Dataset Information

Pharmacological profile of asundexian, a novel, orally bioavailable inhibitor of factor XIa.

ABSTRACT:

Background

Activated coagulation factor XI (FXIa) contributes to the development and propagation of thrombosis but plays only a minor role in hemostasis; therefore, it is an attractive antithrombotic target.

Objectives

To evaluate the pharmacology of asundexian (BAY 2433334), a small molecule inhibitor targeting FXIa, in vitro and in various rabbit models.

Methods

The effects of asundexian on FXIa activity, selectivity versus other proteases, plasma thrombin generation, and clotting assays were evaluated. Antithrombotic effects were determined in FeCl₂ - and arterio-venous (AV) shunt models. Asundexian was administered intravenously or orally, before or during thrombus formation, and with or without antiplatelet drugs (aspirin and ticagrelor). Potential effects of asundexian on bleeding were evaluated in ear-, gum-, and liver injury models.

Results

Asundexian inhibited human FXIa with high potency and selectivity. It reduced FXIa activity, thrombin generation triggered by contact activation or low concentrations of tissue factor, and prolonged activated partial thromboplastin time in human, rabbit, and various other species, but not in rodents. In the FeCl₂ -injury models, asundexian reduced thrombus weight versus control, and in the arterial model when added to aspirin and ticagrelor. In the AV shunt model, asundexian reduced thrombus weight when administered before or during thrombus formation. Asundexian alone or in combination with antiplatelet drugs did not increase bleeding times or blood loss in any of the models studied.

Conclusions

Asundexian is a potent oral FXIa inhibitor with antithrombotic efficacy in arterial and venous thrombosis models in prevention and intervention settings, without increasing bleeding.

SUBMITTER: Heitmeier S

PROVIDER: S-EPMC9313898 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:Background and objectivesCurrent anticoagulants pose an increased risk of bleeding. The development of drugs targeting factor XIa, like asundexian, may provide a safer treatment option. A human mass‑balance study was conducted to gain a deeper understanding of the absorption, distribution, metabolism, excretion, and potential for drug-drug interaction of asundexian. Additionally, an overview of the biotransformation and clearance pathways for asundexian in humans and bile-duct cannulated (BDC) rats in vivo, as well as in vitro in hepatocytes of both species, is reported.MethodsThe mass balance, biotransformation, and excretion pathways of asundexian were investigated in six healthy volunteers (single oral dose of 25 mg [14C]asundexian) and in BDC rats (intravenous [14C]asundexian 1 mg/kg).ResultsOverall recovery of radioactivity was 101% for humans (samples collected up to 14 days after dosing), and 97.9% for BDC rats (samples collected in the 24 h after dosing). Radioactivity was mainly excreted into feces in humans (80.3%) and into bile/feces in BDC rats (> 94%). The predominant clearance pathways in humans were amide hydrolysis to metabolite M1 (47%) and non-labeled M9 with subsequent N-acetylation to M10; oxidative biotransformation was a minor pathway (13%). In rats, hydrolysis of the terminal amide to M2 was the predominant pathway. In human plasma, asundexian accounted for 61.0% of total drug-related area under the plasma concentration-time curve (AUC); M10 was the major metabolite (16.4% of the total drug-related AUC). Excretion of unmetabolized drug was a significant clearance pathway in both species (human, ~ 37%; BDC rat, ~ 24%). The near-complete bioavailability of asundexian suggests negligible limitations on absorption and first-pass metabolism. Comparison with radiochromatograms from incubations with human or rat hepatocytes indicated consistency across species and a good overall in vitro/in vivo correlation.ConclusionsSimilar to preclinical experiments, total asundexian-derived radioactivity is cleared quantitatively predominantly via feces. Excretion occurs mainly via amide hydrolysis and as the unchanged drug.