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 = 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.

Pharmacokinetic/pharmacodynamic modeling of drug interactions at the P2Y12 receptor between selatogrel and oral P2Y12 antagonists

“…The analysis comprised data from 4 phase I and 2 phase II studies. Two single‐ascending dose (SAD) studies covering an s.c. dose range from 0.1 to 16 mg 1 A PD interaction study with the P2Y 12 receptor antagonists clopidogrel, prasugrel, and ticagrelor (the SWITCH study) 10 A study to investigate absorption, distribution, metabolism, and excretion of selatogrel using 14 C‐radiolabeling (PK only) 11 A study to investigate PK and PD in subjects with stable coronary artery disease 12 A study to investigate PK and PD in subjects with AMI 13 …”

“…A PD interaction study with the P2Y 12 receptor antagonists clopidogrel, prasugrel, and ticagrelor (the SWITCH study) 10 …”

“…In analogy to the SWITCH study, interaction was defined as the ≥20 percentage points decrease of arithmetic mean percent IPA at 24 and 36 h following administration of selatogrel or placebo. 10 The primary end point in the clinical study was the difference in mean IPA such that simulations were based on typical profiles. A selatogrel dose of 16 mg was administered at 0 h. A clopidogrel loading dose (600 mg) or a prasugrel loading dose (60 mg) was administered at different times after selatogrel.…”

“… 8 , 9 Similarly, reduced IPA was apparent with clopidogrel and prasugrel if administered shortly after selatogrel. 10 No reduction in IPA was seen for ticagrelor administered after selatogrel.…”

“…dose range from 0.1 to 16 mg 1 • A PD interaction study with the P2Y 12 receptor antagonists clopidogrel, prasugrel, and ticagrelor (the SWITCH study) 10 • A study to investigate absorption, distribution, metabolism, and excretion of selatogrel using 14 C-radiolabeling (PK only) 11 • A study to investigate PK and PD in subjects with stable coronary artery disease 12 • A study to investigate PK and PD in subjects with AMI 13 Table 1 provides details on study designs, populations, study treatments, and PK/PD assessments. The selatogrel plasma concentrations were determined using a validated liquid chromatography assay.…”