Nintedanib (Ofev) is a small tyrosine kinase inhibitor that is used to treat patients with idiopathic pulmonary fibrosis, interstitial lung disease in patients with systemic sclerosis, and non-small cell lung cancer.
Overview of Nintedanib and its indications:
Nintedanib (Ofev) is a small tyrosine kinase inhibitor that primarily targets platelet-derived growth factor receptors (PDGFR), Fibroblast growth factor receptors (FGFR), Vascular endothelial growth factor receptors (VEGFR), Colony-stimulating factor 1 receptor (CSFR), and Fms-like tyrosine kinase-3 (FLT-3).
It has got FDA approval for the treatment of patients with the following diseases:
- Idiopathic pulmonary fibrosis
- Chronic fibrosing interstitial lung disease with a progressive phenotype
- and interstitial lung disease (ILD) associated with systemic sclerosis to slow the progression of lung disease in these patients.
Ofev was developed by Boehringer Ingelheim International GmbH and has got FDA approval in 2014. It has recently been under trials for slowing the progression of fibrosis in patients with COVID-19 infection. It is also being investigated for use in combination with pirfenidone which is also used for the same indications.
Mechanism of action of Nintedanib (Ofev)
Pulmonary fibrosis is a chronic disease characterized by progressive scarring of the lungs (perfusion injury) that impairs normal gas exchange. The tissue in affected lungs becomes stiff and scarred, resulting in restricted airflow. In idiopathic pulmonary fibrosis, the underlying cause is unknown. Fibroblasts accumulate in pulmonary tissues due to damaged blood vessels. Proteins can’t pass through the damaged vasculature and impair gas exchange.
Ofev inhibits protein kinases (inhibitors) called tyrosine kinases (TYK) after binding to PDGFR, FGFR, VEGFR, FLT-3, and CSFR. Ofev (nintedanib) primarily binds to the ATP pocket of these receptors and inhibits their activation. This results in the inhibition of signals that cause the proliferation, migration, and activation of fibroblasts.
When fibroblasts are inhibited, the disease progression as a result of fibrosis is inhibited. furthermore, Ofev is an inhibitor of multiple tyrosine kinases, it has generalized effects.
Ofev is an inhibitor of multiple tyrosine kinases
Pharmacokinetic and pharmacodynamic properties
Anecdotal evidence suggests that nintedanib is well-tolerated at standard doses, but a recommended dose of nintedanib should be determined to take into account an individual patient’s metabolism. The following guidelines apply to nintedanib:
- The usual recommended dose is 150 mg administered twice daily.
- The maximum dose should not exceed 300 mg per day.
- In patients with a mild hepatic impairment such as Child Class A cirrhosis, the dose should not exceed 200 mg per day (100 mg administered twice daily).
If the dose is not administered on a regular basis or missed, doubling the dose should be avoided. Furthermore, co-administration with Pirfenedone and Bosentan does not change the pharmacokinetics of the drug. Dosage adjustment is not required when administering nintedanib in combination with these drugs.
Do not exceed a dose of 300 mg per day
Adverse effects reported with Ofev (Nintedanib):
The most common adverse events reported in clinical trials with the use of nintedanib were GI-related. Drug-induced hepatotoxicity was also reported in a greater number of patients on treatment with nintedanib compared to placebo. Other important and significant adverse drug reactions were thromboembolic events, increased risk of bleeding especially when the drug was taken with NSAIDs or other anticoagulants, and GI perforations.
The following table summarizes the adverse drug reactions associated with nintedanib use compared with placebo medicine in clinical trials [Ref]:
Adverse Drug Reactions | OFEV, 150 mg n=723 | Placebo n=508 |
| Gastrointestinal disorders | ||
| Diarrhea | 62% | 18% |
| Nausea | 24% | 7% |
| Abdominal pain | 15% | 6% |
| Vomiting | 12% | 3% |
| Hepatobiliary disorders | ||
| Elevated liver enzymes | 14% | 3% |
| Nervous system disorders | ||
| Headache | 8% | 5% |
| Miscellaneous | ||
| Weight decreased | 10% | 3% |
| Reduced appetite | 11% | 5% |
| Vascular disorders | ||
| Hypertension | 5% | 4% |
Most Common side effect Of Ofev is Diarrhea
Conclusion:
Nintedanib may be a promising oral, targeted treatment for pulmonary fibrosis and ILD associated with systemic sclerosis. It is an oral medicine and is being investigated in other conditions including COVID-19 infection.