Lapatinib — BrandWiki

Lapatinib

verifiedfields	changed
watchedfields	changed
verifiedrevid	462089041
width	275
tradename	Tykerb, Tyverb, others
medlineplus	a607055
dailymedid	Lapatinib
pregnancy au	C
routes of administration	By mouth
atc prefix	L01
atc suffix	EH01
legal au	S4
legal ca	Rx-only
legal uk	POM
legal us	Rx-only
legal eu	Rx-only
legal eu comment	‡R1R‡
legal status	Rx-only
bioavailability	Variable, increased with food
protein bound	>99%
metabolism	Liver, mostly CYP3A-mediated (minor 2C19 and 2C8 involvement)
elimination half-life	24 hours (repeated dosing), 14.2 hours (single dose)
excretion	Mostly Feces
index2 label	as salt
cas number	231277-92-2
cas number2	388082-78-8
pubchem	208908
iuphar ligand	5692
drugbank	DB01259
drugbank2	DBSALT001785
chemspiderid	181006
chemspiderid2	9731817
unii	0VUA21238F
unii2	G873GX646R
kegg	D08108
kegg2	D04024
chebi	49603
chembl	554
chembl2	1201179
pdb ligand	FMM
iupac name	N-[3-Chloro-4-[(3-fluorophenyl)methoxy]phenyl]-6- [5-[(2-methylsulfonylethylamino)methyl]-2-furyl] quinazolin-4-amine
c	29
h	26
cl	1
f	1
n	4
o	4
s	1
smiles	CS(=O)(=O)CCNCc1ccc(o1)c2ccc3c(c2)c(ncn3)Nc4ccc(c(c4)Cl)OCc5cccc(c5)F
stdinchi	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)
stdinchikey	BCFGMOOMADDAQU-UHFFFAOYSA-N

Lapatinib (INN), used in the form of lapatinib ditosylate (USAN) (trade names Tykerb and Tyverb marketed by Novartis) is an orally active drug for breast cancer and other solid tumours.[2] It is a dual tyrosine kinase inhibitor which interrupts the HER2/neu and epidermal growth factor receptor (EGFR) pathways. It is used in combination therapy for HER2-positive breast cancer. It is used for the treatment of patients with advanced or metastatic breast cancer whose tumors overexpress HER2 (ErbB2).[3]

Status

In March 2007, the U.S. Food and Drug Administration (FDA) approved lapatinib in combination therapy for breast cancer patients already using capecitabine (Xeloda).[3] In January 2010, Tykerb received accelerated approval

Mode of action

Biochemistry

Lapatinib inhibits the tyrosine kinase activity associated with two oncogenes, EGFR (epidermal growth factor receptor) and HER2/neu (human EGFR type 2).[8] Over expression of HER2/neu can be responsible for certain types of high-risk breast cancers in women.[9]

Like sorafenib, lapatinib is a protein kinase inhibitor shown to decrease tumor-causing breast cancer stem cells.[10]

Lapatinib inhibits receptor signal processes by binding to the ATP-binding pocket of the EGFR/HER2 protein kinase domain, preventing self-phosphorylation and subsequent activation of the signal mechanism (see Receptor tyrosine kinase).[11]

Clinical application

Breast cancer

Lapatinib is used as a treatment for women's breast cancer in treatment-naïve, ER+/EGFR+/HER2+ breast cancer patients and in patients who have HER2-positive advanced breast cancer that has progressed after previous treatment with other chemotherapeutic agents, such as anthracycline, taxane-derived drugs, or trastuzumab (Herceptin).

A 2006 GSK-supported randomized clinical trial on female breast cancer previously being treated with those agents (anthracycline, a taxane and trastuzumab) demonstrated that administrating lapatinib in combination with capecitabine delayed the time of further cancer growth compared to regimens that use capecitabine alone. The study also reported that risk of disease progression was reduced by 51%, and that the combination therapy was not associated with increases in toxic side effects.[12] The outcome of this study resulted in a somewhat complex and rather specific initial indication for lapatinib—use only in combination with capecitabine for HER2-positive breast cancer in women whose cancer have progressed following previous chemotherapy with anthracycline, taxanes and trastuzumab.

Early clinical trials have been performed suggesting that high dose intermittent lapatinib might have better efficacy with manageable toxicities in the treatment of HER2-overexpressing breast cancers.[13]

Breast cancer

Lapatinib is used as a treatment for women's breast cancer in treatment-naïve, ER+/EGFR+/HER2+ breast cancer patients and in patients who have HER2-positive advanced breast cancer that has progressed after previous treatment with other chemotherapeutic agents, such as anthracycline, taxane-derived drugs, or trastuzumab (Herceptin).

A 2006 GSK-supported randomized clinical trial on female breast cancer previously being treated with those agents (anthracycline, a taxane and trastuzumab) demonstrated that administrating lapatinib in combination with capecitabine delayed the time of further cancer growth compared to regimens that use capecitabine alone. The study also reported that risk of disease progression was reduced by 51%, and that the combination therapy was not associated with increases in toxic side effects.[12] The outcome of this study resulted in a somewhat complex and rather specific initial indication for lapatinib—use only in combination with capecitabine for HER2-positive breast cancer in women whose cancer have progressed following previous chemotherapy with anthracycline, taxanes and trastuzumab.

Early clinical trials have been performed suggesting that high dose intermittent lapatinib might have better efficacy with manageable toxicities in the treatment of HER2-overexpressing breast cancers.[13]