title: Evaluation of crizotinib absolute bioavailability, the bioequivalence of three oral formulations, and the effect of food on crizotinib pharmacokinetics in healthy subjects.
abstract: Crizotinib (Xalkori®) is an orally administered, selective, small-molecule, ATP-competitive inhibitor of the anaplastic lymphoma kinase (ALK) and mesenchymal epithelial transition factor/hepatocyte growth factor receptor tyrosine kinases, and has recently been approved for the treatment of ALK-positive non-small cell lung cancer. The absolute bioavailability of crizotinib, effect of a high-fat meal on crizotinib pharmacokinetics (PK), and bioequivalence of several oral formulations (powder in capsule [PIC], immediate-release tablet [IRT], and commercial formulated capsule [FC]) were evaluated in two phase I clinical studies involving healthy volunteers who received single doses of crizotinib. PK parameters for crizotinib and its metabolite, PF-06260182, were determined using non-compartmental methods. The absolute oral bioavailability of crizotinib was approximately 43%, with a slight decrease in crizotinib exposures (area under the plasma concentration-time profile and maximum plasma concentration) following a high-fat meal that was not considered clinically meaningful. The FC was bioequivalent to the clinical development IRT and PIC formulations. No serious adverse events were observed during either study and the majority of adverse events were mild, the most common being diarrhea. Single-dose crizotinib could be safely administered to healthy subjects.
authors.affiliation: Pfizer Inc., La Jolla, CA, USA.
authors.forename: Huiping
authors.initials: H
authors.lastname: Xu
authors.forename: Melissa
authors.initials: M
authors.lastname: O'Gorman
authors.forename: Tanya
authors.initials: T
authors.lastname: Boutros
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Brega
authors.forename: Constantino
authors.initials: C
authors.lastname: Kantaridis
authors.forename: Weiwei
authors.initials: W
authors.lastname: Tan
authors.forename: Akintunde
authors.initials: A
authors.lastname: Bello
mesh_terms: D000284:Administration, Oral; D000328:Adult; D001682:Biological Availability; D002626:Chemistry, Pharmaceutical; D000077547:Crizotinib; D018592:Cross-Over Studies; D005215:Fasting / Q000378:metabolism; D018565:Food-Drug Interactions; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D008875:Middle Aged; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D011720:Pyrazoles / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D011725:Pyridines / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D013810:Therapeutic Equivalency; D055815:Young Adult
chemical_list: D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib
keywords: absolute bioavailability; bioequivalence; crizotinib; pharmacokinetics