SHR2285, the first selectively oral FXIa inhibitor in China: Safety, tolerability, pharmacokinetics and pharmacodynamics combined with aspirin, clopidogrel or ticagrelor

Frontiers in Pharmacology(2022)

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摘要
Purpose: To evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of SHR2285, the first oral coagulation factor XIa (FXIa) inhibitor developed in China in combination with aspirin, clopidogrel or ticagrelor in healthy subjects.Methods: This study was a single-center, randomized, double-blind, placebo-controlled (only SHR2285) design (NCT04945616). A total of 52 healthy subjects, 29 male and 23 female, were completed in this study. The subjects were divided into three groups: A, B and C, 16 subjects in group A [aspirin + clopidogrel + placebo or SHR2285 200 mg bid (1:3, 4 received placebo and 12 received SHR2285)] 16 subjects in group B [aspirin + clopidogrel + placebo or SHR2285 300 mg bid (1:3, 3 received placebo and 13 received SHR2285)] and 20 subjects in group C (aspirin + ticagrelor + placebo or SHR2285 300 mg bid (2:3, 8 received placebo and 12 received SHR2285)), respectively. All groups were administered orally for six consecutive days. Safety, tolerability, pharmacokinetics and pharmacodynamics parameters were assessed.Results: 1) SHR2285 was well tolerated, and all adverse events were mild. There was no evidence of an increased risk of bleeding. 2) After 6 days of twice-daily administration, SHR2285 could reach a steady state. The mean half-life of SHR2285 in group A, group B and group C was 13.9 h, 14.5 h and 13.8 h, respectively. 3) SHR2285 markedly inhibited FXI activity and prolonged activated partial thromboplastin time (APTT). In group A, group B and group C, the mean maximum inhibition rate of FXI activity was 84.8%, 89.3% and 92.2% and the mean maximum prolongation of APTT was 2.08-fold, 2.36-fold and 2.26-fold, respectively.Conclusion: These data suggest that SHR2285, a potential oral FXIa inhibitor, is expected to become a novel, safe and effective anticoagulant when combined with aspirin, clopidogrel or ticagrelor.
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关键词
anticoagulants,coagulation factor inhibitor,dual antiplatelet therapy,pharmacodynamics,pharmacokinetics
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