Pharmacokinetics, Mass Balance, and Biotransformation of [¹⁴C]tinengotinib, A Novel Multi-target Kinase Inhibitor, in Healthy Subjects.

IF 2.2 4区医学 Q3 PHARMACOLOGY & PHARMACY

Drugs in Research & Development Pub Date : 2024-09-01 Epub Date: 2024-09-05 DOI:10.1007/s40268-024-00486-2

Shumao Ni, Sheng Ma, Yingying Yu, Zhenwen Yu, Yujia Zhu, Xiaofen Sun, Lin Li, Caixia Sun, Hui Wang, Peng Peng, Zheming Gu, Hua Zhang, Frank Wu, Liyan Miao, Jean Fan

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引用次数: 0

Abstract

Background and objective: Tinengotinib, a novel multi-target small molecule kinase inhibitor, is currently undergoing phase II clinical trial in the USA and China. The purpose of this open-label study was to investigate the absorption, metabolism, and excretion of [¹⁴C]tinengotinib following a single oral dose in healthy subjects.

Methods: Six healthy male subjects received a single oral dose of [¹⁴C]tinengotinib capsules at 10 mg/100 µCi, and blood, urine, and feces samples were collected. Phenotyping experiments were further conducted to confirm the enzymes involved in its metabolism.

Results: Tinengotinib was rapidly absorbed in plasma with a time to peak drug concentration (T_max) of 1.0-4.0 h post-dose and a long terminal half-life (t_½) of 23.7 h. Blood-to-plasma radioactivity concentration ratios across timepoints ranged from 0.780 to 0.827, which indicated minimal association of radioactivity with blood cells. The mean cumulative excreted radioactivity was 99.57% of the dose, including 92.46% (68.65% as unchanged) in feces and 7.11% (0.28% as unchanged) in urine. In addition to unchanged tinengotinib, a total of 11 radioactive metabolites were identified in plasma, urine, and feces. The most abundant circulating radioactivity was the parent drug in plasma, which comprised 88.23% of the total radioactivity area under the concentration-time curve (AUC). Metabolite M410-3 was a major circulating metabolite, accounting for 5.38% of the parent drug exposure and 4.75% of the total drug-related exposure, respectively. All excreted metabolites accounted for less than 5.10% and 1.82% of the dose in feces and urine, respectively. In addition, no unique metabolites were observed in humans. Tinengotinib was metabolized mainly via CYP3A4.

Conclusions: Overall, tinengotinib demonstrated a complete mass balance with limited renal excretion, no disproportionate blood metabolism, and slow elimination, primarily through the fecal route. The results of this study provide evidence to support the rational use of tinengotinib as a pharmacotherapeutic agent.

Registration: ChinadrugTrials.org.cn identifier: CTR20212852.

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新型多靶点激酶抑制剂 [14C]tinengotinib 在健康受试者中的药代动力学、质量平衡和生物转化。

背景和目的：替能替尼是一种新型多靶点小分子激酶抑制剂，目前正在美国和中国进行II期临床试验。本开放标签研究旨在调查健康受试者单次口服[14C]替能替尼后的吸收、代谢和排泄情况：方法：6 名健康男性受试者单次口服 10 mg/100 µCi 的[14C]替能替尼胶囊，并收集血液、尿液和粪便样本。进一步进行了表型实验，以确认参与其代谢的酶：替能替尼在血浆中吸收迅速，服药后药物浓度达峰时间（Tmax）为1.0-4.0小时，终末半衰期（t½）为23.7小时。平均累积排出的放射性为剂量的 99.57%，其中 92.46%（68.65%未发生变化）从粪便中排出，7.11%（0.28%未发生变化）从尿液中排出。除未改变的替能替尼外，在血浆、尿液和粪便中还发现了 11 种放射性代谢物。血浆中含量最高的循环放射性物质是母药，占总放射性浓度曲线下面积（AUC）的88.23%。代谢物 M410-3 是主要的循环代谢物，分别占母体药物暴露量的 5.38% 和药物相关总暴露量的 4.75%。所有排泄代谢物在粪便和尿液中分别占剂量的 5.10%和 1.82%以下。此外，在人体中未观察到独特的代谢物。替能替尼主要通过CYP3A4代谢：总的来说，替能替尼表现出完全的质量平衡，肾脏排泄有限，没有不成比例的血液代谢，消除缓慢，主要通过粪便途径。本研究结果为合理使用替能替尼作为药物治疗剂提供了证据：CTR20212852：CTR20212852。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Drugs in Research & Development Pharmacology, Toxicology and Pharmaceutics-Pharmacology

CiteScore

5.10

自引率

0.00%

发文量

审稿时长

8 weeks

期刊介绍： Drugs in R&D is an international, peer reviewed, open access, online only journal, and provides timely information from all phases of drug research and development that will inform clinical practice. Healthcare decision makers are thus provided with knowledge about the developing place of a drug in therapy. The Journal includes: Clinical research on new and established drugs; Preclinical research of direct relevance to clinical drug development; Short communications and case study reports that meet the above criteria will also be considered; Reviews may also be considered.