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

IF 1.9 4区 医学 Q3 PHARMACOLOGY & PHARMACY
Isabel Piel, Anna Engelen, Dieter Lang, Simone I Schulz, Michael Gerisch, Christine Brase, Wiebke Janssen, Lukas Fiebig, Stefan Heitmeier, Friederike Kanefendt
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引用次数: 0

Abstract

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 [14C]asundexian) and in BDC rats (intravenous [14C]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.

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新型口服因子XIa抑制剂assundexian在大鼠和人体内的代谢和处置。
背景和目的:目前使用的抗凝药物会增加出血的风险。针对XIa因子的药物的开发,如阿森地仙,可能提供一种更安全的治疗选择。我们进行了一项人体质量平衡研究,以更深入地了解亚散的吸收、分布、代谢、排泄和药物-药物相互作用的可能性。此外,还报道了亚硝胺在人和胆管插管(BDC)大鼠体内以及在体外两种物种的肝细胞中的生物转化和清除途径。方法:研究6名健康志愿者(单次口服[14C]亚桑德仙25 mg)和BDC大鼠(静脉注射[14C]亚桑德仙1 mg/kg)的物质平衡、生物转化和排泄途径。结果:人体(给药后14天内采集的样品)放射性总恢复率为101%,BDC大鼠(给药后24 h采集的样品)放射性总恢复率为97.9%。放射性主要通过人类粪便排出(80.3%),BDC大鼠主要通过胆汁/粪便排出(> 94%)。人类主要的清除途径是酰胺水解为代谢物M1(47%)和未标记的M9,随后n-乙酰化为M10;氧化生物转化是次要途径(13%)。在大鼠中,末端酰胺水解为M2是主要途径。在人血浆中,亚散线占血浆浓度-时间曲线(AUC)下药物相关总面积的61.0%;M10是主要代谢物(占总药物相关AUC的16.4%)。在这两个物种中,未代谢药物的排泄是一个重要的清除途径(人类,~ 37%;BDC大鼠,~ 24%)。亚桑德仙近乎完全的生物利用度表明其在吸收和首过代谢方面的限制可以忽略不计。与人或大鼠肝细胞孵育的放射色谱图比较表明,不同物种之间存在一致性,并且总体上具有良好的体外/体内相关性。结论:与临床前实验相似,总放射性主要通过粪便被定量清除。主要通过酰胺水解和作为原药排出。
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来源期刊
CiteScore
3.70
自引率
0.00%
发文量
64
审稿时长
>12 weeks
期刊介绍: Hepatology International is a peer-reviewed journal featuring articles written by clinicians, clinical researchers and basic scientists is dedicated to research and patient care issues in hepatology. This journal focuses mainly on new and emerging diagnostic and treatment options, protocols and molecular and cellular basis of disease pathogenesis, new technologies, in liver and biliary sciences. Hepatology International publishes original research articles related to clinical care and basic research; review articles; consensus guidelines for diagnosis and treatment; invited editorials, and controversies in contemporary issues. The journal does not publish case reports.
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