Nintedanib is an orally available tyrosine kinase receptor antagonist that inhibits collagen formation and is used to treat idiopathic pulmonary fibrosis. Elevations in serum enzyme levels during nintedanib therapy are not uncommon, but it has yet to be implicated in cases of clinically apparent liver injury with jaundice.
Nintedanib (nin ted' a nib) is a small molecular weight tyrosine kinase receptor inhibitor that has potent activity against several growth factor receptors, including vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR) and platelet derived growth factor receptor (PDGFR). The inhibition of these receptors causes modulation of many intracellular pathways including inhibition of activities of pro-fibrotic mediators such as transforming growth factor-beta (TGF-β), and decrease in synthesis of extracellular matrix proteins including collagen and fibronectin. Nintedanib has been evaluated as therapy of malignant conditions such as non-small cell lung cancer and for benign fibrotic conditions such as idiopathic pulmonary fibrosis. In several large clinical trials, therapy with nintedanib was associated with a decrease in the progressive decline in lung function in patients with idiopathic pulmonary fibrosis and well as with a decrease in symptomatic, acute pulmonary exacerbations. On the bases of these studies, nintedanib was approved for use in idiopathic pulmonary fibrosis in the United States in 2014. It has not been approved for use in cancer. Nintedanib is available as capsules of 100 and 150 mg under the brand name OFEV. The typical initial dose in adults is 150 mg orally twice daily. Temporary dose reduction is advised for management of adverse reactions or poor tolerability. Side effects are not uncommon and include diarrhea, nausea, dyspepsia, abdominal pain, decreased appetite, headache and fatigue. Rare, but potentially severe adverse events include excessive bleeding, poor wound healing, and arterial thrombotic events.
In large randomized controlled trials, serum enzyme elevations occurred in up to 14% of patients receiving nintedanib compared to 3% of controls. Aminotransferase values above 3 times the upper limit of normal (ULN) occurred in only 3% to 5% of patients (compared to <1% of controls), and discontinuation of therapy because ALT elevations was required in less than 1% of nintedanib treated subjects. The enzyme elevations during nintedanib therapy were generally not accompanied by symptoms of liver injury or jaundice and resolved even without dose modification in many subjects. Despite the frequency of ALT elevations during nintedanib therapy, clinically apparent liver injury was not recorded in preregistration studies and has yet to be reported in the published literature since its general availability. Nevertheless, monitoring of liver tests is recommended for patients receiving nintedanib at least monthly for the first 3 months and every 3 months thereafter. Thus, nintedanib is likely to cause clinically apparent liver injury, but careful monitoring and early discontinuation may prevent its occurrence.
Mechanism of Injury
The mechanism by which nintedanib might cause liver injury is not known. It is metabolized in the liver largely via the cytochrome P450 system, predominantly CYP 1A2, and liver injury may be due to production of a toxic or immunogenic metabolite. Nintedanib is also susceptible to drug-drug interactions with strong inducers or inhibitors of CYP 1A2 (such as fluvoxamine).
Outcome and Management
While chronic therapy with nintedanib can be associated with mild-to-moderate serum aminotransferase elevations, it has not been convincingly linked to cases of clinically apparent liver injury. Nevertheless, monitoring of serum aminotransferase levels monthly during the first 3 months and every 3 months thereafter is recommended. Patients who develop aminotransferase elevations on therapy should be monitored more carefully, and nintedanib should be permanently discontinued if jaundice or symptoms of liver injury arise or if serum ALT or AST levels rise above 5 times the ULN.
Drug Class: Pulmonary Fibrosis Agents
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