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

作者：Isabel Piel, Anna Engelen, Dieter Lang, Simone I. Schulz, Michael Gerisch, Christine Brase, Wiebke Janssen, Lukas Fiebig, Stefan Heitmeier, Friederike Kanefendt · 发表于：European Journal of Drug Metabolism and Pharmacokinetics · 年份：2023 · DOI：10.1007/s13318-023-00838-4 · 被引用次数：19 · 研究领域：Coagulation, Bradykinin, Polyphosphates, and Angioedema、Vitamin K Research Studies、Atrial Fibrillation Management and Outcomes

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: 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...