Crizotinib

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C21H22Cl2FN5O
Molecular Weight	450.337
Optical Activity	UNSPECIFIED
Defined Stereocenters	1 / 1
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

SMILES

C[C@@H](OC1=CC(=CN=C1N)C2=CN(N=C2)C3CCNCC3)C4=C(Cl)C=CC(F)=C4Cl

InChI

InChIKey=KTEIFNKAUNYNJU-GFCCVEGCSA-N

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

HIDE SMILES / InChI

Molecular Formula	C21H22Cl2FN5O
Molecular Weight	450.337
Charge	0
Count	MOL RATIO 1 MOL RATIO (average)

Stereochemistry	ABSOLUTE
Additional Stereochemistry	No
Defined Stereocenters	1 / 1
E/Z Centers	0
Optical Activity	UNSPECIFIED

Description

Crizotinib (trade name Xalkori, Pfizer, Inc.) is an anti cancer drug approved for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors are anaplastic lymphoma kinase (ALK)-positive as detected by an FDA-approved test. Crizotinib is an inhibitor of receptor tyrosine kinases including ALK, Hepatocyte Growth Factor Receptor (HGFR, c-Met), ROS1 (c-ros), and Recepteur d’Origine Nantais (RON). Common adverse reactions in clinical trials with crizotinib, occurring at an incidence of 25% or higher, included visual disorders, nausea, diarrhea, vomiting, constipation, edema, elevated transaminases, and fatigue. Crizotinib is currently under investigational study for use in treatment of Uveal Melanoma.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
ALK tyrosine kinase receptor 24	Inhibitor 8,504		24.0 nM [IC50]
Hepatocyte growth factor receptor 56	Inhibitor 8,504		11.0 nM [IC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Metastatic non-small cell lung cancer 13	Primary		Approved 8,583	XALKORI

C_max

Value	Dose	Analyte	Population
475 ng/mL	300 mg 2 times / day steady-state, oral	CRIZOTINIB plasma	Homo sapiens
87 ng/mL	250 mg single, oral	CRIZOTINIB plasma	Homo sapiens
327 ng/mL	250 mg 2 times / day multiple, oral	CRIZOTINIB plasma	Homo sapiens
328 ng/mL	250 mg 2 times / day steady-state, oral	CRIZOTINIB plasma	Homo sapiens
99.6 ng/mL	250 mg single, oral	CRIZOTINIB plasma	Homo sapiens

AUC

Value	Dose	Analyte	Population
3240 ng × h/mL	300 mg 2 times / day steady-state, oral	CRIZOTINIB plasma	Homo sapiens
1817 ng × h/mL	250 mg single, oral	CRIZOTINIB plasma	Homo sapiens
3084 ng × h/mL	250 mg 2 times / day multiple, oral	CRIZOTINIB plasma	Homo sapiens
3054 ng × h/mL	250 mg 2 times / day steady-state, oral	CRIZOTINIB plasma	Homo sapiens
2321 ng × h/mL	250 mg single, oral	CRIZOTINIB plasma	Homo sapiens

T_1/2

Value	Dose	Co-administered	Analyte	Population
42 h	250 mg single, oral		CRIZOTINIB plasma	Homo sapiens
29 h	250 mg single, oral		CRIZOTINIB plasma	Homo sapiens

F_unbound

Value	Dose	Co-administered	Analyte	Population
9.3%			CRIZOTINIB plasma	Homo sapiens

Doses

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Dose	Population	Adverse events
300 mg 2 times / day steady, oral	unhealthy, 49 years	Disc. AE: Fatigue...
250 mg 2 times / day steady, oral Recommended\|MTD	unhealthy, 51 years (range: 21-79 years)	Disc. AE: Autoimmune thyroiditis...
250 mg 2 times / day steady, oral Recommended\|MTD	unhealthy, 52 years (range: 29-82 years)	Disc. AE: ALT increased, Pneumonitis...

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AEs

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AE	Significance	Dose	Population
Fatigue	grade 3, 1 patient Disc. AE	300 mg 2 times / day steady, oral	unhealthy, 49 years
Autoimmune thyroiditis	1 patient Disc. AE	250 mg 2 times / day steady, oral Recommended\|MTD	unhealthy, 51 years (range: 21-79 years)
Pneumonitis	1.5% Disc. AE	250 mg 2 times / day steady, oral Recommended\|MTD	unhealthy, 52 years (range: 29-82 years)
ALT increased	2.2% Disc. AE	250 mg 2 times / day steady, oral Recommended\|MTD	unhealthy, 52 years (range: 29-82 years)

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Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1,946 inducer 1,087	substrate 1,193 inhibitor 2,438	substrate 1,388 inhibitor 2,507	inhibitor 2,217

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP3A 227 P-gp 1,741 CYP1A2 2,153 CYP2B6 926 CYP2C8 1,057 CYP2C19 2,057 OATP1B1 1,079 OATP1B3 961 BCRP 910 Ca2+ channels 59 L-type Ca2+ channels 28 Nav1.5 116	CYP3A5 446 CYP2C19 1,119 CYP2C8 810 CYP1A2 1,197 P-gp 2,052	CYP3A 142 CYP1A2 832

Drug as perpetrator

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Target	Modality	Activity
CYP1A2 2,333	inducer 1,966	no
CYP3A 317	inducer 1,966	no
OATP1B3 970	inhibitor 4,027	weak [IC50 44 uM]
OATP1B1 1,095	inhibitor 4,027	weak [IC50 48 uM]
BCRP 985	inhibitor 4,027	weak [Inhibition 30 uM]

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Drug as victim

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Target	Modality	Activity	Clinical evidence
CYP3A4 1,946	substrate 4,014	major	yes (co-administration study)
CYP3A5 446	substrate 4,014	major	yes (co-administration study)
CYP2C19 1,119	substrate 4,014	minor
CYP2D6 1,388	substrate 4,014	minor
CYP1A2 1,197	substrate 4,014	no

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Tox targets

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Target	Modality	Activity	Metabolite	Clinical evidence
Nav1.5 119	inhibitor 2,237
hERG 2,263	inhibitor 2,237

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Sourcing

Sourcing

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Vendor/Aggregator	ID	URL
ChEBI	CHEBI:64310	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:64310
eMolecules	31526065	https://www.emolecules.com/cgi-bin/more?vid=31526065
MolPort	MolPort-009-679-404	https://www.molport.com/shop/molecule-link/MolPort-009-679-404
Selleck Chemicals	PF-2341066	http://www.selleckchem.com/products/PF-2341066.html
ZINC	ZINC000035902489	http://zinc15.docking.org/substances/ZINC000035902489

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PubMed

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Title	Date	PubMed
		252160340
An orally available small-molecule inhibitor of c-Met, PF-2341066, exhibits cytoreductive antitumor efficacy through antiproliferative and antiangiogenic mechanisms.	2007 May 1	17483355
Trial watch: success for crizotinib in ALK-driven cancer.	2010 Dec	21119722
The neuroblastoma-associated F1174L ALK mutation causes resistance to an ALK kinase inhibitor in ALK-translocated cancers.	2010 Dec 15	21030459
Crizotinib--latest champion in the cancer wars?	2010 Oct 28	20979477

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Patents

Sample Use Guides

In Vivo Use Guide

The recommended dose and schedule for crizotinib is 250 mg orally, twice daily, with or without food.

Route of Administration: fVal

In Vitro Use Guide

PF-2341066 potently inhibited NPM-ALK phosphorylation in Karpas299 or SU-DHL-1 ALCL cells (mean IC50 value of 24 nmol/L). In biochemical and cellular screens, PF-2341066 was shown to be selective for c-Met and ALK at pharmacologically relevant concentrations across a panel of >120 diverse kinases. PF-2341066 potently inhibited cell proliferation, which was associated with G(1)-S-phase cell cycle arrest and induction of apoptosis in ALK-positive ALCL cells at IC50 values of approximately 30 nmol/L but not ALK-negative lymphoma cells.

Substance Class	Chemical
Record UNII	53AH36668S
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

Crizotinib

Official Name

English

XALKORI

Preferred Name

English

CRIZOTINIB [USAN]

Common Name

English

CRIZOTINIB [JAN]

Common Name

English

CRIZOTINIB [ORANGE BOOK]

Common Name

English

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Classification Tree

Code System

Code

Protein kinase inhibitors

WHO-VATC

QL01XE16

Designated

FDA ORPHAN DRUG

379812

Protein kinase inhibitors

WHO-ATC

L01XE16

Designated/Approved

FDA ORPHAN DRUG

834721

Designated/Approved

FDA ORPHAN DRUG

310610

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Code System

Code

Type

Description

MERCK INDEX

m3847

PRIMARY

Merck Index

DRUG BANK

DB08865

PRIMARY

ChEMBL

CHEMBL601719

PRIMARY

DAILYMED

53AH36668S

PRIMARY

NDF-RT

N0000182139

PRIMARY

Cytochrome P450 2B6 Inhibitors [MoA]

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Related Record

Type

Details


					53AH36668S

Crizotinib

EXCRETED UNCHANGED

Qualification:

URINE

Amount:

2.3 % (average)


					53AH36668S

Crizotinib

EXCRETED UNCHANGED

Qualification:

FECAL

Amount:

53 % (average)


					Z63P44CE4Z

Crizotinib hydrochloride

SALT/SOLVATE -> PARENT

Amount:


					22ES734693

MULTIDRUG RESISTANCE PROTEIN 1

TRANSPORTER -> INHIBITOR


					22ES734693

MULTIDRUG RESISTANCE PROTEIN 1

TRANSPORTER -> SUBSTRATE

Comments:

Crizotinib is a substrate for P-glycoprotein in vitro.

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Related Record

Type

Details


					CP57HGS9U5

PF-06268935

METABOLITE LESS ACTIVE -> PARENT

Amount:

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Related Record

Type

Details


					53AH36668S

Crizotinib

ACTIVE MOIETY

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Name	Property Type	Amount	Parameters
ORAL BIOAVAILABILITY	PHARMACOKINETIC	43 % (average)

Volume of Distribution	PHARMACOKINETIC	1772 LITERS (average)	DOSE 50 mg (average) INTRAVENOUS ADMINISTRATION

Biological Half-life	PHARMACOKINETIC	42 hours (average)	SINGLE-DOSE ADMINISTRATION

Tmax	PHARMACOKINETIC	[4 to 6] hours (average)	ORAL SINGLE-DOSE ADMINISTRATION

CSF/PLASMA RATIO	PHARMACOKINETIC	[0.0006 to 0.0026] (average)	COMMENT PHARMACOKINETIC patient with an asymptomatic solitary brain metastasis and leptomeningeal carcinomatosis, crizotinib was initiated, and a complete CNS response was achieved despite a crizotinib CSF-to-serum ratio of 0.0006.

SMILES

InChI

CNS Activity

Originator

Approval Year

Targets

Conditions

Cmax

AUC

T1/2

Funbound

Doses

AEs

Overview

OverviewOther

Drug as perpetrator​

Drug as victim

Tox targets

Sourcing

PubMed

Patents

Sample Use Guides

C_max

T_1/2

F_unbound

Drug as perpetrator