Crizotinib

Identification

Summary

Crizotinib is a receptor tyrosine kinase inhibitor used to treat metastatic non-small cell lung cancer (NSCLC) where the tumors have been confirmed to be anaplastic lymphoma kinase (ALK), or ROS1-positive.

Brand Names
Xalkori
Generic Name
Crizotinib
DrugBank Accession Number
DB08865
Background

Crizotinib an inhibitor of receptor tyrosine kinase for the treatment of non-small cell lung cancer (NSCLC). Verification of the presence of ALK fusion gene is done by Abbott Molecular's Vysis ALK Break Apart FISH Probe Kit. This verification is used to select for patients suitable for treatment. FDA approved in August 26, 2011.

Type
Small Molecule
Groups
Approved
Structure
Thumb
Weight
Average: 450.337
Monoisotopic: 449.11854397
Chemical Formula
C21H22Cl2FN5O
Synonyms
  • (R)-crizotinib
  • Crizotinib
  • Crizotinibum
External IDs
  • 1066
  • PF 02341066
  • PF 2341066
  • PF-02341066
  • PF-2341066

Pharmacology

Indication

Crizotinib is used for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) that is anaplastic-lymphoma kinase (ALK)-positive as detected by a FDA-approved test.

Pharmacology
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Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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Pharmacodynamics

Not Available

Mechanism of action

Crizotinib is a tyrosine kinase receptor inhibitor. More specifically, it inhibits anaplastic lymphoma kinase (ALK), hepatocyte growth factor receptor (HGFR, c-MET), and Recepteur d'Origine Nantais (RON). Abnormalities in the ALK gene caused by mutations or translocations may lead to expression of oncogenic fusion proteins. In patients with NSCLC, they have the EML4-ALK gene. Crizotinib inhibits ALK tyrosine kinase which ultimately results in decreased proliferation of cells that carry the genetic mutation and tumour survivability.

TargetActionsOrganism
AALK tyrosine kinase receptor
inhibitor
Humans
AHepatocyte growth factor receptor
inhibitor
Humans
Absorption

The peak serum concentration was reached in 4 to 6 hours following an oral single-dose administration. Steady state was reached within 15 days when a dose of 250 mg twice daily was administered. The mean absolute bioavailability was 43% (range of 32% to 66%) following a single 250 mg oral dose. When taken with high-fat meal, AUC and Cmax were reduced.

Volume of distribution

Mean volume of distribution (Vss) is 1772 L following intravenous administration of a 50 mg dose. This high volume of distribution suggest extensive distribution into tissue from plasma.

Protein binding

Crizotinib is 91% bound to plasma protein. This is not affected by drug concentration.

Metabolism

Crizotinib is metabolized by CYP3A4 and CYP3A5 in which these enzymes mediates the O-dealkylation of the drug.

Route of elimination

Following the administration of a single 250 mg radiolabeled crizotinib dose to healthy subjects, 63% and 22% of the administered dose was recovered in feces and urine, respectively. Unchanged crizotinib represented approximately 53% and 2.3% of the administered dose in feces and urine, respectively.

Half-life

Plasma terminal half-life, patients = 42 hours

Clearance

The mean apparent clearance (CL/F) of crizotinib was lower at steady state (60 L/hr) after 250 mg twice daily than that after a single 250 mg oral dose (100 L/hr), which was likely due to autoinhibition of CYP3A by crizotinib after multiple dosing.

Adverse Effects
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Toxicity

Not Available

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AbaloparatideThe therapeutic efficacy of Abaloparatide can be decreased when used in combination with Crizotinib.
AbametapirThe serum concentration of Crizotinib can be increased when it is combined with Abametapir.
AbataceptThe metabolism of Crizotinib can be increased when combined with Abatacept.
AbemaciclibThe metabolism of Abemaciclib can be decreased when combined with Crizotinib.
AbirateroneThe metabolism of Crizotinib can be decreased when combined with Abiraterone.
AcalabrutinibThe metabolism of Crizotinib can be decreased when combined with Acalabrutinib.
AcebutololThe risk or severity of QTc prolongation can be increased when Acebutolol is combined with Crizotinib.
AcenocoumarolThe metabolism of Acenocoumarol can be decreased when combined with Crizotinib.
AcetaminophenThe metabolism of Acetaminophen can be increased when combined with Crizotinib.
AcetazolamideThe metabolism of Crizotinib can be decreased when combined with Acetazolamide.
Interactions
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Food Interactions
  • Avoid grapefruit products. Grapefruit inhibits CYP3A4 metabolism, which may increase the serum levels of crizotinib.
  • Avoid St. John's Wort. This herb induces CYP3A4 metabolism, which may reduce serum levels of crizotinib.
  • Take with or without food. High-fat food decreases drug absorption, but not to a clinically significant extent.

Products

Products
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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
XalkoriCapsule250 mg/1OralPfizer Laboratories Div Pfizer Inc2011-08-26Not applicableUS flag
XalkoriCapsuleOralPfizer Europe Ma Eeig2016-09-08Not applicableEU flag
XalkoriCapsule200 mgOralPfizer Canada Ulc2012-05-10Not applicableCanada flag
XalkoriCapsuleOralPfizer Europe Ma Eeig2016-09-08Not applicableEU flag
XalkoriCapsuleOralPfizer Europe Ma Eeig2016-09-08Not applicableEU flag
XalkoriCapsule200 mg/1OralPfizer Laboratories Div Pfizer Inc2011-08-26Not applicableUS flag
XalkoriCapsuleOralPfizer Europe Ma Eeig2016-09-08Not applicableEU flag
XalkoriCapsule250 mgOralPfizer Canada Ulc2012-05-10Not applicableCanada flag

Categories

ATC Codes
L01XE16 — Crizotinib
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as pyrazolylpyridines. These are compounds containing a pyrazolylpyridine skeleton, which consists of a pyrazole linked (not fused) to a pyridine by a bond.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Pyridines and derivatives
Sub Class
Pyrazolylpyridines
Direct Parent
Pyrazolylpyridines
Alternative Parents
Dichlorobenzenes / Alkyl aryl ethers / Aminopyridines and derivatives / Fluorobenzenes / Piperidines / Aryl chlorides / Aryl fluorides / Imidolactams / Pyrazoles / Heteroaromatic compounds
show 7 more
Substituents
1,3-dichlorobenzene / 3-pyrazolylpyridine / Alkyl aryl ether / Amine / Aminopyridine / Aromatic heteromonocyclic compound / Aryl chloride / Aryl fluoride / Aryl halide / Azacycle
show 23 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
3-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-[1-(piperidin-4-yl)pyrazol-4-yl]pyridin-2-amine (CHEBI:64310)
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
53AH36668S
CAS number
877399-52-5
InChI Key
KTEIFNKAUNYNJU-GFCCVEGCSA-N
InChI
InChI=1S/C21H22Cl2FN5O/c1-12(19-16(22)2-3-17(24)20(19)23)30-18-8-13(9-27-21(18)25)14-10-28-29(11-14)15-4-6-26-7-5-15/h2-3,8-12,15,26H,4-7H2,1H3,(H2,25,27)/t12-/m1/s1
IUPAC Name
3-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]pyridin-2-amine
SMILES
C[C@@H](OC1=CC(=CN=C1N)C1=CN(N=C1)C1CCNCC1)C1=C(Cl)C=CC(F)=C1Cl

References

General References
  1. Timm A, Kolesar JM: Crizotinib for the treatment of non-small-cell lung cancer. Am J Health Syst Pharm. 2013 Jun 1;70(11):943-7. doi: 10.2146/ajhp120261. [PubMed:23686600]
  2. Forde PM, Rudin CM: Crizotinib in the treatment of non-small-cell lung cancer. Expert Opin Pharmacother. 2012 Jun;13(8):1195-201. doi: 10.1517/14656566.2012.688029. [PubMed:22594847]
KEGG Drug
D09731
PubChem Compound
11626560
PubChem Substance
310264901
ChemSpider
9801307
BindingDB
50306682
RxNav
1148495
ChEBI
64310
ChEMBL
CHEMBL601719
ZINC
ZINC000035902489
PharmGKB
PA165946122
PDBe Ligand
VGH
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Crizotinib
AHFS Codes
  • 10:00.00 — Antineoplastic Agents
PDB Entries
2wgj / 2xp2 / 2yfx / 3zbf / 4anq / 4ans / 4c9w / 5aaa / 5aab / 5aac
show 1 more
FDA label
Download (279 KB)
MSDS
Download (105 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4RecruitingTreatmentALK or ROS1-positive NSCLC1
4RecruitingTreatmentALK-Positive Anaplastic Large Cell Lymphoma1
4WithdrawnTreatmentSystemic Anaplastic Large Cell Lymphoma / Systemic Anaplastic Large-Cell Lymphoma1
3Active Not RecruitingTreatmentAnaplastic Lymphoma Kinase-positive Non-small Cell Lung Cancer1
3Active Not RecruitingTreatmentNeoplasms1
3Active Not RecruitingTreatmentNon-Small Cell Lung Carcinoma (NSCLC)3
3CompletedTreatmentAdvanced Malignancies / Carcinoma NOS / Lung Cancers / Non-Small Cell Lung Carcinoma (NSCLC)1
3CompletedTreatmentNon-Small Cell Lung Carcinoma (NSCLC)2
3Not Yet RecruitingTreatmentNon-Small Cell Lung Carcinoma (NSCLC)1
3RecruitingTreatmentALK Gene Rearrangement / ALK Gene Translocation / ALK positive / Stage IB Non-Small Cell Lung Carcinoma AJCC v7 / Stage II Non-Small Cell Lung Cancer AJCC v7 / Stage IIA Non-Small Cell Lung Carcinoma AJCC v7 / Stage IIB Non-Small Cell Lung Carcinoma AJCC v7 / Stage IIIA Non-Small Cell Lung Cancer AJCC v71

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
CapsuleOral
CapsuleOral200 mg/1
CapsuleOral250 mg/1
Capsule, coatedOral
CapsuleOral200 mg
CapsuleOral250 mg
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
CA2517256No2013-04-302024-02-26Canada flag
CA2577937No2010-12-212025-08-15Canada flag
CA2578066No2011-10-112025-08-15Canada flag
CA2632286No2011-11-152026-11-23Canada flag
US7825137No2010-11-022027-05-12US flag
US7858643No2010-12-282029-10-08US flag
US7230098No2007-06-122025-08-26US flag
US8217057No2012-07-102029-11-06US flag
US8785632No2014-07-222025-03-01US flag

Properties

State
Solid
Experimental Properties
PropertyValueSource
logP1.83 MSDS
Predicted Properties
PropertyValueSource
Water Solubility0.00611 mg/mLALOGPS
logP3.82ALOGPS
logP3.57ChemAxon
logS-4.9ALOGPS
pKa (Strongest Basic)10.12ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area77.99 Å2ChemAxon
Rotatable Bond Count5ChemAxon
Refractivity128.43 m3·mol-1ChemAxon
Polarizability45.44 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption+1.0
Blood Brain Barrier+0.9721
Caco-2 permeable-0.5672
P-glycoprotein substrateSubstrate0.6938
P-glycoprotein inhibitor INon-inhibitor0.6713
P-glycoprotein inhibitor IIInhibitor0.7105
Renal organic cation transporterInhibitor0.5464
CYP450 2C9 substrateNon-substrate0.7545
CYP450 2D6 substrateNon-substrate0.7023
CYP450 3A4 substrateSubstrate0.6029
CYP450 1A2 substrateInhibitor0.6676
CYP450 2C9 inhibitorInhibitor0.5
CYP450 2D6 inhibitorNon-inhibitor0.8662
CYP450 2C19 inhibitorInhibitor0.6237
CYP450 3A4 inhibitorNon-inhibitor0.6301
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.8676
Ames testNon AMES toxic0.5981
CarcinogenicityNon-carcinogens0.8018
BiodegradationNot ready biodegradable1.0
Rat acute toxicity2.6581 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Strong inhibitor0.643
hERG inhibition (predictor II)Inhibitor0.7877
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available
LC-MS/MS Spectrum - LC-ESI-qTof , PositiveLC-MS/MSNot Available
MS/MS Spectrum - , positiveLC-MS/MSsplash10-0udi-1693800000-fc52c38f3359a378554a

Targets

Drugtargets
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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Transmembrane receptor protein tyrosine kinase activity
Specific Function
Neuronal orphan receptor tyrosine kinase that is essentially and transiently expressed in specific regions of the central and peripheral nervous systems and plays an important role in the genesis a...
Gene Name
ALK
Uniprot ID
Q9UM73
Uniprot Name
ALK tyrosine kinase receptor
Molecular Weight
176440.535 Da
References
  1. Forde PM, Rudin CM: Crizotinib in the treatment of non-small-cell lung cancer. Expert Opin Pharmacother. 2012 Jun;13(8):1195-201. doi: 10.1517/14656566.2012.688029. [PubMed:22594847]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Protein tyrosine kinase activity
Specific Function
Receptor tyrosine kinase that transduces signals from the extracellular matrix into the cytoplasm by binding to hepatocyte growth factor/HGF ligand. Regulates many physiological processes including...
Gene Name
MET
Uniprot ID
P08581
Uniprot Name
Hepatocyte growth factor receptor
Molecular Weight
155540.035 Da
References
  1. Forde PM, Rudin CM: Crizotinib in the treatment of non-small-cell lung cancer. Expert Opin Pharmacother. 2012 Jun;13(8):1195-201. doi: 10.1517/14656566.2012.688029. [PubMed:22594847]
  2. Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE: The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42. [PubMed:10592235]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. Timm A, Kolesar JM: Crizotinib for the treatment of non-small-cell lung cancer. Am J Health Syst Pharm. 2013 Jun 1;70(11):943-7. doi: 10.2146/ajhp120261. [PubMed:23686600]
  2. Xalkori (Crizotinib) FDA Label [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
General Function
Oxygen binding
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP3A5
Uniprot ID
P20815
Uniprot Name
Cytochrome P450 3A5
Molecular Weight
57108.065 Da
References
  1. Timm A, Kolesar JM: Crizotinib for the treatment of non-small-cell lung cancer. Am J Health Syst Pharm. 2013 Jun 1;70(11):943-7. doi: 10.2146/ajhp120261. [PubMed:23686600]
  2. Xalkori (Crizotinib) FDA Label [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Steroid hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP2B6
Uniprot ID
P20813
Uniprot Name
Cytochrome P450 2B6
Molecular Weight
56277.81 Da
Kind
Protein group
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...

Components:
References
  1. Filppula AM, Neuvonen PJ, Backman JT: In vitro assessment of time-dependent inhibitory effects on CYP2C8 and CYP3A activity by fourteen protein kinase inhibitors. Drug Metab Dispos. 2014 Jul;42(7):1202-9. doi: 10.1124/dmd.114.057695. Epub 2014 Apr 8. [PubMed:24713129]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
General Function
Xenobiotic-transporting atpase activity
Specific Function
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name
ABCB1
Uniprot ID
P08183
Uniprot Name
Multidrug resistance protein 1
Molecular Weight
141477.255 Da
References
  1. Timm A, Kolesar JM: Crizotinib for the treatment of non-small-cell lung cancer. Am J Health Syst Pharm. 2013 Jun 1;70(11):943-7. doi: 10.2146/ajhp120261. [PubMed:23686600]

Drug created on March 28, 2013 17:22 / Updated on May 06, 2021 06:19