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ONO‐7684 a novel oral FXIa inhibitor: Safety, tolerability, pharmacokinetics and pharmacodynamics in a first‐in‐human study
Author(s) -
Beale Dominic,
Dennison Jeremy,
Boyce Malcolm,
Mazzo Francesca,
Honda Naoki,
Smith Paul,
Bruce Mark
Publication year - 2021
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/bcp.14732
Subject(s) - tolerability , pharmacokinetics , pharmacodynamics , placebo , medicine , partial thromboplastin time , dosing , adverse effect , pharmacology , anesthesia , gastroenterology , coagulation , alternative medicine , pathology
Aims The objectives of this study were to investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of single and multiple oral doses of ONO‐7684, a novel activated factor XI (FXIa) inhibitor, in healthy subjects. Methods This was a first‐in‐human (FIH), randomised, placebo‐controlled, double‐blind, single and multiple dose study in healthy subjects under fed and fasted conditions. This study consisted of two parts: single ascending dose (Part A; 1, 5, 20, 80, 150 or 300 mg ONO‐7684 or placebo) and multiple ascending doses (Part B; 80, 150 or 250 mg ONO‐7684 or placebo daily for 14 days). In both parts, subjects were randomised in a 3:1 ratio to receive ONO‐7684 or placebo. Results ONO‐7684 was well tolerated at all dose levels tested following both single and repeated doses, with a low overall incidence of treatment‐emergent adverse events. There was no evidence to suggest a bleeding risk. Dose proportionality in exposure was observed for the range of 1–300 mg ONO‐7684 in Part A. In Part A, the half‐life of ONO‐7684 administered in the fasted state ranged from 16.0 to 19.8 hours. In Part B, the half‐life of ONO‐7684 administered in the fed state ranged from 22.1 to 27.9 hours, supporting once daily oral dosing. ONO‐7684 strongly inhibited factor XI coagulation activity (FXI:C) and increased activated partial thromboplastin time (aPTT), with a mean maximum on treatment percentage inhibition versus baseline of 92% and a mean maximum on treatment ratio‐to‐baseline of 2.78, respectively, at 250 mg ONO‐7684 daily. Conclusions The data generated in this FIH study demonstrate the promising potential of oral FXIa inhibition and ONO‐7684 for indications requiring anticoagulation.