title: Metabolism, excretion and pharmacokinetics of [14C]crizotinib following oral administration to healthy subjects.
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 [(14)C]crizotinib to six healthy male subjects. 3. Mean recovery of [(14)C]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.
authors.affiliation: Department of Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc. , San Diego, CA , USA .
authors.forename: Theodore R
authors.initials: TR
authors.lastname: Johnson
authors.forename: Weiwei
authors.initials: W
authors.lastname: Tan
authors.forename: Lance
authors.initials: L
authors.lastname: Goulet
authors.forename: Evan B
authors.initials: EB
authors.lastname: Smith
authors.forename: Shinji
authors.initials: S
authors.lastname: Yamazaki
authors.forename: Gregory S
authors.initials: GS
authors.lastname: Walker
authors.forename: Melissa T
authors.initials: MT
authors.lastname: O'Gorman
authors.forename: Gabriella
authors.initials: G
authors.lastname: Bedarida
authors.forename: Helen Y
authors.initials: HY
authors.lastname: Zou
authors.forename: James G
authors.initials: JG
authors.lastname: Christensen
authors.forename: Leslie N
authors.initials: LN
authors.lastname: Nguyen
authors.forename: Zhongzhou
authors.initials: Z
authors.lastname: Shen
authors.forename: Deepak
authors.initials: D
authors.lastname: Dalvie
authors.forename: Akintunde
authors.initials: A
authors.lastname: Bello
authors.forename: Bill J
authors.initials: BJ
authors.lastname: Smith
mesh_terms: D000284:Administration, Oral; D000328:Adult; D002250:Carbon Radioisotopes; D000077547:Crizotinib; D005243:Feces / Q000737:chemistry; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D008875:Middle Aged; D047428:Protein Kinase Inhibitors / Q000032:analysis / Q000378:metabolism* / Q000493:pharmacokinetics; D011720:Pyrazoles / Q000032:analysis / Q000378:metabolism* / Q000493:pharmacokinetics; D011725:Pyridines / Q000032:analysis / Q000378:metabolism* / Q000493:pharmacokinetics
chemical_list: D002250:Carbon Radioisotopes; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib
keywords: Crizotinib; excretion; human; metabolism; oncology; pharmacokinetics