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

◢ Clinical Trial Cancer Chemother Pharmacol. 2020 Dec;86(6):719-730. doi: 10.1007/s00280-020-04159-0. Epub 2020 Oct 12.

Sufeng Zhou ¹, Wei Liu ², Chen Zhou ¹, Lingling Zhang ³, Lijun Xie ¹, Zhaoqiang Xu ², Lu Wang ¹, Yuqing Zhao ¹, Lian Guo ³, Juan Chen ¹, Lieming Ding ⁴, Li Mao ⁴, Yi Tao ³, Chen Zhang ², Sijia Ding ¹, Feng Shao ^5 6

¹Phase I Clinical Trial Unit, The First Affiliated Hospital with Nanjing Medical University, #300 Guangzhou Road, Nanjing, 

²10029, Jiangsu, China.2Nulear Medicine Department, The First Affiliated Hospital with Nanjing Medical University, Nanjing, 210029, China.

³Lab Testing Division, Department of DMPK Service, WuXi AppTec Co. Ltd., Nanjing, 210038, China.

⁴Betta Pharmaceuticals Co., Ltd., Hangzhou, 311100, China.

⁵Phase I Clinical Trial Unit, The First Affiliated Hospital with Nanjing Medical University, #300 Guangzhou Road, Nanjing, 210029, Jiangsu, China. jsphshaofeng@hotmail.com.

⁶Department of Clinical Pharmacology, Pharmacy College, Nanjing Medical University, Nanjing, 211166, China. jsphshaofeng@hotmail.com.

Abstract

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.