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 [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.

• Crizotinib
• excretion
• human
• metabolism
• oncology
• pharmacokinetics

Acknowledgements

We thank personnel from Covance Laboratories Inc. (Madison, WI and Indianapolis, IN) for radioanalysis support of the human ADME study and for quantitation of crizotinib in human plasma and urine samples; Yao (Grace) Ni for facilitating clinical study conduct; Chunze Li for preliminary pharmacokinetic analyses; Nicoletta Brega for clinical support; and Klaas Schildknegt for preparation of radiolabeled crizotinib. The support of these colleagues is gratefully acknowledged.

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the writing and content of this article.

These studies were sponsored by Pfizer Inc. All authors are employees of Pfizer Inc. or were at the time of conducting these studies.