Lapatinib

Details

Stereochemistry	ACHIRAL
Molecular Formula	C29H26ClFN4O4S
Molecular Weight	581.058
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

SMILES

CS(=O)(=O)CCNCC1=CC=C(O1)C2=CC3=C(C=C2)N=CN=C3NC4=CC(Cl)=C(OCC5=CC(F)=CC=C5)C=C4

InChI

InChIKey=BCFGMOOMADDAQU-UHFFFAOYSA-N

InChI=1S/C29H26ClFN4O4S/c1-40(36,37)12-11-32-16-23-7-10-27(39-23)20-5-8-26-24(14-20)29(34-18-33-26)35-22-6-9-28(25(30)15-22)38-17-19-3-2-4-21(31)13-19/h2-10,13-15,18,32H,11-12,16-17H2,1H3,(H,33,34,35)

HIDE SMILES / InChI

Molecular Formula	C29H26ClFN4O4S
Molecular Weight	581.058
Charge	0
Count	MOL RATIO 1 MOL RATIO (average)

Stereochemistry	ACHIRAL
Additional Stereochemistry	No
Defined Stereocenters	0 / 0
E/Z Centers	0
Optical Activity	NONE

Description

Lapatinib is a small molecule and a member of the 4-anilinoquinazoline class of kinase inhibitors. It is present as the monohydrate of the ditosylate salt (trade name TYKERB). Lapatinib is dual inhibitor of the EGFR (epidermal growth factor receptor; also called HER1 or ErbB1) and HER2 receptor tyrosine kinases. Lapatinib was developed by GlaxoSmithKline, however, Novartis subsequently acquired all the rights to the drug from GlaxoSmithKline. TYKERB is indicated in combination therapy for the treatment of metastatic breast cancer that overexpresses the HER2 receptor.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Epidermal growth factor receptor erbB1 62	Inhibitor 8,504		3.0 nM [Ki]
Receptor protein-tyrosine kinase erbB-2 35	Inhibitor 8,504		13.0 nM [Ki]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Breast cancer 432	Primary		Approved 8,583	TYKERB

C_max

Value	Dose	Co-administered	Analyte	Population
2.43 μg/mL	1250 mg 1 times / day steady-state, oral		LAPATINIB plasma	Homo sapiens

AUC

Value	Dose	Co-administered	Analyte	Population
36.2 μg × h/mL	1250 mg 1 times / day steady-state, oral		LAPATINIB plasma	Homo sapiens

T_1/2

Value	Dose	Co-administered	Analyte	Population
24 h	1250 mg 1 times / day steady-state, oral		LAPATINIB plasma	Homo sapiens

F_unbound

Value	Dose	Co-administered	Analyte	Population
1%			LAPATINIB plasma	Homo sapiens

Doses

Show entries

Dose	Population	Adverse events
1250 mg 1 times / day steady, oral MTD	unhealthy, 50 years (range: 30–78 years)	DLT: Rash, Diarrhea...
1500 mg 1 times / day steady, oral	unhealthy, 50 years (range: 30–78 years)	DLT: Mucositis, Rash...
1250 mg 1 times / day steady, oral Recommended	unhealthy, 53 years	Disc. AE: Diarrhea... Other AEs: Diarrhea, Diarrhea...
1800 mg 1 times / day steady, oral MTD	unhealthy, 60 years (range: 37 – 73 years)	DLT: Diarrhea, Gamma GT increased... Other AEs: Stomatitis, Rash...
1250 mg 1 times / day steady, oral Recommended	unhealthy, 63 years	Other AEs: Hepatotoxicity, Bilirubin total increased...

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AEs

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AE	Significance	Dose	Population
Hypoxia	grade 3, 1 patient DLT	1250 mg 1 times / day steady, oral MTD	unhealthy, 50 years (range: 30–78 years)
Diarrhea	grade 3, 2 patients DLT	1250 mg 1 times / day steady, oral MTD	unhealthy, 50 years (range: 30–78 years)
Rash	grade 3, 2 patients DLT	1250 mg 1 times / day steady, oral MTD	unhealthy, 50 years (range: 30–78 years)
Pulmonary embolus	grade 4, 2 patients DLT	1250 mg 1 times / day steady, oral MTD	unhealthy, 50 years (range: 30–78 years)
Mucositis	grade 3, 2 patients DLT	1500 mg 1 times / day steady, oral	unhealthy, 50 years (range: 30–78 years)

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Overview

CYP3A4	CYP2C9	CYP2D6	hERG
inhibitor 2,252 substrate 1,946 inducer 1,087	substrate 1,193 inhibitor 2,438 inducer 440	substrate 1,388 inhibitor 2,507	inhibitor 2,217

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP2C8 1,057 P-gp 1,741 CYP1A2 2,153 CYP2C19 2,057 UGT 45 BCRP 910 OATP1B1 1,079 OAT3 747	P-gp 2,052 CYP3A5 446 CYP2C8 810 CYP2C19 1,119 CYP1A2 1,197 CYP2B6 776 CYP2A6 626 CYP2E1 729 BCRP 697	CYP1A2 832

Drug as perpetrator

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Target	Modality	Activity
CYP1A2 2,333	inducer 1,966	no
CYP1A2 2,333	inhibitor 4,027	no
CYP2C19 2,141	inhibitor 4,027	no
CYP2C9 2,497	inducer 1,966	no
CYP2C9 2,497	inhibitor 4,027	no

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Drug as victim

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Target	Modality	Activity	Clinical evidence
CYP3A5 446	substrate 4,014	major
CYP3A4 1,946	substrate 4,014	major	yes (co-administration study)
CYP2C19 1,119	substrate 4,014	minor
CYP2C8 810	substrate 4,014	minor	unknown (co-administration study)
CYP1A2 1,197	substrate 4,014	no

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Tox targets

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Target	Modality	Activity	Metabolite	Clinical evidence
hERG 2,263	inhibitor 2,237

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Sourcing

Sourcing

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Vendor/Aggregator	ID	URL
ChEBI	CHEBI:49603	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:49603
ChemicalBook	CB8855402	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB8855402
eMolecules	6757269	https://www.emolecules.com/cgi-bin/more?vid=6757269
MolPort	MolPort-006-069-221	https://www.molport.com/shop/molecule-link/MolPort-006-069-221
Selleck Chemicals	lapatinib	http://www.selleckchem.com/products/lapatinib.html

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PubMed

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Title	Date	PubMed
The effects of the novel, reversible epidermal growth factor receptor/ErbB-2 tyrosine kinase inhibitor, GW2016, on the growth of human normal and tumor-derived cell lines in vitro and in vivo.	2001 Dec	12467226
Targeting HER2 in brain metastases from breast cancer.	2003 Nov 15	14654521
Gateways to clinical trials.	2003 Oct	14671684
Truncated ErbB2 receptor (p95ErbB2) is regulated by heregulin through heterodimer formation with ErbB3 yet remains sensitive to the dual EGFR/ErbB2 kinase inhibitor GW572016.	2004 Jan 22	14737100
Endocrinology and hormone therapy in breast cancer: new insight into estrogen receptor-alpha function and its implication for endocrine therapy resistance in breast cancer.	2005	16168139

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Patents

Sample Use Guides

In Vivo Use Guide

The recommended dosage of TYKERB for advanced or metastatic breast cancer is 1,250 mg (5 tablets) given orally once daily on Days 1-21 continuously in combination with capecitabine 2,000 mg/m2 /day (administered orally in 2 doses approximately 12 hours apart) on Days 1-14 in a repeating 21 day cycle. The recommended dose of TYKERB for hormone receptor positive, HER2 positive metastatic breast cancer is 1500 mg (6 tablets) given orally once daily continuously in combination with letrozole. When TYKERB is coadministered with letrozole, the recommended dose of letrozole is 2.5 mg once daily. • TYKERB should be taken at least one hour before or one hour after a meal. However, capecitabine should be taken with food or within 30 minutes after food. • TYKERB should be taken once daily. Do not divide daily doses of TYKERB. • Modify dose for cardiac and other toxicities, severe hepatic impairment, and CYP3A4 drug interactions.

Route of Administration: Oral

In Vitro Use Guide

lapatinib-induced time- and dose-dependent phosphorylation dynamics in SKBR3 breast cancer cells. Among 4953 identified phosphopeptides from 1548 proteins, a small proportion (5-7%) was regulated at least twofold by 1-10 μm lapatinib.

Substance Class	Chemical
Record UNII	0VUA21238F
Record Status	`Validated (UNII)`
Record Version

Show entries

Name

Type

Language

GSK-572016

Preferred Name

English

Lapatinib

Official Name

English

LAPATINIB [EMA EPAR]

Common Name

English

lapatinib [INN]

Common Name

English

GW-572016X

Code

English

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Classification Tree

Code System

Code

Established Pharmacologic Class

NDF-RT

N0000175605

Kinase Inhibitors

NDF-RT

N0000175076

Protein kinase inhibitors

WHO-VATC

QL01XE07

Angiogenesis Inhibitor

NCI_THESAURUS

C155764

Breast Cancer

LIVERTOX

NBK547971

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Code System

Code

Type

Description

SMS_ID

100000089379

PRIMARY

ChEMBL

CHEMBL554

PRIMARY

RXCUI

480167

PRIMARY

RxNorm

LACTMED

Lapatinib

PRIMARY

DRUG CENTRAL

1548

PRIMARY

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Show entries

Related Record

Type

Details


					22ES734693

MULTIDRUG RESISTANCE PROTEIN 1

TRANSPORTER -> INHIBITOR


					PUO0521HZV

CYTOCHROME P450 3A4

METABOLIC ENZYME -> INHIBITOR

Comments:

Lapatinib is a mechanism-based inactivator of CYP3A4, most likely via the formation and further oxidation of its O-dealkylated metabolite to a quinoneimine that covalently modifies the CYP3A4 apoprotein and/or heme moiety.

Interaction Type:

TIME-DEPENDENT INHIBITION

Amount:


					6D53G0FD0Z

PLASMA PROTEIN FRACTION (HUMAN)

BINDER->LIGAND

Interaction Type:

BINDING

Amount:

[>99] % (average)


					RO03J093CP

EPIDERMAL GROWTH FACTOR RECEPTOR

TARGET -> INHIBITOR


					G873GX646R

Lapatinib ditosylate

SALT/SOLVATE -> PARENT

Amount:

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Related Record

Type

Details


					2T859UZJ2V

2-FURANCARBOXYLIC ACID, 5-(4-((3-CHLORO-4-((3-FLUOROPHENYL)METHOXY)PHENYL)AMINO)-6-QUINAZOLINYL)-

METABOLITE -> PARENT


					8PL9CEZ8WK

O-DEALKYLATED LAPATINIB

METABOLITE TOXIC -> PARENT

Comments:

Specifically, the structure of O-dealkylated lapatinib has the potential to generate a reactive quinoneimine similar to the model hepatotoxin acetaminophen. lapatinib is a mechanism-based inactivator of CYP3A4, most likely via the formation and further oxidation of its O-dealkylated metabolite to a quinoneimine that covalently modifies the CYP3A4 apoprotein and/or heme moiety.

Interaction Type:

MAJOR

Amount: