Metabolism, excretion and pharmacokinetics of [14C]crizotinib following oral administration to healthy subjects. (January 2015)

• Record Type: Journal Article
• 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.
• Is Part Of: Xenobiotica. Volume 45:Number 1(2015:Jan.)
• Page Start: 45
• Page End: 59
• Publication Date: 2015-01
• Subjects: Metabolism -- Periodicals; Drugs -- Physiological effect -- Periodicals; Food additives -- Periodicals; Chemicals -- Physiological effect -- Periodicals; Biochemistry -- Periodicals; Pharmaceutical Preparations -- metabolism -- Periodicals; Metabolism -- Periodicals; 574.133
• DOI: 10.3109/00498254.2014.941964
• Languages: English
• ISSNs: 0049-8254

Abstract

<abstract> <title>Abstract</title> <p>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.</p> <p>2. The metabolism, excretion and pharmacokinetics of crizotinib were investigated following administration of a single oral dose of 250 mg/100 µCi [<sup>14</sup>C]crizotinib to six healthy male subjects.</p> <p>3. Mean recovery of [<sup>14</sup>C]crizotinib-related radioactivity in excreta samples was 85% of the dose (63% in feces and 22% in urine).</p> <p>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 <italic>O</italic>-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.</p> <p>5. Based on plasma exposure in healthy subjects following a single dose of crizotinib and <italic>in vitro</italic> potency against ALK and c-Met, the crizotinib lactam diastereomers are not anticipated to contribute significantly to <italic>in vivo</italic> activity; however, additional assessment in cancer patients is warranted.</p> </abstract>