Metabolism and Disposition of the Novel Oral Factor XIa Inhibitor Asundexian in Rats and in Humans

Background and Objectives Current 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, metaboli...

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Published in:European journal of drug metabolism and pharmacokinetics 2023-07, Vol.48 (4), p.411-425
Main Authors: Piel, Isabel, Engelen, Anna, Lang, Dieter, Schulz, Simone I., Gerisch, Michael, Brase, Christine, Janssen, Wiebke, Fiebig, Lukas, Heitmeier, Stefan, Kanefendt, Friederike
Format: Article
Language:English
Subjects:
Administration, Oral
Animals
Anticoagulants
Biological Availability
Biomedical and Life Sciences
Biomedicine
Biotransformation
Factor XIa
Feces
Human Physiology
Humans
Medical Biochemistry
Original
Original Research Article
Oxidation-Reduction
Pharmaceutical Sciences/Technology
Pharmacology/Toxicology
Pharmacy
Rats
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Summary:Background and Objectives Current 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. Methods The mass balance, biotransformation, and excretion pathways of asundexian were investigated in six healthy volunteers (single oral dose of 25 mg [ 14 C]asundexian) and in BDC rats (intravenous [ 14 C]asundexian 1 mg/kg). Results Overall 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. Conclusions Similar to preclinical experiments, total asundexian-derived radioactivity is cleared quantitatively predominantly via feces. Excretion occurs mainly via amide hydrolysis and as the unchanged drug.
ISSN:0378-7966
2107-0180
DOI:10.1007/s13318-023-00838-4