Lapatinib
Encyclopedia
Lapatinib used in the form of lapatinib ditosylate, (USAN
) (Tykerb/Tyverb, GSK
) is an orally active drug
for breast cancer
and other solid tumours. It is a dual tyrosine kinase inhibitor which interrupts the HER2 growth receptor pathway. 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).
for breast cancer patients already using capecitabine (Xeloda, Roche). In January 2010, Tykerb received accelerated approval for the treatment of postmenopausal women with hormone receptor positive metastatic breast cancer that overexpresses the HER2 receptor and for whom hormonal therapy is indicated.
Pharmaceutical company GlaxoSmithKline
(GSK) markets the drug under the propriety names Tykerb (mostly US) and Tyverb (mostly Europe).
The drug currently has approval for sale and clinical use in the US, Australia, Bahrain, Israel, Kuwait, Venezuela, Brazil, New Zealand, South Korea, Switzerland, Japan, the European Union, India and Pakistan.
The drug lapatinib ditosylate is classified as S/NM (a synthetic compound
showing competitive inhibition of the natural product) that is naturally derived or inspired
substrate (Gordon M. Cragg, Paul G. Grothaus, and David J. Newman, Impact of Natural Products on Developing New Anti-Cancer Agents, Chem. Rev. 2009, 109, 3012–3043)
the tyrosine kinase
activity associated with two oncogene
s, 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.
Like Sorafenib
, lapatinib is a protein kinase inhibitor
shown to decrease tumor-causing breast cancer stem cells.
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).
, 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. 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.
reported are diarrhea
, fatigue, nausea
and rash
es. In ongoing studies the drug have shown to provoke toxic hepatitis, the toxicity is reversible when the treatment is stopped.
United States Adopted Name
United States Adopted Names are unique nonproprietary names assigned to pharmaceuticals marketed in the United States. Each name is assigned by the USAN Council, which is co-sponsored by the American Medical Association , the United States Pharmacopeial Convention , and the American Pharmacists...
) (Tykerb/Tyverb, GSK
GlaxoSmithKline
GlaxoSmithKline plc is a global pharmaceutical, biologics, vaccines and consumer healthcare company headquartered in London, United Kingdom...
) is an orally active drug
Chemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
for breast cancer
Breast cancer
Breast cancer is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas...
and other solid tumours. It is a dual tyrosine kinase inhibitor which interrupts the HER2 growth receptor pathway. It is used in combination therapy
Combination therapy
Combination therapy or polytherapy is the use of more than one medication or other therapy. In contrast, monotherapy is any therapy which is taken by itself....
for HER2-positive breast cancer. It is used for the treatment of patients with advanced or metastatic breast cancer whose tumors overexpress HER2 (ErbB2).
Status
On March 13, 2007, the U.S. Food and Drug Administration (FDA) approved lapatinib in combination therapyCombination therapy
Combination therapy or polytherapy is the use of more than one medication or other therapy. In contrast, monotherapy is any therapy which is taken by itself....
for breast cancer patients already using capecitabine (Xeloda, Roche). In January 2010, Tykerb received accelerated approval for the treatment of postmenopausal women with hormone receptor positive metastatic breast cancer that overexpresses the HER2 receptor and for whom hormonal therapy is indicated.
Pharmaceutical company GlaxoSmithKline
GlaxoSmithKline
GlaxoSmithKline plc is a global pharmaceutical, biologics, vaccines and consumer healthcare company headquartered in London, United Kingdom...
(GSK) markets the drug under the propriety names Tykerb (mostly US) and Tyverb (mostly Europe).
The drug currently has approval for sale and clinical use in the US, Australia, Bahrain, Israel, Kuwait, Venezuela, Brazil, New Zealand, South Korea, Switzerland, Japan, the European Union, India and Pakistan.
The drug lapatinib ditosylate is classified as S/NM (a synthetic compound
showing competitive inhibition of the natural product) that is naturally derived or inspired
substrate (Gordon M. Cragg, Paul G. Grothaus, and David J. Newman, Impact of Natural Products on Developing New Anti-Cancer Agents, Chem. Rev. 2009, 109, 3012–3043)
Biochemistry
Lapatinib inhibitsEnzyme inhibitor
An enzyme inhibitor is a molecule that binds to enzymes and decreases their activity. Since blocking an enzyme's activity can kill a pathogen or correct a metabolic imbalance, many drugs are enzyme inhibitors. They are also used as herbicides and pesticides...
the tyrosine kinase
Tyrosine kinase
A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to a protein in a cell. It functions as an "on" or "off" switch in many cellular functions....
activity associated with two oncogene
Oncogene
An oncogene is a gene that has the potential to cause cancer. In tumor cells, they are often mutated or expressed at high levels.An oncogene is a gene found in the chromosomes of tumor cells whose activation is associated with the initial and continuing conversion of normal cells into cancer...
s, EGFR
Epidermal growth factor receptor
The epidermal growth factor receptor is the cell-surface receptor for members of the epidermal growth factor family of extracellular protein ligands...
(epidermal growth factor receptor) and HER2/neu
HER2/neu
HER-2 also known as proto-oncogene Neu, receptor tyrosine-protein kinase erbB-2, CD340 or p185 is an enzyme that in humans is encoded by the ERBB2 gene. Over expression of this gene is correlated with higher aggressiveness in breast cancers...
(Human EGFR type 2). Over expression of HER2/neu can be responsible for certain types of high-risk breast cancers in women.
Like Sorafenib
Sorafenib
Sorafenib , is a drug approved for the treatment of primary kidney cancer and advanced primary liver cancer ....
, lapatinib is a protein kinase inhibitor
Protein kinase inhibitor
A protein kinase inhibitor is a type of enzyme inhibitor that specifically blocks the action of one or more protein kinases. Hence, they can be subdivided or characterised by the amino acids whose phosphorylation is inhibited:...
shown to decrease tumor-causing breast cancer stem cells.
Lapatinib inhibits receptor signal processes by binding to the ATP-binding pocket of the EGFR/HER2 protein kinase
Kinase
In chemistry and biochemistry, a kinase is a type of enzyme that transfers phosphate groups from high-energy donor molecules, such as ATP, to specific substrates, a process referred to as phosphorylation. Kinases are part of the larger family of phosphotransferases...
domain
Protein domain
A protein domain is a part of protein sequence and structure that can evolve, function, and exist independently of the rest of the protein chain. Each domain forms a compact three-dimensional structure and often can be independently stable and folded. Many proteins consist of several structural...
, preventing self-phosphorylation
Phosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
and subsequent activation of the signal mechanism (see Receptor tyrosine kinase#Signal transduction).
Breast cancer
Lapatinib is used as a treatment for women's breast cancer in treatment naive, ER+/EGFR+/HER2+ breast cancer patients (now often called "triple positive") and in patients who have HER2-positive advanced breast cancer that has progressed after previous treatment with other chemotherapeutic agents, such as anthracyclineAnthracycline
Anthracyclines are a class of drugs used in cancer chemotherapy derived from Streptomyces bacterium Streptomyces peucetius var...
, taxane
Taxane
The taxanes are diterpenes produced by the plants of the genus Taxus . As their name suggests, they were first derived from natural sources, but some have been synthesized artificially. Taxanes include paclitaxel and docetaxel . Paclitaxel was originally derived from the Pacific yew tree.Taxanes...
-derived drugs, or trastuzumab
Trastuzumab
Trastuzumab is a monoclonal antibody that interferes with the HER2/neu receptor.The HER receptors are proteins that are embedded in the cell membrane and communicate molecular signals from outside the cell to inside the cell, and turn genes on and off...
(Herceptin, Genentech
Genentech
Genentech Inc., or Genetic Engineering Technology, Inc., is a biotechnology corporation, founded in 1976 by venture capitalist Robert A. Swanson and biochemist Dr. Herbert Boyer. Trailing the founding of Cetus by five years, it was an important step in the evolution of the biotechnology industry...
).
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. The outcome of this study resulted in a somewhat complex and rather specific initial indication
Indication (medicine)
In medicine, an indication is a valid reason to use a certain test, medication, procedure, or surgery. The opposite of indication is contraindication.-Drugs:...
for lapatinib—use only in combination
Combination therapy
Combination therapy or polytherapy is the use of more than one medication or other therapy. In contrast, monotherapy is any therapy which is taken by itself....
with capecitabine for HER2-positive breast cancer in women whose cancer have progressed following previous chemotherapy with anthracycline, taxanes and trastuzumab.
Adverse effects
Like many small molecule tyrosine kinase inhibitors, lapatinib is regarded as well tolerated. The most common side effectsAdverse effect
In medicine, an adverse effect is a harmful and undesired effect resulting from a medication or other intervention such as surgery.An adverse effect may be termed a "side effect", when judged to be secondary to a main or therapeutic effect. If it results from an unsuitable or incorrect dosage or...
reported are diarrhea
Diarrhea
Diarrhea , also spelled diarrhoea, is the condition of having three or more loose or liquid bowel movements per day. It is a common cause of death in developing countries and the second most common cause of infant deaths worldwide. The loss of fluids through diarrhea can cause dehydration and...
, fatigue, nausea
Nausea
Nausea , is a sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit. It often, but not always, precedes vomiting...
and rash
Rash
A rash is a change of the skin which affects its color, appearance or texture. A rash may be localized in one part of the body, or affect all the skin. Rashes may cause the skin to change color, itch, become warm, bumpy, chapped, dry, cracked or blistered, swell and may be painful. The causes, and...
es. In ongoing studies the drug have shown to provoke toxic hepatitis, the toxicity is reversible when the treatment is stopped.