Mass balance, metabolic disposition, and pharmacokinetics of [14C]ensartinib, a novel potent anaplastic lymphoma kinase (ALK) inhibitor, in healthy subjects following oral administration

• Published in: Cancer chemotherapy and pharmacology Vol. 86; no. 6; pp. 719 - 730
• Main Authors: Zhou, Sufeng, Liu, Wei, Zhou, Chen, Zhang, Lingling, Xie, Lijun, Xu, Zhaoqiang, Wang, Lu, Zhao, Yuqing, Guo, Lian, Chen, Juan, Ding, Lieming, Mao, Li, Tao, Yi, Zhang, Chen, Ding, Sijia, Shao, Feng
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.12.2020; Springer Nature B.V
• Subjects: Cancer Research; Drug dosages; Enzyme inhibitors; Feces; Half-life; Liquid chromatography; Lymphoma; Mass spectroscopy; Medicine; Medicine & Public Health; Metabolites; NCT; NCT03804541; Non-small cell lung carcinoma; Oncology; Oral administration; Original Article; Pharmacokinetics; Pharmacology/Toxicology; Plasma; Protein-tyrosine kinase; Radioactivity; Small cell lung carcinoma; Toxicity; Urine; Excretion; Ensartinib; Pharmacokinetics; Metabolism; X-396
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-020-04159-0

Purpose Ensartinib is a novel, potent and highly selective inhibitor of anaplastic lymphoma kinase (ALK) that has promising clinical activity and low toxicity in patients with ALK-positive non-small cell lung cancer. This study was conducted to investigate the pharmacokinetics, metabolism and excretion of ensartinib following a single 200 mg/100 μCi oral dose of radiolabeled ensartinib to healthy subjects. Methods Six healthy male subjects were enrolled and administrated an oral suspension in a fasted state. Blood, urine and feces were collected. Radioactivity concentrations were measured by liquid scintillation counting and plasma concentrations of ensartinib by liquid chromatography-tandem mass spectrometry. Both techniques were applied for metabolite profiling and characterization. Results The mean total recovery was 101.21% of the radiolabeled dose with 91.00% and 10.21% excreted in feces and urine, respectively. Unchanged ensartinib was the predominant drug-related component in urine and feces, representing 4.39% and 38.12% of the administered dose, respectively. Unchanged ensartinib and its metabolite M465 were the major circulating components, accounting for the same 27.45% of the plasma total radioactivity (AUC 0–24h pool), while other circulating metabolites were minor, accounting for less than 10%. Mean C max , AUC 0–∞, T 1/2 and T max values for ensartinib in plasma were 185 ng/mL, 3827 h ng/mL, 18.3 h and 3.25 h, respectively. The total radioactivity in plasma was cleared with terminal half-life of 27.2 h. Treatment with ensartinib was well tolerated, and no serious adverse events were reported. Conclusion It was well tolerated in the six healthy male subjects following a single oral administration of 200 mg/100 μCi dose of ensartinib. Besides unchanged ensartinib, metabolite of M465 was the predominant circulating drug-related component. The drug was primarily eliminated in feces. Clinical trial registration ClinicalTrials.gov NCT03804541.