|Trade names||Vargatef, Ofev|
|AHFS/Drugs.com||Consumer Drug Information|
|Oral and intravenous|
|ATC code||L01XE31 (WHO)|
|Biological half-life||10–15 hrs|
|Excretion||93% via faeces|
|Chemical and physical data|
|Molar mass||539.6248 g/mol|
|3D model (Jmol)||Interactive image|
|(what is this?)|
Nintedanib, marketed under the brand names Ofev and Vargatef, is a medication used for the treatment of idiopathic pulmonary fibrosis (IPF) and along with other medications for some types of non-small-cell lung cancer.
Common side effects include abdominal pain, vomiting, and diarrhea. It is a small molecule tyrosine-kinase inhibitor, targeting vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR) and platelet derived growth factor receptor (PDGFR).
It was developed by Boehringer Ingelheim. At an assumed cost of 39,300 pounds per year it does not appear to be cost effective for IPF in the United Kingdom.
Idiopathic pulmonary fibrosis
It is also used in combination with docetaxel as a second line treatment for adult patients with locally advanced, metastatic, or locally recurring NSCLC of adenocarcinoma histology. It is unclear how this combination compares to other second line agents as the comparisons have not been done as of 2014.
Preclinical studies have shown that nintedanib binds in a highly selective manner to the ATP binding pocket of its three target receptor families, without binding to similarly shaped ATP domains in other proteins, which reduces the potential for undesirable side effects.
The most common side effects observed with nintedanib were reversible elevation in liver enzymes (10 to 28% of patients) and gastrointestinal disturbance (up to 50%). Side effects observed with nintedanib were worse with the higher dose, for this reason subsequent trials have used the equally clinically effective lower dose.
Nintedanib inhibits the growth and reshaping of blood vessels which is also an essential process in normal wound healing and tissue repair. Therefore, a theoretical side effect of nintedanib is reduced wound healing however, unlike other anti-angiogenic agents, this side effect has not been observed in patients receiving nintedanib.
Nintedanib is a substrate of the transporter P-glycoprotein (P-gp) which moves the absorbed substance back in to the gut's lumen. The P-gp inhibitor ketoconazole is known to increase blood plasma levels of nintedanib by a factor of 1.8; other inhibitors such as erythromycin or ciclosporin are expected to have a similar effect. On the other hand, the P-gp inductor rifampicin has been shown to cut nintedanib plasma levels in half; other inductors such as carbamazepine, phenytoin or St. John's Wort probably lower plasma levels as well.
Mechanism of action
Idiopathic pulmonary fibrosis
Nintedanib targets growth factor receptors, which have been shown to be involved in the mechanisms by which pulmonary fibrosis occurs. Most importantly nintedanib inhibits platelet-derived growth factor receptor (PDGFR), fibroblast growth factor receptor (FGFR) and vascular endothelial growth factor receptor (VEGFR). It is believed that nintedanib reduces disease progression in IPF and slows the decline in lung function by blocking the signalling pathways that are involved in fibrotic processes.
Nintedanib is an indolinone-derived drug that inhibits the process of blood vessel formation (angiogenesis). Angiogenesis inhibitors stop the formation and reshaping of blood vessels in and around tumours, which reduces the tumour's blood supply, starving tumour cells of oxygen and nutrients leading to cell death and tumour shrinkage. Unlike conventional anti-cancer chemotherapy which has a direct cell killing effect on cancer cells, angiogenesis inhibitors starve the tumour cells of oxygen and nutrients which results in tumour cell death. One of the advantages of this method of anti-cancer therapy is that it is more specific than conventional chemotherapy agents, therefore results in fewer and less severe side effects than conventional chemotherapy.
Angiogenesis is a process that is essential for the growth and spread of all solid tumours, blocking it prevents the tumour from growing and may result in tumour shrinkage as well as a reduction in the spread of the cancer to other parts of the body. Nintedanib exerts its anti-cancer effect by binding to and blocking the activation of cell receptors involved in blood vessel formation and reshaping (i.e. VEGFR 1-3, FGFR 1-3 and PDGFRα and β). Inhibition of these receptors in the cells that make up blood vessels (endothelial cells, smooth muscle cells and pericytes) by nintedanib leads to programmed cell death, destruction of tumor blood vessels and a reduction in blood flow to the tumour. Reduced tumour blood flow inhibits tumor cell proliferation and migration hence slowing the growth and spread of the cancer.
Only a small percentage of orally taken nintedanib is absorbed in the gut, partially due to transport proteins (such as P-glycoprotein) moving the substance back into the lumen. Combined with a high first-pass effect, this results in an oral bioavailability of about 4.7%.
Nintedanib is mainly inactivated by esterases that cleave the methyl ester, resulting in the free carboxylic acid (BIBF 1202), which is then glucuronidated by enzymes called uridinediphosphate-glucuronosyltransferases (UGTs) and excreted mostly via the bile and faeces. No relevant cytochrome P450 mediated metabolism has been observed.
The drug is used in form of its salt with ethanesulfonic acid. This salt, nintedanib esliate, is a yellow, crystalline solid that melts at 244 °C (471 °F) to 251 °C (484 °F). It is very badly soluble in water, and somewhat better soluble in dimethyl sulfoxide (DMSO) at 25 g/l.
Idiopathic pulmonary fibrosis
Nintedanib was approved for idiopathic pulmonary fibrosis on 15 Oct 2014 by the Food and Drug Administration, and received a positive opinion from the European Medicines Agency on 20 November 2014, being approved in the EU in January 2015. It is also approved in Canada, Japan, Switzerland, and other countries.
Society and culture
Nintedanib is being tested in several phase I to III clinical trials for cancer. Angiogenesis inhibitors such as nintedanib may be effective in a range of solid tumour types including lung, ovarian, metastatic bowel, liver and brain cancer.
Current phase II trials are investigating the effect of nintedanib in patients with metastatic bowel cancer, liver cancer and the brain tumour glioblastoma multiforme.
Phase III trials are investigating the use of nintedanib in combination with carboplatin and paclitaxel as a first line treatment for patients with ovarian cancer.
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- ClinicalTrials.gov: BIBF 1120
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