Absorption, Metabolism, Distribution and Excretion (ADME) and Absolute Bioavailability Assessment of Zongertinib in Healthy Male Volunteers.

IF 3.1 3区医学 Q2 PHARMACOLOGY & PHARMACY

Clinical Drug Investigation Pub Date : 2026-02-01 Epub Date: 2025-12-05 DOI:10.1007/s40261-025-01509-9

Rolf Grempler, David Joseph, Guanfa Gan, Adam M Auclair, Renger G Tiessen, Hlaing H Maw, Ralf Laux, Sven Wind, Philipp M Roessner, Behbood Sadrolhefazi, Fabian Müller, David Minich

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引用次数: 0

Abstract

Background and objectives: Zongertinib is an irreversible tyrosine kinase inhibitor that selectively inhibits human epidermal growth factor receptor 2 (HER2) while sparing epidermal growth factor receptor (EGFR), minimizing related toxicities. This non-randomized, open-label, Phase I study evaluated the absorption, distribution, metabolism and excretion (ADME) of zongertinib (Part A) and its absolute bioavailability (F) (Part B) in healthy male volunteers.

Methods: In Part A, eight subjects received a single oral 60 mg dose of zongertinib (C-14)-solution containing radiolabeled [¹⁴C]zongertinib [3.7 MBq] and unlabeled drug. In Part B, seven subjects received an oral unlabeled zongertinib 60-mg film-coated tablet after fasting, followed by a 15-min intravenous (IV) infusion of 100 μg zongertinib solution (C-14), consisting of 10 μg [¹⁴C]zongertinib [~ 0.03 MBq] and 90 μg unlabeled drug. Plasma pharmacokinetics, excretion pathways, metabolism, and bioavailability were assessed. Safety was evaluated in both study parts.

Results: After oral dosing in Part A, peak plasma concentration occurred at a median of 1-h post-dose (range 0.5‒2.0 h). Mean recovery of the radioactive dose was 93.8%, primarily in feces (92.5%) and minimally in urine (1.30%). Unchanged zongertinib accounted for most circulating radioactivity (74.6%) in plasma and was the most abundant component in feces (31.4% of the dose) and urine (0.18% of dose). In vitro metabolism involved oxidation (48-62%), glucuronidation (13-25%), and glutathione conjugation (13-25%). In part B, the mean F of the oral tablet was 76.2%. Following IV administration, zongertinib showed low plasma clearance (106 mL/min) and a moderate volume of distribution of 138 L. Zongertinib had a manageable safety profile in both study parts.

Conclusions: Zongertinib was rapidly absorbed with high absolute bioavailability. The unchanged zongertinib was the predominant form in plasma and excreta, with fecal excretion as the main elimination pathway. Metabolism occurred primarily through oxidation, with minor contributions from glucuronidation and glutathione conjugation.

Clinical trial registration: Registered under identifier NCT05879991 (25 May 2023).

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宗尔替尼在健康男性志愿者体内的吸收、代谢、分布和排泄（ADME）及绝对生物利用度评价。

背景和目的：宗厄尔替尼是一种不可逆酪氨酸激酶抑制剂，可选择性抑制人表皮生长因子受体2 (HER2)，同时保留表皮生长因子受体（EGFR），将相关毒性降至最低。这项非随机、开放标签的I期研究评估了zongertinib （A部分）在健康男性志愿者中的吸收、分布、代谢和排泄（ADME）及其绝对生物利用度(F)。方法：在A部分，8名受试者接受单次口服60 mg剂量的含放射性标记[14C]宗尔替尼[3.7 MBq]和未标记药物的宗尔替尼（C-14）溶液。在B部分，7名受试者在禁食后口服无标记的宗尔替尼60 mg薄膜包衣片，随后静脉（IV）输注100 μg的宗尔替尼溶液（C-14），该溶液由10 μg [14C]宗尔替尼[~ 0.03 MBq]和90 μg无标记药物组成。评估血浆药代动力学、排泄途径、代谢和生物利用度。对两个研究部分的安全性进行了评估。结果：A部分口服给药后，血药浓度峰值出现在给药后1小时（0.5-2.0小时）。放射性剂量的平均回收率为93.8%，主要在粪便中（92.5%），最低在尿液中（1.30%）。未改变的宗尔替尼在血浆中循环放射性含量最高（74.6%），在粪便（31.4%）和尿液（0.18%）中含量最高。体外代谢包括氧化（48-62%）、葡萄糖醛酸化（13-25%）和谷胱甘肽结合（13-25%）。B部分口服片剂的平均F值为76.2%。静脉给药后，宗尔替尼显示出低血浆清除率（106 mL/min）和中等体积分布（138 l）。在两个研究部分中，宗尔替尼具有可控的安全性。结论：宗尔替尼吸收快，绝对生物利用度高。血浆和排泄物中以不变的宗尔替尼为主，粪便排泄是主要的消除途径。代谢主要通过氧化发生，葡萄糖醛酸化和谷胱甘肽偶联的作用较小。临床试验注册：注册编号NCT05879991（2023年5月25日）。

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

Clinical Drug Investigation 医学-药学

CiteScore

5.90

自引率

3.10%

发文量

108

审稿时长

6-12 weeks

期刊介绍： Clinical Drug Investigation provides rapid publication of original research covering all phases of clinical drug development and therapeutic use of drugs. The Journal includes: -Clinical trials, outcomes research, clinical pharmacoeconomic studies and pharmacoepidemiology studies with a strong link to optimum prescribing practice for a drug or group of drugs. -Clinical pharmacodynamic and clinical pharmacokinetic studies with a strong link to clinical practice. -Pharmacodynamic and pharmacokinetic studies in healthy volunteers in which significant implications for clinical prescribing are discussed. -Studies focusing on the application of drug delivery technology in healthcare. -Short communications and case study reports that meet the above criteria will also be considered. Additional digital features (including animated abstracts, video abstracts, slide decks, audio slides, instructional videos, infographics, podcasts and animations) can be published with articles; these are designed to increase the visibility, readership and educational value of the journal’s content. In addition, articles published in Clinical Drug Investigation may be accompanied by plain language summaries to assist readers who have some knowledge, but non in-depth expertise in, the area to understand important medical advances.