FENIFIB 801

Indications

• Idiopathic pulmonary fibrosis (IPF)

Dosage

Children: The safety and efficacy of pirfenidone in children under 18 years have not been established, and it is not typically recommended for use in paediatric populations.

Adults: The recommended dosage for adults is 267 mg taken three times daily, with adjustments based on tolerance and liver function. Treatment should be initiated under specialist supervision.

Mechanism of action

The precise mechanism of action of pirfenidone is not completely elucidated. However, it is thought to modulate various pathways involved in the fibrotic process, including inhibition of TGF-β (transforming growth factor-beta) signaling, which plays a critical role in fibrosis development. Pirfenidone may also exhibit antioxidant properties and influence the secretion of inflammatory cytokines.

Pharmacodynamics

Pirfenidone has been shown to reduce fibrosis in lung tissue and improve lung function in patients with IPF. Its antifibrotic activity may be mediated through actions on fibroblasts and myofibroblasts, reducing their proliferation and activity, which are pivotal in the fibrotic process. Additionally, pirfenidone's anti-inflammatory effects may help mitigate the inflammatory component of lung injury.

Pharmacokinetics

Pirfenidone is well absorbed after oral administration, with peak plasma concentrations typically occurring within 4 hours. It has a bioavailability of approximately 60%. The drug is extensively metabolized in the liver, primarily via the cytochrome P450 enzyme system. The elimination half-life is approximately 12 to 25 hours, and it is excreted mainly through the urine and feces, with renal impairment potentially affecting its clearance.

Adverse effects

• Skin sensitisation
• Photosensitivity
• Appetite decreased
• Arthralgia
• Asthenia
• Constipation
• Diarrhoea
• Dizziness
• Drowsiness
• Gastrointestinal discomfort
• Gastrointestinal disorders
• Headache
• Hot flush
• Increased risk of infection
• Insomnia
• Musculoskeletal pain
• Myalgia
• Nausea
• Productive cough
• Taste altered
• Vomiting
• Weight decreased
• Agranulocytosis
• Angioedema
• Hepatic disorders
• Hyponatraemia
• Severe cutaneous adverse reactions

Interactions

• Rifampicin: Severe (decreases exposure)
• Mexiletine: Moderate (increases exposure)
• Osilodrostat: Moderate (increases exposure)
• Rucaparib: Moderate (increases exposure)
• Vemurafenib: Moderate (increases exposure)
• Ciprofloxacin: Moderate (increases exposure)
• Axitinib: Unknown (increases exposure)
• Ritonavir: Unknown (decreases exposure)
• Leflunomide: Unknown (decreases exposure)
• Teriflunomide: Unknown (decreases exposure)

Precautions

• Caution with concomitant use of ciprofloxacin, reduce dose of pirfenidone to 534 mg three times daily with high-dose ciprofloxacin (750 mg twice daily)
• Monitor liver function due to the risk of serious liver injury
• Advise patients to seek immediate medical attention for signs and symptoms of liver injury
• Avoid exposure to direct sunlight due to the risk of photosensitivity reactions

Pregnancy

The safety of pirfenidone in pregnancy has not been established; use only if the potential benefit justifies the potential risk to the fetus.

Breast-feeding

It is not known whether pirfenidone is excreted in human milk; caution should be exercised when administering to nursing women.

Storage

Store in a cool, dry place

Mechanism of action

The exact mechanism of action of pirfenidone is not fully understood. It is suggested that the antioxidant effects of pirfenidone contribute to its anti-inflammatory effects, leading to antifibrotic effects. Pirfenidone attenuates the production of transforming growth factor-β1 (TGF-β1), a key profibrotic and pro-inflammatory cytokine implicated in idiopathic pulmonary fibrosis (IPF). By suppressing TGF-β1, pirfenidone inhibits TGF-β1-induced differentiation of human lung fibroblasts into myofibroblasts, thereby preventing excess collagen synthesis and extracellular matrix production. Some evidence suggests that pirfenidone downregulates pro-inflammatory cytokines, including TNF-α, interleukin-1 (IL-1), IL-6, interferon-gamma (IFN-γ), and platelet-derived growth factor (PDGF). Animal models demonstrated that pirfenidone promotes the production of anti-inflammatory IL-10 and prevents the accumulation of various inflammatory cells, including lymphocytes, macrophages and neutrophils. In animal models, pirfenidone inhibited the influx of inflammatory cells and ameliorated bleomycin-induced pulmonary vascular permeability. Several _in vitro_ studies show that pirfenidone mediates antioxidant actions by scavenging reactive oxygen species (ROS) and inhibiting lipid peroxidation, thereby reducing cellular injury in IPF. Dysfunctional mitochondria participate in the progression of chronic kidney disease (CKD). Pirfenidone is a newly identified anti-fibrotic drug. However, its mechanism remains unclear. Mitochondrial dysfunction is an early event that occurs prior to the onset of renal fibrosis. In this context, we investigated the protective effect of pirfenidone on mitochondria and its relevance to apoptosis and oxidative stress in renal proximal tubular cells. A remnant kidney rat model was established. Human renal proximal tubular epithelial cells (HK2) using rotenone, a mitochondrial respiratory chain complex I inhibitor were further investigated in vitro to examine the mitochondrial protective effect of pirfenidone. Pirfenidone protected mitochondrial structures and functions by stabilizing the mitochondrial membrane potential, maintaining ATP production and improving the mitochondrial DNA (mtDNA) copy number. Pirfenidone decreased tubular cell apoptosis by inhibiting the mitochondrial apoptotic signaling pathway. Pirfenidone also reduced oxidative stress by enhancing manganese superoxide dismutase (Mn-SOD) and inhibiting intracellular reactive oxygen species (ROS) generation, which suggested that the anti-oxidant effects occurred at least partially via the mitochondrial pathway. Pirfenidone may be effective prior to the onset of renal fibrosis because this drug exerts its anti-fibrotic effect by protection of mitochondria in renal proximal tubular cells. Pirfenidone is a drug recently approved for idiopathic pulmonary fibrosis but its mechanisms of action are partially unknown. We have previously demonstrated that the airways of patients with idiopathic pulmonary fibrosis contain procoagulant microparticles that activate coagulation factor X to its active form, Xa, a proteinase that signals fibroblast growth and differentiation, thus potentially contributing to the pathogenesis of the disease. We also reported that in vitro exposure of human alveolar cells to H2O2 causes microparticle generation. Since p38 activation is involved in microparticle generation in some cell models and p38 inhibition is one of the mechanisms of action of pirfenidone, we investigated the hypothesis that H2O2-induced generation of microparticles by alveolar cells is dependent on p38 phosphorylation and is inhibited by pirfenidone. H2O2 stimulation of alveolar cells caused p38 phosphorylation that was inhibited by pirfenidone. The drug also inhibited H2O2 induced microparticle generation as assessed by two independent methods (solid phase thrombin generation and flow cytometry). The shedding of microparticle-bound tissue factor activity was also inhibi

Pharmacodynamics

Pirfenidone is a novel agent with anti-inflammatory, antioxidant, and antifibrotic properties. It may improve lung function and reduce the number of acute exacerbations in patients with idiopathic pulmonary fibrosis (IPF).