Metabolism, excretion and pharmacokinetics of [14C]crizotinib following oral administration to healthy subjects

• Published in: Xenobiotica Vol. 45; no. 1; pp. 45 - 59
• Main Authors: Johnson, Theodore R., Tan, Weiwei, Goulet, Lance, Smith, Evan B., Yamazaki, Shinji, Walker, Gregory S., O'Gorman, Melissa T., Bedarida, Gabriella, Zou, Helen Y., Christensen, James G., Nguyen, Leslie N., Shen, Zhongzhou, Dalvie, Deepak, Bello, Akintunde, Smith, Bill J.
• Format: Journal Article
• Language: English
• Published: England Informa UK Ltd 01.01.2015; Informa Healthcare
• Subjects: Administration, Oral; Adult; Carbon Radioisotopes; Crizotinib; excretion; Feces - chemistry; Healthy Volunteers; human; Humans; Male; metabolism; Middle Aged; oncology; pharmacokinetics; Protein Kinase Inhibitors - analysis; Protein Kinase Inhibitors - metabolism; Protein Kinase Inhibitors - pharmacokinetics; Pyrazoles - analysis; Pyrazoles - metabolism; Pyrazoles - pharmacokinetics; Pyridines - analysis; Pyridines - metabolism; Pyridines - pharmacokinetics; Crizotinib; pharmacokinetics; metabolism; excretion; human; oncology
• ISSN: 0049-8254; 1366-5928
• DOI: 10.3109/00498254.2014.941964

Abstract 1. Crizotinib (XALKORI®), an oral inhibitor of anaplastic lymphoma kinase (ALK) and mesenchymal-epithelial transition factor kinase (c-Met), is currently approved for the treatment of patients with non-small cell lung cancer that is ALK-positive. 2. The metabolism, excretion and pharmacokinetics of crizotinib were investigated following administration of a single oral dose of 250 mg/100 µCi [14C]crizotinib to six healthy male subjects. 3. Mean recovery of [14C]crizotinib-related radioactivity in excreta samples was 85% of the dose (63% in feces and 22% in urine). 4. Crizotinib and its metabolite, crizotinib lactam, were the major components circulating in plasma, accounting for 33% and 10%, respectively, of the 0-96 h plasma radioactivity. Unchanged crizotinib was the major excreted component in feces (∼53% of the dose). In urine, crizotinib and O-desalkyl crizotinib lactam accounted for ∼2% and 5% of the dose, respectively. Collectively, these data indicate that the primary clearance pathway for crizotinib in humans is oxidative metabolism/hepatic elimination. 5. Based on plasma exposure in healthy subjects following a single dose of crizotinib and in vitro potency against ALK and c-Met, the crizotinib lactam diastereomers are not anticipated to contribute significantly to in vivo activity; however, additional assessment in cancer patients is warranted.