Pharmacokinetics of crizotinib in NSCLC patients.
BACKGROUND
For a subpopulation of NSCLC patients genetic rearrangement of the anaplastic lymphoma kinase (ALK) was found as driver mutation, which can be targeted by the selective inhibitor crizotinib.


METHODS
This article presents an overview of the clinical studies that provided the characterization of the pharmacokinetic parameters for the administration of crizotinib to cancer patients and the factors influencing the clinical profiles of this drug.


CONCLUSIONS
Crizotinib is administered orally as a capsule and clinical studies indicated 250 mg crizotinib BID continuously as the maximal tolerated dose in cancer patients. Bioavailability is ∼ 40% and pharmacokinetic parameters are influenced by food only to a minor degree. This dose of the drug corresponds to a significant inhibition of the mutated ALK, retards tumor growth and achieves clinical responses in the majority of patients. Crizotinib lactam is the single metabolite with minor inhibitory activity for the ALK fusion protein. Metabolization is executed mainly by CYP3A4/5 and is modulated by other drugs interacting with this cytochrome oxidase. Despite the one-fits-all approach in administration of crizotinib at a fixed dose the pharmacokinetic parameters indicate a stable steady state upon continuous administration, which achieves sufficient inhibition of the ALK drug target.
Ludwig Boltzmann Cluster of Translational Oncology , 1090 Vienna , Austria +43 1 40400 66270 ; +43 1 40400 66270 ; gerhard.hamilton@toc.lbg.ac.at.
Gerhard
G
Hamilton
Barbara
B
Rath
Otto
O
Burghuber
D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics; D000077547:Crizotinib; D015321:Gene Rearrangement; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics; D020714:Maximum Tolerated Dose; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D011720:Pyrazoles / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D011725:Pyridines / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics
D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases
NSCLC; anaplastic lymphoma kinase; crizotinib; pharmacokinetics; tyrosine kinase inhibitor