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Background and Objectives <p>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 (<i>F</i>) (Part B) in healthy male volunteers.</p> Methods <p>In Part A, eight subjects received a single oral 60&#xa0;mg dose of zongertinib (C-14)-solution containing radiolabeled [<sup>14</sup>C]zongertinib [3.7&#xa0;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&#xa0;μg zongertinib solution (C-14), consisting of 10&#xa0;μg [<sup>14</sup>C]zongertinib [~&#xa0;0.03&#xa0;MBq] and 90&#xa0;μg unlabeled drug. Plasma pharmacokinetics, excretion pathways, metabolism, and bioavailability were assessed. Safety was evaluated in both study parts.</p> Results <p>After oral dosing in Part A, peak plasma concentration occurred at a median of 1-h post-dose (range 0.5‒2.0&#xa0;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 <i>F</i> of the oral tablet was 76.2%. Following IV administration, zongertinib showed low plasma clearance (106&#xa0;mL/min) and a moderate volume of distribution of 138&#xa0;L. Zongertinib had a manageable safety profile in both study parts.</p> Conclusions <p>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.</p> Clinical Trial Registration <p>Registered under identifier NCT05879991 (25 May 2023).</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月5日

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  • 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

摘要

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).