|Trade names||Vargatef, Ofev|
|AHFS/Drugs.com||Consumer Drug Information|
|Elimination half-life||10–15 hrs|
|Excretion||93% via faeces|
|Chemical and physical data|
|Molar mass||539.6248 g/mol g·mol−1|
|3D model (JSmol)|
|(what is this?)|
Nintedanib, marketed under the brand names Ofev and Vargatef, is an oral medication used for the treatment of idiopathic pulmonary fibrosis 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, fibroblast growth factor receptor and platelet derived growth factor receptor.
- 1 Medical uses
- 2 Contraindications
- 3 Adverse effects
- 4 Interactions
- 5 Pharmacology
- 6 Chemistry
- 7 History
- 8 Society and culture
- 9 Research
- 10 References
- 11 External links
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 non-small cell lung cancer 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.
Nintedanib is contraindicated in patients with known hypersensitivity to nintedanib, peanut or soya. Nintedanib has not been tested in patients with moderate to severe impairment of liver function. Given that the drug is metabolised in the liver, it may not be safe in such patients. Nintedanib can be used in geriatric population without any dose modifications. It has not been studied in paediatric populations and hence cannot be given in patients below 18 years of age. It is also contraindicated in pregnancy
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%). Hence it is recommended to take nintedanib after food. 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 was shown in trials to have higher incidences of strokes and myocardial ischaemia. Hence it should be used to with caution in patients with a known history of these events.
Nintedanib might cause weight loss.
Nintedanib is a substrate of the transporter P-glycoprotein which moves the absorbed substance back into the gut's lumen. The P-glycoprotein 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-glycoprotein inducer rifampicin cuts nintedanib plasma levels in half; other inducers 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, fibroblast growth factor receptor and vascular endothelial growth factor receptor. It is believed that nintedanib reduces disease progression of idiopathic pulmonary fibrosis 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, or angiogenesis. Inhibitors of angiogenesis 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, inhibitors of angiogenesis 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. vascular endothelial growth factor receptor 1-3, vascular endothelial growth factor receptor 1-3 and platelet derived growth factor receptor α 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% with a 100mg tablet. The drug reaches peak plasma levels in 2 to 4 hours after oral intake in the form of a soft gelatin capsule
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 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 has poor solubility in water, and somewhat better solubility in dimethyl sulfoxide at 25 g/l.
Idiopathic pulmonary fibrosis
Nintedanib was approved for idiopathic pulmonary fibrosis on 15 October 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
A review, which assumed the price of nintebanib was 39,300 pounds a year found that it was not cost effective.
Boehringer is using the brand name Ofev for marketing nintedanib for idiopathic pulmonary fibrosis and Vargatef for marketing the medication for lung cancer.
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.
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- Sicherheitsdatenblatt [Safety data sheet] Nintedanibesilat (in German)
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- ClinicalTrials.gov: BIBF 1120
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