Lapatinib

__NOTOC__drugbox
IUPAC_name = "N"- [3-chloro-4- [(3-fluorophenyl)methoxy] phenyl] -6-
[5- [(2-methylsulfonylethylamino)methyl] -2-furyl]
quinazolin-4-amine

---

---

|3D structure of the Lapatinib molecule
CAS_number = 388082-78-8
ATC_prefix = L01
ATC_suffix = XE07
PubChem = 208908
DrugBank =
C = 29 | H = 26 | Cl = 1 | F = 1 | N = 4 | O = 4 | S = 1
molecular_weight = 581.058 g/mol
bioavailability =
protein_bound =
metabolism =
elimination_half-life = 24 hours
excretion =
t_max = 3 - 6 hours
pregnancy_AU =
pregnancy_US =
pregnancy_category =
legal_AU = S4
legal_CA =
legal_UK =
legal_US = Rx-only
legal_status =
routes_of_administration = Oral
licence_EU = Tyverb
licence_US = Lapatinib

Lapatinib (INN) or lapatinib ditosylate (USAN) (Tykerb®/Tyverb®, GSK) is an orally active chemotherapeutic drug treatment for solid tumours such as breast cancer.cite journal |author=Burris HA |title=Dual kinase inhibition in the treatment of breast cancer: initial experience with the EGFR/ErbB-2 inhibitor lapatinib |journal=Oncologist |volume=9 Suppl 3 |issue= |pages=10–5 |year=2004 |pmid=15163842 |doi= |url=http://theoncologist.alphamedpress.org/cgi/pmidlookup?view=long&pmid=15163842] During development it was known as small molecule GW572016.Patients who meet specific indication criteria may be prescribed lapatinib as part of combination therapy for breast cancer.cite web | url = http://newsmax.com/archives/articles/2007/3/13/155445.shtml | title = FDA Approves Advanced Breast Cancer Drug | accessdate = 2008-09-25 | date = 2007-03-13 | work = NewsMax.com Wires | publisher = Associated Press | location = Washington] Pharmacologically, lapatinib is a dual tyrosine kinase inhibitor that interrupts cancer-causing cellular signals.

Approval

On March 13, 2007, the FDA approved lapatinib in combination therapy for breast cancer patients already using capecitabine (Xeloda®, Roche).

Pharmaceutical company GlaxoSmithKline (GSK) markets the drug under the propriety names Tykerb (mostly US) and Tyverb (mostly Europe).cite press release
title = GlaxoSmithKline receives marketing authorisation in the EU for Tyverb® (lapatinib), the first oral targeted therapy for ErbB2-positive breast cancer
publisher = GlaxoSmithKline
date = 2008-06-12
url = http://www.gsk.com/media/pressreleases/2008/2008_pressrelease_10063.htm
accessdate = 2008-06-21] The drug currently has approval for sale and clinical use in the US, Australia,, Bahrain,, Kuwait,, Venezuela, New Zealand,Fact|date=September 2008 South Korea,Fact|date=September 2008 Switzerland,, and the European Union..

Mode of action

Biochemistry

Lapatanib inhibits the tyrosine kinase activity associated with two oncogenes, EGFR (epidermal growth factor receptor) and HER2/neu (Human EGFR type 2). Over expression of HER2/neu can be responsible for certain types of high-risk breast cancers in women.cite journal |author= Higa GM & Abraham J |year= 2007 |month= September |title= Lapatinib in the treatment of breast cancer |journal= Expert Review of Anticancer Therapy |volume= 7 |issue= 9 |pages= 1183-92 |publisher= Future Drugs |pmid= 17892419 |doi= 10.1586/14737140.7.9.1183 |url= http://www.expert-reviews.com/doi/abs/10.1586/14737140.7.9.1183 |format= log in required] Lapatanib 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#Signal transduction).cite journal |author=Nelson MH, Dolder CR |title=Lapatinib: a novel dual tyrosine kinase inhibitor with activity in solid tumors |journal=Ann Pharmacother |volume=40 |issue=2 |pages=261–9 |year=2006 |month=February |pmid=16418322 |doi=10.1345/aph.1G387 |url=]

Clinical application

Lapatinib is used as a treatment for women's breast cancer 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,Genentech).

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 regime 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 effectscite journal |author=Geyer CE, Forster J, Lindquist D, "et al" |title=Lapatinib plus capecitabine for HER2-positive advanced breast cancer |journal=N. Engl. J. Med. |volume=355 |issue=26 |pages=2733–43 |year=2006 |month=December |pmid=17192538 |doi=10.1056/NEJMoa064320 |url=] .

The results from studies like these leave lapatinib with its somewhat complex and rather specific indication — use only in combination with capecitabine for HER2-positive breast cancer afflicted women who have completely responded to previous chemotherapy with anthracycline, taxanes and trastuzumab.

A number of studies are underway attempting to evaluate the efficacy of lapatinib as a first-line therapy for HER2-positive cancer. As of 2007 they have only progressed to Phase II trials

Adverse effects

Like many small molecule tyrosine kinase inhibitors, lapatinib is regarded as well tolerated. The most common side effects to reported reported are diarrhea, fatigue, nausea and rashes. cite journal |author=Burris HA, Hurwitz HI, Dees EC, "et al" |title=Phase I safety, pharmacokinetics, and clinical activity study of lapatinib (GW572016), a reversible dual inhibitor of epidermal growth factor receptor tyrosine kinases, in heavily pretreated patients with metastatic carcinomas |journal=J. Clin. Oncol. |volume=23 |issue=23 |pages=5305–13 |year=2005 |month=August |pmid=15955900 |doi=10.1200/JCO.2005.16.584 |url=] In ongoing studies the drug have shown to provoke toxic hepatitis, the toxicity is reversibel when the treatment is stopped.Fact|date=September 2008

References

External links

* [http://www.cancer.gov/cancertopics/druginfo/lapatinibditosylate Lapatinib Ditosylate - National Cancer Institute]
* [http://www.ctv.ca/servlet/ArticleNews/story/CTVNews/20070603/cancer_drug_070603/20070603?hub=Health Canadian drug touted for advanced breast cancer]