Abstract
Purpose
Envonalkib (TQ-B3139) is a novel, potent anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor used to treat ALK-positive non-small cell lung cancer. This phase I mass balance study investigated the pharmacokinetics, metabolism, and excretion of 14C-radiolabeled envonalkib in healthy Chinese male subjects.
Methods
A single oral dose of 600 mg (150 µCi) [14C]envonalkib was administered to healthy male subjects under fasted state. Samples of blood, urine and feces were collected for quantitative determination of total radioactivity and unchanged envonalkib, and the metabolites identification.
Results
After dosing, the median Tmax of radioactivity was 4 h and the mean t1/2 was 65.2 h in plasma. The exposure of total radioactivity was much higher than that of unchanged envonalkib in plasma. The mean total recovery of the radiolabeled dose was 93.93% over 504 h post-dose, with 15.23% in urine and 78.71% in feces. Envonalkib underwent extensive metabolism and a total of 15 metabolites were identified in plasma, urine, and feces. Unchanged envonalkib and its major metabolite M315 were the main components in plasma, accounting for 20.37% and 33.33% of total plasma radioactivity. In urine, O-dealkylation metabolite M315 was the major component accounted for 7.98% of dose. In feces, 16.01% of dose was excreted as cysteine conjugate M434-1. Envonalkib was well tolerated and there were no serious adverse events observed in the study.
Conclusion
Envonalkib was extensively metabolized prior to excretion and eliminated primarily as metabolites via feces.
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Data availability
The authors confirm that the data supporting the findings of this study are available within the article.
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Acknowledgements
The authors are thankful to Shanghai Institute of Materia Medica for the bioanalysis in this study.
Funding
Xin Wang, Xiaojing Wan, Dawei Ding, Ding Yu, Xunqiang Wang are employees of Chia Tai Tianqing Pharmaceutical Group Co., Ltd. which provided funding for this study.
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SM, LYM and HZ designed and executed this study. XJW, DWD, DY and XQW supported this study. SY and XXD performed bioanalysis. XW wrote the main manuscript text. All authors reviewed the manuscript.
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The studies involving humans were approved by the Medical Ethics Committee of the First Affiliated Hospital of Soochow University (Approval No.: 2021308). All procedures performed in studies involving human participants were in accordance with ethical principles of the Helsinki Declaration. This article does not contain any studies with animals performed by any of the authors.
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Ma, S., Wang, X., Yan, S. et al. Pharmacokinetics, mass balance, and metabolism of [14C]envonalkib (TQ-B3139), a novel ALK tyrosine kinase inhibitor, in healthy Chinese subjects. Cancer Chemother Pharmacol (2024). https://doi.org/10.1007/s00280-024-04647-7
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DOI: https://doi.org/10.1007/s00280-024-04647-7