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Ibrutinib and acalabrutinib: effects on platelet functions
form of Src-kinases) were investigated in washed platelets from the two groups of healthy donors. Ibrutinib, at the clinically relevant dose of 0.5 mM, inhibited phosphoryla- tion at both sites, with a significantly more intense effect in the ibrutinib HS group. The strong inhibition of phospho- rylation observed in the ibrutinib HS group correlated with the inhibition of platelet aggregation. The weaker inhibi- tion of phosphorylation in the ibrutinib LS group was accompanied by a weaker decrease of aggregation. Acalabrutinib efficiently inhibited Btk phosphorylation, sig- nificantly decreased PLCγ2 Tyr-753 but had no effect on Src phosphorylation in either group, even at a dose of 2 mM which is above the 1.3 mM mean peak of free plasma drug concentrations measured in patients.9 These data are consis- tent with the better selectivity of acalabrutinib on Btk, also shown by the whole tyrosine phosphorylation profile of collagen-stimulated platelets. However, it is worth noting that while a dose of 2 mM acalabrutinib had no effect on Src activation it did decrease platelet aggregation significantly in the ibrutinib HS group.
A relevant clinical scenario is the association of Btk inhibitors with dual antiplatelet therapy in patients with
coronary intervention with stent placement. The current dual antiplatelet therapy is based on aspirin and a P2Y12 ADP receptor antagonist such as clopidogrel, prasugrel, ticagrelor or cangrelor. Our data are consistent with those of a previous study showing that ibrutinib amplifies the effect of cangrelor on platelets12 and also demonstrate that acalabrutinib strongly potentiated the effect of indomethacin or cangrelor on platelet aggregation induced by collagen both in the ibrutinib HS and LS groups of healthy donors. This is important information for guiding therapeutic strategies in patients under antiplatelet therapy at high risk of bleeding.
In conclusion, this study provides new insights into the impact of the first- and second-generation Btk inhibitors, ibrutinib and acalabrutinib, on platelets and contributes to the improvement of evidence-based recommendations for a safer use of these targeted therapies.
Acknowledgments
This work was supported by grants from Inserm, Fondation pour la Recherche Médicale (DEQ20170336737) and Janssen. We thank the Genotoul imaging facility of I2MC (Inserm U1048). BP is a scholar of the Institut Universitaire de France.
cardiovascular diseases, particularly after
percutaneous
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