Uses
BIBF1120 (Vargatef) is a potent inhibitor of VEGFR1/2/3, FGFR1/2/3 and PDGFRα/β with IC50 of 34 nM/13 nM/13 nM, 69 nM/37 nM/108 nM and 59 nM/65 nM, respectively.
Uses
It is an indolinone derivative potently blocking VEGF-, PDGF-, and FGF-receptor kinases; an indolinone as triple angiokinase inhibitors.
Definition
ChEBI: A member of the class of oxindoles that is a kinase inhibitor used (in the form of its ethylsulfonate salt) for the treatment of idiopathic pulmonary fibrosis and cancer.
Biological Activity
nintedanib (bibf 1120,656247-17-5) is an indolinone-derived oral active, triple angiokinase inhibitor of vascular endothelial growth factor receptor (vegfr)1-3, fibroblast growth factor receptor (fgfr)1-3 and platelet-derived growth factor receptor (pdgfr)α/β1. it has shown potent antiangiogenic activity at nanomolar (ic50, 20-100 nmol/l) by blocking these receptor-mediated signaling pathways1,2. nintedanib (bibf 1120) is in clinical development for the treatment of idiopathic pulmonary fibrosis as these receptors have been shown to be potentially involved in the pathogenesis of pulmonary fibrosis3,4. as a novel angiogenesis inhibitor, it is also being widely evaluated in different cancer models and has displayed significant anti-tumor activities by inhibiting tumor blood vessel formation5-7.to further evaluate its antitumor effects on multiple tumors, nintedanib is currently entering several
Clinical Use
Tyrosine kinase inhibitor:
Treatment of locally advanced, metastatic or locally
recurrent non-small cell lung cancer (NSCLC) of
adenocarcinoma tumour histology in combination
with docetaxel
Treatment of Idiopathic Pulmonary Fibrosis (IPF)
Side effects
The most common side effects of Nintedanib(656247-17-5) in clinical studies were gastrointestinal-related side effects, including nausea (31%), vomiting (23%), diarrhoea (76%), abdominal pain (10%) and decreased appetite (10%). Other side effects were hepatic impairment commonly seen as elevated liver enzymes, weight loss (7 per cent), nasopharyngitis (7 per cent), cough (14 per cent), upper respiratory tract infections (14 per cent), headache (12 per cent), fatigue (14 per cent), skin ulcers (16 per cent) and urinary tract infections (12 per cent).
Reported post-marketing adverse events include gastrointestinal perforation, proteinuria and pancreatitis. In several clinical trials, nidanib has also been found to be associated with an increased risk of bleeding, possibly secondary to VEGFR inhibition. Although serious bleeding and arterial thromboembolic events (e.g., myocardial infarction (MI) and stroke) are rare, bleeding events with serious and fatal consequences have been reported in post-marketing surveillance. Therefore, the use of nidazanib has been associated with an increased risk of bleeding, possibly secondary to VEGFR inhibition. Therefore, patients treated with nidazanib and receiving full anticoagulation therapy need to be closely monitored for adverse bleeding events.
Drug interactions
Potentially hazardous interactions with other drugs
Antibacterials: concentration reduced by rifampicin
- avoid.
Antifungals: concentration increased by
ketoconazole.
Antipsychotics: increased risk of agranulocytosis
with clozapine - avoid.
Metabolism
Nintedanib(656247-17-5) is metabolised in the liver, initially
by hydrolytic cleavage by esterases and then
by glucuronidation by uridine diphosphate
glucuronosyltransferase enzymes. Only a minor portion
is metabolised by cytochrome P450 isoenzymes, mainly
CYP3A4.
More than 90% of a dose is eliminated by faecal/biliary
excretion.
References
[1]hilberg, f. et al. bibf 1120: triple angiokinase inhibitor with sustained receptor blockade and good antitumor efficacy. cancer research 68, 4774-4782, doi:10.1158/0008-5472.can-07-6307 (2008).
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