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 = 12), an open-label loading dose of 300 or 600 mg clopidogrel, 60 mg prasugrel,
or 180 mg ticagrelor was administered 30 minutes (i.e., at t
max of selatogrel) or 12 hours after a single subcutaneous dose of 16 mg selatogrel or
placebo. Inhibition of platelet aggregation (IPA) was assessed at various time points
up to 48 hours. Reduced IPA was determined when clopidogrel or prasugrel was administered
30 minutes after selatogrel (∼40 and 70% lower IPA, respectively, at 24 hours postdosing).
However, when administering prasugrel 12 hours 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 minutes 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.
Keywords
pharmacodynamics - antiplatelet effects - clinical studies
