Unravelling the human disposition of [ 14 C]‐vebreltinib: Faecal recovery of parent drug and a major circulating metabolite defines its mass balance profile

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Background Vebreltinib is a novel, highly selective inhibitor of the hepatocyte growth factor receptor (HGFR, also known as c‐MET or MET) tyrosine kinase under development for non‐small cell lung cancer. This study aimed to characterize the absorption, metabolism, excretion and mass balance of [ 14 C]‐vebreltinib in humans. Methods In this open‐label study, six healthy Chinese male subjects received a single 200 mg (100 μCi) oral dose of [ 14 C]‐vebreltinib. Serial blood was collected for up to 216‐h post‐dose. Serial urine and faeces were collected for up to 240‐h post‐dose. Total radioactivity was measured by liquid scintillation counting, and metabolite profiling was conducted using HPLC‐radiochromatography coupled with high‐resolution mass spectrometry. Results Vebreltinib was slowly absorbed, with a mean plasma elimination half‐life of 20.1 ± 5.3 h. The half‐life of total radioactivity was longer, consistent with the formation and persistence of metabolites. The mean total recovery of radioactivity was 93.0% ± 2.1%, with the majority recovered in faeces (79.5% ± 5.5% of the dose) and 13.5% ± 4.3% recovered in urine. Unchanged vebreltinib was the most abundant drug‐related component in excreta, with the N‐demethylated metabolite M2 as the major circulating metabolite. Conclusion Following oral administration, the predominant radioactive component recovered in faeces was unchanged parent drug. The quantitative metabolic profile confirms significant systemic exposure to the M2 metabolite. These data provide critical insights into the human disposition of vebreltinib, including a MIST assessment, and support its continued clinical development.

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