on epidemiological grounds and whether it is possible to ameliorate impaired AC responsiveness, both in the short-and long-term. Ultimately, the key question is whether this form of individualization of patient drug dosing can improve the efficacy and safety of P2Y₁₂ receptor antagonists.