Insights from In Vitro and Clinical Data to Guide Transition from the Novel P2Y12 Antagonist Selatogrel to Clopidogrel, Prasugrel, and Ticagrelor.

Abstract

Reduced pharmacodynamic (PD) effects of irreversible oral P2Y12 receptor antagonists have been reported when administered during cangrelor infusion. Therefore, the PD interaction liability of the novel P2Y12 receptor antagonist selatogrel with irreversible (i.e., clopidogrel, prasugrel) and reversible (i.e., ticagrelor) oral P2Y12 receptor antagonists was investigated in vitro and in healthy subjects. In vitro, selatogrel reduced the effects of clopidogrel and prasugrel in a concentration-dependent manner, while additive effects were observed for the combination of selatogrel and ticagrelor. Accordingly, a single-center, randomized, double-blind, two-way crossover study was conducted consisting of six groups. In each group (N\u2009=\u200912), an open-label loading dose of 300 or 600\u2009mg clopidogrel, 60\u2009mg prasugrel, or 180\u2009mg ticagrelor was administered 30\u2009minutes (i.e., at t max of selatogrel) or 12\u2009hours after a single subcutaneous dose of 16\u2009mg selatogrel or placebo. Inhibition of platelet aggregation (IPA) was assessed at various time points up to 48\u2009hours. Reduced IPA was determined when clopidogrel or prasugrel was administered 30\u2009minutes after selatogrel (∼40 and 70% lower IPA, respectively, at 24\u2009hours postdosing). However, when administering prasugrel 12\u2009hours after selatogrel, IPA was not impacted (>90% IPA) and in the case of clopidogrel reduced effects were partially mitigated. Similar IPA was determined for ticagrelor when administered 30\u2009minutes after selatogrel or placebo. In conclusion, reduced IPA was observed for clopidogrel and prasugrel when administered after selatogrel, which can be mitigated by applying an appropriate time interval. No PD interaction with ticagrelor was observed.