Lenvatinib

Lenvatinib, sold under the brand name Lenvima among others, is an anti-cancer medication for the treatment of certain kinds of thyroid cancer and for other cancers as well. It was developed by Eisai Co. and acts as a multiple kinase inhibitor against the VEGFR1, VEGFR2 and VEGFR3 kinases.^[4]

Lenvatinib

Clinical data
Trade names	Lenvima, others
Other names	E7080
AHFS/Drugs.com	Monograph
License data	US DailyMed: Lenvatinib
Pregnancy category	AU: D
Routes of administration	By mouth
ATC code	L01EX08 (WHO)
Legal status
Legal status	AU: S4 (Prescription only)[1] CA: ℞-only[2] US: ℞-only EU: Rx-only[3]
Pharmacokinetic data
Bioavailability	85% (estimated)
Protein binding	98–99%
Metabolism	CYP3A4, aldehyde oxidase, non-enzymatic
Metabolites	Desmethyl-lenvatinib (M2) and others
Elimination half-life	28 hours
Excretion	~65% feces, 25% urine
Identifiers
IUPAC name 4-[3-Chloro-4-(cyclopropylcarbamoylamino)phenoxy]-7-methoxy-quinoline-6-carboxamide
CAS Number	417716-92-8 N
PubChem CID	9823820
IUPHAR/BPS	7426
DrugBank	DB09078 N
ChemSpider	7999567 Y
UNII	EE083865G2
KEGG	D09919 N as salt: D09920 N
ChEBI	CHEBI:85994 N
ChEMBL	ChEMBL1289601 N
CompTox Dashboard (EPA)	DTXSID50194605
Chemical and physical data
Formula	C21H19ClN4O4
Molar mass	426.86 g·mol−1
3D model (JSmol)	Interactive image
SMILES C4CC4NC(=O)Nc3ccc(cc3Cl)Oc1ccnc(cc2OC)c1cc2C(=O)N
InChI InChI=1S/C21H19ClN4O4/c1-29-19-10-17-13(9-14(19)20(23)27)18(6-7-24-17)30-12-4-5-16(15(22)8-12)26-21(28)25-11-2-3-11/h4-11H,2-3H2,1H3,(H2,23,27)(H2,25,26,28) Y Key:WOSKHXYHFSIKNG-UHFFFAOYSA-N Y
NY (what is this?)  (verify)

Medical uses

Lenvatinib is approved (since 2015) for the treatment of differentiated thyroid cancer that is either locally recurrent or metastatic, progressive, and did not respond to treatment with radioactive iodine (radioiodine).^[5][6]

In May 2016, the US Food and Drug Administration (FDA) approved it (in combination with everolimus) for the treatment of advanced renal cell carcinoma following one prior anti-angiogenic therapy.^[7]

The drug is also approved in the US and in the European Union for hepatocellular carcinoma that cannot be removed surgically in patients who have not received cancer therapy by mouth or injection.^[8][9]

Adverse effects

Hypertension (high blood pressure) was the most common side effect in studies (73% of patients, versus 16% in the placebo group), followed by diarrhoea (67% vs. 17%) and fatigue (67% vs. 35%).^[6] Other common side effects included decreased appetite, hypotension (low blood pressure), thrombocytopenia (low blood platelet count), nausea, muscle and bone pain.^[5]

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. No relevant interactions with enzyme inhibitors and inducers are expected.^[6]

Pharmacology

Mechanism of action

Lenvatinib acts as a multiple kinase inhibitor. It inhibits the three main vascular endothelial growth factor receptors VEGFR1, 2 and 3, as well as fibroblast growth factor receptors (FGFR) 1, 2, 3 and 4, platelet-derived growth factor receptor (PDGFR) alpha, c-Kit, and the RET proto-oncogene. Some of these proteins play roles in cancerogenic signalling pathways. VEGFR2 inhibition is thought to be the main reason for the most common side effect, hypertension.^[5]

Pharmacokinetics

Lenvatinib is absorbed quickly from the gut, reaching peak blood plasma concentrations after one to four hours (three to seven hours if taken with food). Bioavailability is estimated to be about 85%. The substance is almost completely (98–99%) bound to plasma proteins, mainly albumin.^[5]

Lenvatinib is oxidized by cytochrome P450 enzymes (CYP), and further metabolized to the quinolinones M2' and M3' by aldehyde oxidase (AO).^[10]

Lenvatinib is metabolized by the liver enzyme CYP3A4 to desmethyl-lenvatinib (M2). M2 and lenvatinib itself are oxidized by aldehyde oxidase (AO) to substances called M2' and M3',^[10] 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.^[5]

Terminal half-life is 28 hours, with about two thirds being excreted via the feces, and one quarter via the urine.^[5]

Chemistry

Lenvatinib is used in form of the mesylate salt (CAS number 857890-39-2 ).

History

A phase I clinical trial in cancer patients was performed in 2006.^[11] A phase III trial treating thyroid cancer patients started in March 2011.^[12]

Lenvatinib was granted orphan drug 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.^[13]

In February 2015, the U.S. FDA approved lenvatinib for treatment of progressive, radioiodine refractory differentiated thyroid cancer.^[14] In May 2015, European Medicines Agency (EMA) approved the drug for the same indication.^[15]

In May 2016, the FDA approved it (in combination with everolimus) for the treatment of advanced renal cell carcinoma following one prior anti-angiogenic therapy.^[7]

In August 2018, the FDA approved lenvatinib for the first-line treatment of people with unresectable hepatocellular carcinoma (HCC).^[9]