Lapatinib: Information from Answers.com

Lapatinib
Systematic (IUPAC) name


N-[3-chloro-4-[(3-fluorophenyl)methoxy]phenyl]-6- [5-[(2-methylsulfonylethylamino)methyl]-2-furyl] quinazolin-4-amine
Identifiers
CAS number	231277-92-2 388082-78-8
ATC code	L01XE07
PubChem	208908
DrugBank	DB01259
ChemSpider	181006
Chemical data
Formula	C₂₉H₂₆Cl F N₄O₄S
Mol. mass	581.058 g/mol
Pharmacokinetic data
Bioavailability	Variable, increased with food
Protein binding	>99%
Metabolism	Hepatic, mostly CYP3A-mediated (minor 2C19 and 2C8 involvement)
Half life	24 hours
Excretion	Mostly fecal
Therapeutic considerations
Licence data	EU EMEA:link, US FDA:link
Pregnancy cat.	D
Legal status	Prescription Only (S4) (AU) ℞-only (US)
Routes	Oral

Lapatinib (INN) or lapatinib ditosylate (USAN) (Tykerb/Tyverb, GSK) is an orally active drug for breast cancer and other solid tumours.^[1] It is a dual tyrosine kinase inhibitor which interrupts the HER2 growth receptor pathway.^[2] It is used in combination therapy for HER2-positive breast cancer after other treatments have failed.^[3]

Contents

1 Status
2 Mode of action
- 2.1 Biochemistry
- 2.2 Clinical application
3 Adverse effects
4 References
5 External links

Status

On March 13, 2007, the U.S. Food and Drug Administration (FDA) approved lapatinib in combination therapy for breast cancer patients already using capecitabine (Xeloda, Roche).^[3]^[2]

Pharmaceutical company GlaxoSmithKline (GSK) markets the drug under the propriety names Tykerb (mostly US) and Tyverb (mostly Europe).^[4] The drug currently has approval for sale and clinical use in the US,^[2]^[4] Australia,^[2] Bahrain,^[2] Israel, Kuwait,^[2] Venezuela,^[2] Brazil,^[5] New Zealand,^[5]^[6] South Korea,^[5] Switzerland,^[4] and the European Union and pakistan ^[4]

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). Over expression of HER2/neu can be responsible for certain types of high-risk breast cancers in women.^[2] Like Sorafenib, lapatinib is a protein kinase inhibitor shown to decrease tumor-causing breast cancer stem cells. ^[7] 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#Signal transduction).^[8]

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 effects.^[9]

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 in women whose cancer have progressed following 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^[update] they have only progressed to Phase II trials.^[2]

Adverse effects

Like many small molecule tyrosine kinase inhibitors, lapatinib is regarded as well tolerated. The most common side effects reported are diarrhea, fatigue, nausea and rashes.^[2]^[10] In ongoing studies the drug have shown to provoke toxic hepatitis, the toxicity is reversible when the treatment is stopped.^{[citation needed]}

References

^ Burris HA (2004). "Dual kinase inhibition in the treatment of breast cancer: initial experience with the EGFR/ErbB-2 inhibitor lapatinib". Oncologist 9 Suppl 3: 10–5. doi:10.1634/theoncologist.9-suppl_3-10. PMID 15163842. http://theoncologist.alphamedpress.org/cgi/pmidlookup?view=long&pmid=15163842.
^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j Higa GM & Abraham J (September 2007). "Lapatinib in the treatment of breast cancer" (log in required). Expert Review of Anticancer Therapy (Future Drugs) 7 (9): 1183–92. doi:10.1586/14737140.7.9.1183. PMID 17892419. http://www.expert-reviews.com/doi/abs/10.1586/14737140.7.9.1183.
^ ^a ^b "FDA Approves Advanced Breast Cancer Drug". NewsMax.com Wires. Washington: Associated Press. 2007-03-13. http://newsmax.com/archives/articles/2007/3/13/155445.shtml. Retrieved 2008-09-25.
^ ^a ^b ^c ^d GlaxoSmithKline (2008-06-12). "GlaxoSmithKline receives marketing authorisation in the EU for Tyverb (lapatinib), the first oral targeted therapy for ErbB2-positive breast cancer". Press release. http://www.gsk.com/media/pressreleases/2008/2008_pressrelease_10063.htm. Retrieved 2008-06-21.
^ ^a ^b ^c Medical News Today (June 4, 2007). "GlaxoSmithKline Reports Positive New Data On Tykerb (lapatinib) At The 2007 American Society Of Clinical Oncology (ASCO) Annual Meeting". Press release. http://www.medicalnewstoday.com/articles/72987.php. Retrieved December 2, 2008.
^ "Data Sheet: TYKERB". Medsafe. New Zealand Medicines and Medical Devices Safety Authority. March 12, 2008. http://www.medsafe.govt.nz/profs/datasheet/t/tykerbtab.htm. Retrieved December 2, 2008.
^ Dr. Angel Rodriguez (April 2008). "New type of drug shrinks primary breast cancer tumors significantly in just six weeks; research provides leads to a new target in cancer treatment – the cancer stem cell". http://www.ecco-org.eu/News/Press-room/Press-release/page.aspx/439?xf_itemId=265&xf_catId=27.
^ Nelson MH, Dolder CR (February 2006). "Lapatinib: a novel dual tyrosine kinase inhibitor with activity in solid tumors". Ann Pharmacother 40 (2): 261–9. doi:10.1345/aph.1G387. PMID 16418322.
^ Geyer CE, Forster J, Lindquist D, et al. (December 2006). "Lapatinib plus capecitabine for HER2-positive advanced breast cancer". N. Engl. J. Med. 355 (26): 2733–43. doi:10.1056/NEJMoa064320. PMID 17192538.
^ Burris HA, Hurwitz HI, Dees EC, et al. (August 2005). "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". J. Clin. Oncol. 23 (23): 5305–13. doi:10.1200/JCO.2005.16.584. PMID 15955900.

External links

Targeted therapy / extracellular chemotherapeutic agents/antineoplastic agents (L01)

CI monoclonal antibodies ("-mab")

Receptor tyrosine kinase	ErbB: HER1/EGFR (Cetuximab, Panitumumab) · HER2/neu (Trastuzumab)

Others for solid tumors	EpCAM (Catumaxomab, Edrecolomab) · VEGF-A (Bevacizumab)

Leukemia/lymphoma	lymphoid: CD20 (Ibritumomab, Ofatumumab, Rituximab, Tositumomab) myeloid: CD52 (Alemtuzumab) L+M: CD33 (Gemtuzumab)

Tyrosine kinase inhibitors ("-nib")

Receptor tyrosine kinase	ErbB: HER1/EGFR (Erlotinib, Gefitinib, Vandetanib) · HER1/EGFR and HER2/neu (BIBW 2992, Lapatinib, Neratinib) RTK class III: C-kit and PDGFR (Axitinib, Pazopanib, Sunitinib, Sorafenib, Toceranib) · FLT3 (Lestaurtinib) VEGFR (Axitinib, Cediranib, Pazopanib, Regorafenib, Semaxanib, Sorafenib, Sunitinib, Toceranib, Vandetanib)

Non-receptor	bcr-abl (Dasatinib, Imatinib, Nilotinib) Src (Bosutinib) Janus kinase 2 (Lestaurtinib)

Other

fusion protein against VEGF (Aflibercept) · exotoxin against IL-2 (Denileukin diftitox)

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