Thromb Haemost 2021; 121(06): 755-766
DOI: 10.1055/s-0040-1721773
Cellular Haemostasis and Platelets

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

1  Department of Clinical Pharmacology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
,
1  Department of Clinical Pharmacology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
,
Michael Dobrow
2  Biotrial Inc., Newark, New Jersey, United States
,
Martine Baumann
3  Department of Drug Discovery Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
,
3  Department of Drug Discovery Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
,
1  Department of Clinical Pharmacology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
,
1  Department of Clinical Pharmacology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
› Author Affiliations
Funding This study was sponsored by Idorsia Pharmaceuticals Ltd., Allschwil, Switzerland.

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.

Supplementary Material



Publication History

Received: 07 August 2020

Accepted: 04 November 2020

Publication Date:
07 January 2021 (online)

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