Pharmacodynamics, pharmacokinetics, and safety of single-dose subcutaneous administration of selatogrel, a novel P2Y12 receptor antagonist, in patients with chronic coronary syndromes

Abstract

Aims: To study the pharmacodynamics and pharmacokinetics of selatogrel, a novel P2Y12 receptor antagonist for subcutaneous administration, in patients with chronic coronary syndromes (CCS).

Methods and results: In this double-blind, randomized study of 345 patients with CCS on background oral antiplatelet therapy, subcutaneous selatogrel (8 mg, n = 114; or 16 mg, n = 115) was compared with placebo (n = 116) (ClinicalTrials.gov: NCT03384966). Platelet aggregation was assessed over 24 h (VerifyNow assay) and 8 h (light transmittance aggregometry; LTA). Pharmacodynamic responders were defined as patients having P2Y12 reaction units (PRU) <100 at 30 min post-dose and lasting ≥3 h. At 30 min post-dose, 89% of patients were responders to selatogrel 8 mg, 90% to selatogrel 16 mg, and 16% to placebo (P < 0.0001). PRU values (mean ± standard deviation) were 10 ± 25 (8 mg), 4 ± 10 (16 mg), and 163 ± 73 (placebo) at 15 min and remained <100 up to 8 h for both doses, returning to pre-dose or near pre-dose levels by 24 h post-dose. LTA data showed similarly rapid and potent inhibition of platelet aggregation. Selatogrel plasma concentrations peaked ∼30 min post-dose. Selatogrel was safe and well-tolerated with transient dyspnoea occurring overall in 7% (16/229) of patients (95% confidence interval: 4-11%).

Conclusions: Selatogrel was rapidly absorbed following subcutaneous administration in CCS patients, providing prompt, potent, and consistent platelet P2Y12 inhibition sustained for ≥8 h and reversible within 24 h. Further studies of subcutaneous selatogrel are warranted in clinical scenarios where rapid platelet inhibition is desirable.

Keywords: Coronary artery disease; P2Y12 receptor antagonist; Pharmacodynamics; Pharmacokinetics; Platelet aggregation; Selatogrel.

© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Cardiology.

Figures

Figure 1

Patient screening and randomization schedule.

Figure 2

Effects of selatogrel on adenosine diphosphate-induced platelet aggregation. (A) P2Y12 reaction units assessed by VerifyNow PRUTest assay and (B) maximum platelet aggregation response to adenosine diphosphate 20 μmol/L determined by LTA at the indicated time points before and after administration of subcutaneous selatogrel 8 mg (n = 114), selatogrel 16 mg (n = 115), or placebo (n = 116). Data are mean and error bars indicate 95% confidence interval. Exploratory P values comparing each dose of selatogrel with placebo at each time point are derived from the Student’s t-test.

Figure 3

Effects of selatogrel on platelet reactivity assessed as P2Y12 reaction units by VerifyNow PRUTest assay according to treatment with (A) no oral P2Y12 inhibitor (n = 30–35 per group), (B) clopidogrel (n = 18–21 per group), (C) prasugrel (n = 3–6 per group), or (D) ticagrelor (n = 7–11 per group). Data are mean and error bars indicate 95% confidence interval. Exploratory P values comparing each dose of selatogrel with placebo at each time point are derived from the Student’s t-test.

Figure 4

Selatogrel concentrations in plasma over time and by dose. Plasma concentrations (ng/mL) of selatogrel following single doses of either 8 mg or 16 mg, shown on (A) linear scale and (B) semi-logarithmic scale, measured using a validated liquid chromatography-tandem mass spectrometry assay. Data are mean and error bars indicate standard deviation.

Take home figure

Effect of selatogrel on platelet reactivity assessed by VerifyNow P2Y12 reaction units test showing response to subcutaneous administration of selatogrel 8 mg, selatogrel 16 mg, or placebo within 60 min, between 2 and 8 h, and at 24 h. Data are mean and error bars indicate 95% confidence interval.