Pharmacokinetics, mass balance, and metabolism of [14C]envonalkib (TQ-B3139), a novel ALK tyrosine kinase inhibitor, in healthy Chinese subjects

• Published in: Cancer chemotherapy and pharmacology Vol. 94; no. 5; pp. 647 - 657
• Main Authors: Ma, Sheng, Wang, Xin, Yan, Shu, Miao, Liyan, Wan, Xiaojing, Ding, Dawei, Yu, Ding, Diao, Xingxing, Wang, Xunqiang, Zhang, Hua
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.11.2024; Springer Nature B.V
• Subjects: Administration, Oral; Adult; Anaplastic Lymphoma Kinase - antagonists & inhibitors; Anaplastic Lymphoma Kinase - metabolism; Asian People; blood; Cancer Research; Carbon Radioisotopes; cysteine; Dealkylation; Dosage; East Asian People; Excretion; Feces; Feces - chemistry; Healthy Volunteers; Humans; Lung cancer; lung neoplasms; lymphoma; Male; males; Medicine; Medicine & Public Health; Metabolism; Metabolites; Middle Aged; Non-small cell lung carcinoma; Oncology; oral administration; Original Article; Pharmacokinetics; Pharmacology/Toxicology; Plasma; Protein Kinase Inhibitors - administration & dosage; Protein Kinase Inhibitors - pharmacokinetics; Protein-tyrosine kinase; quantitative analysis; Radioactivity; radiolabeling; Receptor Protein-Tyrosine Kinases - antagonists & inhibitors; Receptor Protein-Tyrosine Kinases - metabolism; Small cell lung carcinoma; tyrosine; Tyrosine Kinase Inhibitors; Urine; Young Adult; Mass balance; TQ-B3139; Excretion; Pharmacokinetics; Metabolism; Envonalkib
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-024-04647-7

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 14 C-radiolabeled envonalkib in healthy Chinese male subjects. Methods A single oral dose of 600 mg (150 µCi) [ 14 C]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 T max of radioactivity was 4 h and the mean t 1/2 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.