Nintedanib

MECHANISM OF ACTION

Nintedanib works by inhibiting multiple receptor tyrosine kinases, mainly those for VEGF, FGF, and PDGF. By blocking these signaling pathways, it reduces fibroblast proliferation, migration, and transformation into active scar-forming cells. This leads to decreased production of extracellular matrix and collagen, thereby slowing tissue fibrosis in the lungs and limiting disease progression.

PHARMACOKINETICS

Absorption

Nintedanib is absorbed orally but has relatively low absolute bioavailability due to extensive first-pass metabolism. Food intake increases its exposure, so it is recommended to take it with food to improve gastrointestinal tolerance and reduce side effects. Peak plasma concentrations are usually reached within a few hours after oral administration.

Distribution

Nintedanib is widely distributed in the body after oral absorption and shows very high plasma protein binding (mainly albumin), which limits the free active fraction in circulation. It has a moderate volume of distribution, indicating distribution into tissues, including the lungs where it exerts its antifibrotic effects by targeting fibroblast activity.

Metabolism

Nintedanib is primarily metabolized in the liver through ester cleavage by esterases, forming its major active metabolite. It undergoes limited involvement of the cytochrome P450 system, especially CYP3A4, which contributes only to a minor extent. The resulting metabolites are pharmacologically less active and are further processed for elimination.

Elimination

Nintedanib is eliminated mainly through fecal excretion via biliary secretion, with a smaller portion excreted in urine as metabolites. The parent drug is minimally excreted unchanged. It has a moderate elimination half-life, and steady-state levels are achieved with regular dosing.

PHARMACODYNAMICS

Nintedanib produces its pharmacodynamic effects by inhibiting multiple receptor tyrosine kinases, mainly VEGFR, FGFR, and PDGFR, which are key mediators of angiogenesis and fibroblast activation. By blocking these pathways, it reduces fibroblast proliferation, migration, and transformation into collagen-producing cells, thereby decreasing extracellular matrix deposition and slowing tissue fibrosis. This action helps reduce disease progression in fibrotic lung diseases and also inhibits tumor angiogenesis in certain cancers.

ADMINISTRATION

Nintedanib is administered orally in capsule form, usually taken twice daily at 12-hour intervals. It is recommended to take the drug with food to improve gastrointestinal tolerance and reduce side effects. Capsules should be swallowed whole and not opened or crushed, and dosing is adjusted based on indication, patient tolerance, and liver function.

DOSAGE AND STRENGTH

Nintedanib is available as oral capsules in strengths of 100 mg and 150 mg. The usual adult dose for idiopathic pulmonary fibrosis and other progressive fibrosing interstitial lung diseases is 150 mg twice daily, taken about 12 hours apart with food. In patients who cannot tolerate this dose, it may be reduced to 100 mg twice daily. Dose adjustments are required in cases of adverse effects or liver impairment.

DRUG INTERACTIONS

Nintedanib has several important drug interactions:

• P-glycoprotein (P-gp) inhibitors (e.g., ketoconazole, erythromycin, cyclosporine) → increase drug levels and risk of toxicity

• P-gp inducers (e.g., rifampin, carbamazepine, St. John’s wort) → decrease effectiveness

• Anticoagulants/antiplatelets (e.g., warfarin, aspirin) → increased risk of bleeding

• NSAIDs → may increase gastrointestinal and bleeding risk

• CYP3A4 inhibitors/inducers → minor effect but still require caution

FOOD INTERACTIONS

Nintedanib should be taken with food to reduce gastrointestinal side effects like nausea and diarrhea. Food does not significantly affect its effectiveness, but taking it without food may increase stomach discomfort.

CONTRAINDICATIONS

Nintedanib is contraindicated in patients with known hypersensitivity to nintedanib or any of its components. It should be avoided in individuals with severe hepatic impairment due to increased risk of toxicity and drug accumulation. It is also contraindicated in patients with active major bleeding or a high risk of bleeding, as it may increase bleeding complications.

SIDE EFFECTS

Nintedanib commonly causes gastrointestinal side effects such as diarrhea, nausea, vomiting, abdominal pain, and loss of appetite. Other effects include elevated liver enzymes, fatigue, headache, and weight loss. Less commonly, it may increase the risk of bleeding, hypertension, and skin rash, and rarely cause serious liver injury or gastrointestinal perforation.

OVER DOSAGE

Nintedanib overdose mainly causes severe gastrointestinal effects like diarrhea, nausea, vomiting, abdominal pain, and dehydration, along with elevated liver enzymes. In severe cases, it may lead to liver injury or bleeding risk. Management is supportive with stopping the drug and providing fluids and monitoring.

TOXICITY

Nintedanib toxicity mainly causes severe gastrointestinal effects like diarrhea, nausea, vomiting, and abdominal pain, along with elevated liver enzymes. In severe cases, it may lead to liver injury and increased bleeding risk. Management is supportive with drug discontinuation, fluids, and monitoring.