Ligand id: 4903

Name: crizotinib

Structure and Physico-chemical Properties

2D Structure
Calculated Physico-chemical Properties
Hydrogen bond acceptors 5
Hydrogen bond donors 2
Rotatable bonds 5
Topological polar surface area 77.99
Molecular weight 449.12
XLogP 2.83
No. Lipinski's rules broken 0

Molecular properties generated using the CDK

No information available.
Summary of Clinical Use
Crizotinib was originally approved for treatment of anaplastic lymphoma kinase (ALK)-positive non-small cell lung carcinomas (NSCLC).
In March 2016, the US FDA expanded marketing authorisation to include treatment of patients with ROS1-positive metastatic NSCLC. Clinical trials for anaplastic large cell lymphoma, neuroblastoma, and other advanced solid tumours are ongoing.
In mid-2018, the FDA granted breakthrough designations for Xalkori as a treatment for NSCLC with MET exon 14 alterations (and with disease progression on or after platinum-based chemotherapy), and as a treatment for ALK-positive relapsed/refractory systemic anaplastic large cell lymphoma.
Mechanism Of Action and Pharmacodynamic Effects
Critzotinib inhibits receptor tyrosine kinases, including anaplastic lymphoma kinase (ALK, including its oncogenic variants i.e. ALK fusion events and selected ALK mutations), recepteur d'origine nantais (RON) and hepatocyte growth factor receptor (HGFR, c-Met) [7]. Crizotinib demonstrates dose-dependent anti-tumour efficacy, including marked cytoreductive anti-tumour activity, in mice bearing tumour xenografts that express ALK fusion proteins, which correlates with pharmacodynamic inhibition of phosphorylation of ALK fusion proteins (including EML4-ALK and NPM-ALK) in tumours in vivo. Crizotinib is currently thought to exert its effects through modulation of the growth, migration, and invasion of malignant cells and/or by inhibiting angiogenesis in malignant tumours. .
Peak circulating concentrations are achieved between 4 to 6 hours after oral dosing. Absolute bioavailability ranges between 32% and 66%. Crizotinib may be taken with or without food. A high volume of distribution (1772 L) following intravenous administration of a 50 mg dose indicates extensive distribution from the plasma into tissues. Binding of crizotinib to human plasma proteins in vitro is 91% and is not related to drug concentration. In vitro studies suggest that crizotinib is a substrate for P-glycoprotein (P-gp), therefore crizotinib may have the potential to increase curculating concentrations of coadministered medicinal products that are also substrates of P-gp.
Predominantly metabolized in the liver by CYP3A4 and CYP3A5.
Following the administration of a single 250 mg radiolabeled crizotinib dose to healthy subjects, 63% (53% unchanged) was recovered in feces and 22% (2.3% unchanged) in urine.
Population pharmacokinetics
Cmax and AUC are higher in Asian compared to non-Asian patients.
Organ function impairment
Hepatic impairment: Results from clinical studies excluded patients with ALT or AST >2.5 x ULN or, if due to underlying malignancy, >5.0 x ULN or with total bilirubin >1.5 x ULN from crizotinib treatment. Renal impairment: No starting dose adjustment is recommended for patients with mild and moderate renal impairment. No formal dosing recommendation can be made regarding patients with severe and end-stage renal disease as no data are available. Cardiac electrophysiology: A pharmacokinetic/pharmacodynamic analysis of all patients who received crizotinib 250 mg twice daily suggested a relationship between crizotinib plasma concentration and QTc as measured by automated machine-read evaluation of ECG.
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