ONO-7684 a novel oral FXIa inhibitor: Safety, tolerability, pharmacokinetics and pharmacodynamics in a first-in-human study.
Br J Clin Pharmacol
; 87(8): 3177-3189, 2021 08.
Article
em En
| MEDLINE
| ID: mdl-33450079
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.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Administração Oral
Tipo de estudo:
Clinical_trials
/
Prognostic_studies
Limite:
Humans
Idioma:
En
Revista:
Br J Clin Pharmacol
Ano de publicação:
2021
Tipo de documento:
Article