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

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

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; Excretion; Metabolism; Pharmacokinetics; X-396.

Publication types

  • Clinical Trial, Phase I
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Adult
  • Anaplastic Lymphoma Kinase / antagonists & inhibitors
  • Anaplastic Lymphoma Kinase / genetics
  • Carbon Radioisotopes
  • Carcinoma, Non-Small-Cell Lung / drug therapy
  • Carcinoma, Non-Small-Cell Lung / genetics
  • Feces / chemistry
  • Healthy Volunteers
  • Humans
  • Intestinal Absorption
  • Intestinal Elimination
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / genetics
  • Male
  • Metabolic Clearance Rate
  • Piperazines / administration & dosage
  • Piperazines / analysis
  • Piperazines / chemistry
  • Piperazines / pharmacokinetics*
  • Protein Kinase Inhibitors / administration & dosage
  • Protein Kinase Inhibitors / pharmacokinetics*
  • Pyridazines / administration & dosage
  • Pyridazines / analysis
  • Pyridazines / chemistry
  • Pyridazines / pharmacokinetics*
  • Scintillation Counting

Substances

  • Carbon Radioisotopes
  • Piperazines
  • Protein Kinase Inhibitors
  • Pyridazines
  • Carbon-14
  • ALK protein, human
  • Anaplastic Lymphoma Kinase
  • ensartinib

Associated data

  • ClinicalTrials.gov/NCT03804541