Mass balance, metabolic disposition, and pharmacokinetics of [ 14 C]ensartinib, a novel potent anaplastic lymphoma kinas
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ORIGINAL ARTICLE
Mass balance, metabolic disposition, and pharmacokinetics of [14C] ensartinib, a novel potent anaplastic lymphoma kinase (ALK) inhibitor, in healthy subjects following oral administration Sufeng Zhou1 · Wei Liu2 · Chen Zhou1 · Lingling Zhang3 · Lijun Xie1 · Zhaoqiang Xu2 · Lu Wang1 · Yuqing Zhao1 · Lian Guo3 · Juan Chen1 · Lieming Ding4 · Li Mao4 · Yi Tao3 · Chen Zhang2 · Sijia Ding1 · Feng Shao1,5 Received: 30 April 2020 / Accepted: 30 September 2020 / Published online: 12 October 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
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 (AUC0–24h pool), while other circulating metabolites were minor, accounting for less than 10%. Mean Cmax, AUC0–∞, T1/2 and Tmax 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. Keywords Ensartinib · X-396 · Pharmacokinetics · Excretion · Metabolism
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00280-020-04159-0) contains supplementary material, which is available to authorized users. * Feng Shao [email protected]; [email protected] 1
Phase I Clinical Trial Unit, The First Affiliated Hospital with Nanjing Medical University, #300 Guangzhou Road, Nanjing 210029, Jiangsu, China
Nulear Medicine Departmen
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