Nintedanib and Pirfenidone

Mechanism

🧬 Nintedanib

• Class: Intracellular triple tyrosine kinase inhibitor.
• Targets: Blocks VEGFR (1-3), PDGFR (α/β) and FGFR (1-3) receptors.
• Inhibits the proliferation and migration of alveolar fibroblasts stimulated by growth factors.

🧪 Pirfenidone

• Class: Oral antifibrotic and anti-inflammatory synthetic molecule.
• Mechanism: Decreases the synthesis and activity of the profibrotic cytokine TGF-β.
• Reduces the differentiation of fibroblasts to active myofibroblasts and the synthesis of fibrillar collagen.

Mechanism of action

The pathogenesis of pulmonary fibrosis is initiated by recurrent alveolar epithelial microlesions that stimulate the continuous release of cell growth mediators and profibrotic cytokines by injured macrophages and pneumocytes.

Nintedanib: It is a small molecule that competes directly for the ATP binding site in the intracellular kinase catalytic domain of three families of transmembrane receptors:

• Fibroblast Growth Factor Receptor (FGFR).
• Platelet Derived Growth Factor Receptor (PDGFR).
• Vascular Endothelial Growth Factor Receptor (VEGFR).

By blocking cellular autophosphorylation of these receptors, nintedanib interrupts the secondary intracellular signaling cascades of Lck, Src and Lyn kinases. This coordinately stops cell proliferation and migration, as well as the transformation of fibroblasts into collagen-secreting myofibroblasts.

Pirfenidone: Its exact cellular mechanism remains under investigation, but it exerts a powerful anti-fibrosing action by:

1. Suppress the TGF-β (Transforming Growth Factor Beta) signaling cascade: Drastically decreases the phosphorylation and translocation of the transducer proteins Smad2 and Smad3, inactivating the production of extracellular collagen type I and III.
2. Decrease the synthesis of proinflammatory cytokines such as TNF-α and IL-1β.
3. Reduce the accumulation and cellular differentiation of fibroblasts induced by allergens or local chemokines.

Pharmacokinetics

Pharmacokinetics

• Nintedanib: Low oral bioavailability of only 4.7% due to extensive hepatic first-pass metabolism. Highly bound to plasma proteins (>97%). It is predominantly metabolized by enzymatic hydrolysis (via plasma esterases) followed by glucuronidation. Less than 1% is eliminated through the kidneys; Its main route is fecal/biliary (93%). Half-life of 9.5 hours.
• Pirfenidone: Bioavailability of 80%, extensively metabolized in the liver by 95% via the CYP1A2 pathway to inactive metabolites. Excretion in the urine (80%). Half-life of 2.5 hours.

Indicators and dose

Dosage and Clinical Adjustment

• Nintedanib (Ofev): 150 mg orally twice daily with food. If refractory diarrhea or elevated transaminases occur, the dose may be temporarily reduced to 100 mg twice daily.
• Pirfenidone (Esbriet): Mandatory weekly ascending titration schedule: Weekly 1: 267 mg three times a day; Week 2: 534 mg three times a day; Week 3 and later: 801 mg three times daily (total maintenance dose of 2403 mg daily given with food).

Adjustment in Liver Failure: Contraindicated in patients with moderate to severe liver failure (Child-Pugh B or C) due to the high risk of irreversible hepatoxicity.

Security

Adverse effects (ADRs)

• Nintedanib: The limiting adverse effect is moderate to severe watery diarrhea (occurs in ≈ 62% of patients due to stimulation of VEGFR at the level of the enteric villi), nausea, vomiting, elevation of transaminases and potential risk of bleeding or arterial thromboembolic events.
• Pirfenidone: The limiting adverse effect is the skin photosensitivity reaction and severe dermal rash (occurs in ≈ 30% of patients, requires the mandatory daily use of broad-spectrum sunscreen SPF 50 and avoidance of direct sun exposure), nausea, dyspepsia, extreme fatigue and increased transaminases.

Clinical

Efficacy in Pivot Clinical Trials (FPI)

Phase III clinical trials of nintedanib (INPULSIS-1 and 2 studies) and pirfenidone (ASCEND study) conclusively demonstrated that both treatments slow the rate of disease progression comparably, achieving an approximately 50% reduction in the annual rate of decline in Forced Vital Capacity (FVC) in patients with idiopathic pulmonary fibrosis.