Lenvatinib, sold under the brand name Lenvima among others, is an

anti-cancer medication Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a type of cancer treatment that uses one or more anti-cancer drugs (chemotherapeutic agents or alkylating agents) as part of a standardized chemotherapy regimen. Chemotherap ...

for the treatment of certain kinds of

thyroid cancer Thyroid cancer is cancer that develops from the tissues of the thyroid gland. It is a disease in which cells grow abnormally and have the potential to spread to other parts of the body. Symptoms can include swelling or a lump in the neck. C ...

and for other cancers as well. It was developed by

Eisai Co. is a Japanese pharmaceutical company headquartered in Tokyo, Japan. It has some 10,000 employees, among them about 1,500 in research. Eisai is listed on the Tokyo Stock Exchange and is a member of the Topix 100 and Nikkei 225 stock indices. ...

and acts as a multiple

kinase inhibitor A protein kinase inhibitor is a type of enzyme inhibitor that blocks the action of one or more protein kinases. Protein kinases are enzymes that phosphorylate (add a phosphate, or PO4, group) to a protein and can modulate its function. The phospha ...

against the

VEGFR1 Vascular endothelial growth factor receptor 1 is a protein that in humans is encoded by the ''FLT1'' gene. Function ''FLT1'' is a member of VEGF receptor gene family. It encodes a receptor tyrosine kinase which is activated by VEGF-A, VEGF-B, ...

VEGFR2 Kinase insert domain receptor (KDR, a type IV receptor tyrosine kinase) also known as vascular endothelial growth factor receptor 2 (VEGFR-2) is a VEGF receptor. ''KDR'' is the human gene encoding it. KDR has also been designated as CD309 (cluster ...

and

VEGFR3 Fms-related tyrosine kinase 4, also known as FLT4, is a protein which in humans is encoded by the ''FLT4'' gene. This gene encodes a tyrosine kinase receptor for vascular endothelial growth factors C and D. The protein is thought to be involve ...

kinases.

Medical uses

Lenvatinib is approved (since 2015) for the treatment of differentiated

that is either locally recurrent or

metastatic Metastasis is a pathogenic agent's spread from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, then, ...

, progressive, and did not respond to treatment with

radioactive iodine There are 37 known isotopes of iodine (53I) from 108I to 144I; all undergo radioactive decay except 127I, which is stable. Iodine is thus a monoisotopic element. Its longest-lived radioactive isotope, 129I, has a half-life of 15.7 million year ...

(radioiodine). for Lenvima. In May 2016, the U.S.

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...

(FDA) approved it (in combination with

everolimus Everolimus, sold under the brand name Afinitor among others, is a medication used as an immunosuppressant to prevent rejection of organ transplants and as a targeted therapy in the treatment of renal cell cancer and other tumours. It is the 40 ...

) for the treatment of advanced

renal cell carcinoma Renal cell carcinoma (RCC) is a kidney cancer that originates in the lining of the proximal convoluted tubule, a part of the very small tubes in the kidney that transport primary urine. RCC is the most common type of kidney cancer in adults, resp ...

following one prior anti-angiogenic therapy. The drug is also approved in the US and in the European Union for

hepatocellular carcinoma Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer in adults and is currently the most common cause of death in people with cirrhosis. HCC is the third leading cause of cancer-related deaths worldwide. It occurs in t ...

that cannot be removed surgically in patients who have not received cancer therapy by mouth or injection.

Adverse effects

Hypertension Hypertension (HTN or HT), also known as high blood pressure (HBP), is a long-term medical condition in which the blood pressure in the arteries is persistently elevated. High blood pressure usually does not cause symptoms. Long-term high bl ...

(high blood pressure) was the most common side effect in studies (73% of patients, versus 16% in the

placebo A placebo ( ) is a substance or treatment which is designed to have no therapeutic value. Common placebos include inert tablets (like sugar pills), inert injections (like Saline (medicine), saline), sham surgery, and other procedures. In general ...

group), followed by diarrhoea (67% vs. 17%) and

fatigue Fatigue describes a state of tiredness that does not resolve with rest or sleep. In general usage, fatigue is synonymous with extreme tiredness or exhaustion that normally follows prolonged physical or mental activity. When it does not resolve ...

(67% vs. 35%). Other common side effects included decreased appetite,

hypotension Hypotension is low blood pressure. Blood pressure is the force of blood pushing against the walls of the arteries as the heart pumps out blood. Blood pressure is indicated by two numbers, the systolic blood pressure (the top number) and the dias ...

(low blood pressure),

thrombocytopenia Thrombocytopenia is a condition characterized by abnormally low levels of platelets, also known as thrombocytes, in the blood. It is the most common coagulation disorder among intensive care patients and is seen in a fifth of medical patients an ...

(low blood platelet count), nausea, muscle and bone pain.

Interactions

As lenvatinib moderately prolongs QT time, addition of other drugs with this property could increase the risk of a type of abnormal heart rhythm, namely

torsades de pointes ''Torsades de pointes, torsade de pointes'' or ''torsades des pointes'' (TdP) (, , translated as "twisting of peaks") is a specific type of abnormal heart rhythm that can lead to sudden cardiac death. It is a polymorphic ventricular tachycardia t ...

. No relevant interactions with

enzyme inhibitor An enzyme inhibitor is a molecule that binds to an enzyme and blocks its activity. Enzymes are proteins that speed up chemical reactions necessary for life, in which substrate molecules are converted into products. An enzyme facilitates a sp ...

s and

inducer In molecular biology, an inducer is a molecule that regulates gene expression. An inducer functions in two ways; namely: *By disabling repressors. The gene is expressed because an inducer binds to the repressor. The binding of the inducer to the r ...

s are expected.

Pharmacology

Mechanism of action

Lenvatinib acts as a multiple

. It inhibits the three main

vascular endothelial growth factor receptor VEGF receptors are receptors for vascular endothelial growth factor (VEGF). There are three main subtypes of VEGFR, numbered 1, 2 and 3. Also, they may be membrane-bound (mbVEGFR) or soluble (sVEGFR), depending on alternative splicing. Inh ...

s VEGFR1, 2 and 3, as well as fibroblast growth factor receptors (FGFR) 1, 2, 3 and 4,

platelet-derived growth factor receptor Platelet-derived growth factor receptors (PDGF-R) are cell surface tyrosine kinase receptors for members of the platelet-derived growth factor (PDGF) family. PDGF subunits -A and -B are important factors regulating cell proliferation, cellu ...

(PDGFR) alpha,

c-Kit Proto-oncogene c-KIT is the gene encoding the receptor tyrosine kinase protein known as tyrosine-protein kinase KIT, CD117 (cluster of differentiation 117) or mast/stem cell growth factor receptor (SCFR). Multiple transcript variants encoding diff ...

, and the

RET proto-oncogene The ''RET'' proto-oncogene encodes a receptor tyrosine kinase for members of the glial cell line-derived neurotrophic factor (GDNF) family of extracellular signalling molecules. ''RET'' loss of function mutations are associated with the develop ...

. Some of these proteins play roles in cancerogenic

signalling pathway In biology, cell signaling (cell signalling in British English) or cell communication is the ability of a cell to receive, process, and transmit signals with its environment and with itself. Cell signaling is a fundamental property of all cellula ...

s. VEGFR2 inhibition is thought to be the main reason for the most common side effect, hypertension.

Pharmacokinetics

Lenvatinib is absorbed quickly from the gut, reaching peak

blood plasma Blood plasma is a light amber-colored liquid component of blood in which blood cells are absent, but contains proteins and other constituents of whole blood in suspension. It makes up about 55% of the body's total blood volume. It is the intra ...

concentrations after one to four hours (three to seven hours if taken with food).

Bioavailability In pharmacology, bioavailability is a subcategory of absorption and is the fraction (%) of an administered drug that reaches the systemic circulation. By definition, when a medication is administered intravenously, its bioavailability is 100%. H ...

is estimated to be about 85%. The substance is almost completely (98–99%) bound to

plasma protein Blood-proteins, also termed plasma proteins, are proteins present in blood plasma. They serve many different functions, including transport of lipids, hormones, vitamins and minerals in activity and functioning of the immune system. Other blood pr ...

s, mainly

albumin Albumin is a family of globular proteins, the most common of which are the serum albumins. All the proteins of the albumin family are water-soluble, moderately soluble in concentrated salt solutions, and experience heat denaturation. Albumins ...

Lenvatinib is metabolized by the liver enzyme

CYP3A4 Cytochrome P450 3A4 (abbreviated CYP3A4) () is an important enzyme in the body, mainly found in the liver and in the intestine. It oxidizes small foreign organic molecules (xenobiotics), such as toxins or drugs, so that they can be removed from t ...

to desmethyl-lenvatinib (M2). M2 and lenvatinib itself are oxidized by

aldehyde oxidase Aldehyde oxidase (AO) is a metabolizing enzyme, located in the cytosolic compartment of tissues in many organisms. AO catalyzes the oxidation of aldehydes into carboxylic acid, and in addition, catalyzes the hydroxylation of some heterocycles. ...

(AO) to substances called M2' and M3', the main metabolites in the feces. Another metabolite, also mediated by a CYP enzyme, is the ''N''-oxide M3. Non-enzymatic metabolization also occurs, resulting in a low potential for interactions with enzyme inhibitors and inducers.

Terminal half-life Biological half-life (also known as elimination half-life, pharmacologic half-life) is the time taken for concentration of a biological substance (such as a medication) to decrease from its maximum concentration ( Cmax) to half of Cmax in the bl ...

is 28 hours, with about two thirds being excreted via the feces, and one quarter via the urine.

Chemistry

Lenvatinib is used in form of the

mesylate In organosulfur chemistry, a mesylate is any salt or ester of methanesulfonic acid (). In salts, the mesylate is present as the anion. When modifying the international nonproprietary name of a pharmaceutical substance containing the group ...

salt (

CAS number A CAS Registry Number (also referred to as CAS RN or informally CAS Number) is a unique identification number assigned by the Chemical Abstracts Service (CAS), US to every chemical substance described in the open scientific literature. It inclu ...

History

A phase I clinical trial in cancer patients was performed in 2006. A phase III trial treating thyroid cancer patients started in March 2011. Lenvatinib was granted

orphan drug An orphan drug is a pharmaceutical agent developed to treat medical conditions which, because they are so rare, would not be profitable to produce without government assistance. The conditions are referred to as orphan diseases. The assignment of ...

status for treatment of various types of thyroid cancer that do not respond to radioiodine in the US and Japan in 2012 and in Europe in 2013. In February 2015, the

U.S. FDA The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food s ...

approved lenvatinib for treatment of progressive, radioiodine refractory differentiated thyroid cancer. In May 2015,

European Medicines Agency The European Medicines Agency (EMA) is an agency of the European Union (EU) in charge of the evaluation and supervision of medicinal products. Prior to 2004, it was known as the European Agency for the Evaluation of Medicinal Products or Euro ...

(EMA) approved the drug for the same indication. In May 2016, the FDA approved it (in combination with

) for the treatment of advanced

following one prior anti-angiogenic therapy. In August 2018, the FDA approved lenvatinib for the first-line treatment of people with unresectable hepatocellular carcinoma (HCC).

Brand names

In Bangladesh under the brand name Lenvanix.

References

External links

* * {{Portal bar , Medicine Protein kinase inhibitors Orphan drugs Cyclopropanes Chloroarenes Ureas Carboxamides Breakthrough therapy