Pirfenidone

Pirfenidone is a medication used for the treatment of idiopathic pulmonary fibrosis (IPF), a progressive lung disease that leads to scarring of the lung tissue and difficulty breathing. Pirfenidone works by reducing the production of certain growth factors that are involved in the formation of scar tissue in the lungs, thereby slowing down the progression of the disease..

Pirfenidone is well absorbed from the gastrointestinal tract and reaches peak plasma concentrations within 2-4 hours after oral administration. Pirfenidone is widely distributed throughout the body, with a volume of distribution of approximately 0.5 L/kg. It is highly protein-bound (more than 99%) and does not readily cross the blood-brain barrier. It reaches peak plasma concentrations within 1-2 hours of ingestion. Pirfenidone is metabolized in the liver primarily by cytochrome P450 (CYP) 1A2 and CYP2C9 enzymes to several inactive metabolites. The metabolism of pirfenidone is not affected by other drugs that inhibit or induce CYP enzymes. Pirfenidone is primarily excreted in the urine (approximately 80%) and feces (approximately 20%). The elimination half-life of pirfenidone is approximately 2-4 hours.

The Tmax is approximately 2-4 hours after administration.

Cmax of Pirfenidone after a single oral dose 0.5-0.7 mg/mL

Pirfenidone shows common side effects like Drowsiness or tiredness, Dry mouth, Headache, Nausea, Dizziness, Sore throat, Abdominal pain, Diarrhea and Vomiting .

Pirfenidone is available in tablets and capsules.

Pirfenidone is available in India, Germany, Canada, France.

The exact mechanism of action of pirfenidone is not fully understood, but it is believed to have anti-inflammatory, antioxidant, and anti-fibrotic properties, which make it useful in the treatment of idiopathic pulmonary fibrosis (IPF).

Pirfenidone works by reducing the production of certain growth factors and cytokines, such as transforming growth factor-beta (TGF-β) and tumor necrosis factor-alpha (TNF-α), which are involved in the formation of scar tissue in the lungs. By inhibiting these factors, pirfenidone helps to slow down the progression of IPF and improve lung function.

Pirfenidone is available in the form of tablets and capsules.

Perfenidone is used in the treatment of idiopathic pulmonary fibrosis.

The main benefit of pirfenidone is its ability to slow down the progression of idiopathic pulmonary fibrosis (IPF), a progressive lung disease that leads to scarring of the lung tissue and difficulty breathing. In clinical studies, pirfenidone has been shown to significantly reduce the decline in lung function and improve the quality of life of patients with IPF.

Perfenidone is approved for the use of following clinical indications:

Idiopathic pulmonary fibrosis: Treatment of idiopathic pulmonary fibrosis.

Oral

Idiopathic pulmonary fibrosis

Adult: Initially, 267 mg tid for 7 days, then increase dose to 534 mg tid for 7 days, then to usual maintenance dose: 801 mg tid. Max: 2403 mg daily. Adjust dosage according to toxicity.

Pirfenidone is available in the dosage strength of

• Tablets: 267 and 801mg
• Capsule: 267mg

Pirfenidone is available in the form of tablets and capsules.

• Dosage Adjustment in Kidney Patient

CrCl ≥30 mL/minute: There are no dosage adjustments provided in the manufacturer’s labeling. Use with caution; consider dose modification or discontinuation as needed.

CrCl <30 mL/minute: There are no dosage adjustments provided in the manufacturer’s labeling. Use with caution; consider dose modification or discontinuation as needed.

End-stage kidney disease requiring dialysis: Use is not recommended.

• Dosage Adjustment in Hepatic impairment Patient

Hepatic impairment prior to treatment initiation:

Mild to moderate impairment (Child-Pugh class A and B): There are no dosage adjustments provided in the manufacturer’s labeling. Use with caution; consider dose modification or discontinuation as needed.

Severe impairment (Child-Pugh class C): Use is not recommended (has not been studied).

Hepatotoxicity during treatment:

ALT/AST >3 to ≤5 × ULN without hyperbilirubinemia or symptoms: Rule out alternative causes and discontinue potentially confounding medications. As clinically appropriate, may continue current dose, may reduce dose (specific dosing reductions are not provided in manufacturer’s labeling), or may temporarily discontinue therapy. Once aminotransferase elevations have resolved, may be re-titrated to the recommended daily dose. Monitor LFTs closely thereafter.

ALT/AST >3 to ≤5 × ULN with hyperbilirubinemia or symptoms: Discontinue therapy promptly and do not reinitiate.

ALT/AST >5 × ULN (regardless of serum bilirubin concentrations): Discontinue therapy promptly and do not reinitiate.

Take after eating and with a full glass of water to decrease gastric upset.

Hypersensitivity: Pirfenidone should not be used in individuals who have a known hypersensitivity or allergy to the medication or any of its components.

Severe hepatic impairment: Pirfenidone is contraindicated in patients with severe hepatic impairment (Child-Pugh Class C).

End-stage renal disease: Pirfenidone is contraindicated in patients with end-stage renal disease requiring dialysis.

Pregnancy and breastfeeding: Pirfenidone is contraindicated in pregnancy and breastfeeding, as it may cause fetal harm or be excreted in breast milk.

Use with strong CYP1A2 inhibitors: Pirfenidone is contraindicated in patients receiving strong CYP1A2 inhibitors, such as fluvoxamine, due to the risk of increased pirfenidone exposure and potential adverse effects.

Concerns related to adverse effects:

• CNS depression: May cause drowsiness in some patients; instruct patient to use caution when driving or operating machinery. Effects may be additive with CNS depressants and/or ethanol.

• Nasal ulcerations: Periodically examine nasal mucosa for ulceration and consider discontinuing if ulceration occurs.

Pirfenidone may cause liver problems, and using it with substantial quantities of ethanol may increase that risk.

Pirfenidone is present in breast milk.

Pirfenidone is contraindicated during breastfeeding, as it is not known whether pirfenidone or its metabolites are excreted in human milk. There is a potential risk of serious adverse reactions in nursing infants, and it is recommended that women should not breastfeed during treatment with pirfenidone.

Decreased absorption with food. May increase toxicity with grapefruit juice.

• Common Adverse effects:

Eye irritation or burning (when used as eye drops), Headache, Taste disturbances, Dry mouth, Fatigue or drowsiness, Dizziness, Nausea.

• Less Common Adverse effects:

Nausea, vomiting, diarrhoea, dyspepsia, GERD, abdominal pain, photosensitivity, weight loss, dizziness, increased ALT/AST, angioedema. Rarely, hyperbilirubinaemia. Gastrointestinal disorders: Constipation, flatulence, gastritis. General disorders and administration site conditions: Fatigue, asthenia, lethargy, non-cardiac chest pain. Investigations: Increased γ-glutamyl transferase. Metabolism and nutrition disorders: Anorexia, decreased appetite. Musculoskeletal and connective tissue disorders: Myalgia, arthralgia. Nervous system disorders: Headache, dysgeusia. Psychiatric disorders: Insomnia, somnolence. Renal and urinary disorders: UTI

• Rare Adverse effects

Severe allergic reaction, such as swelling of the face, lips, tongue, or throat, difficulty breathing, or hives, Respiratory, thoracic and mediastinal disorders: Dyspnoea, cough, upper respiratory tract infection. Skin and subcutaneous tissue disorders: Rash, pruritus, erythema, dry skin, sunburn. Vascular disorders: Hot flush.

Increased toxicity with strong (e.g. fluvoxamine) and moderate (e.g. ciprofloxacin) CYP1A2 inhibitors. Decreased efficacy with CYP1A2 inducers (e.g. omeprazole).

The common side effects of Pirfenidone include the following :

Symptoms: Confusion, diarrhea, dizziness, fatigue, headache, malaise, mydriasis, pruritus, restlessness, sedation, somnolence, stupor, tachycardia, tremor, and urinary retention.

Management: Symptomatic and supportive treatment. Gastric lavage may be performed following early ingestion.

Pharmacodynamic

Pirfenidone, a piperazine derivative and metabolite of hydroxyzine, is an antihistamine which competitively and selectively inhibits H1 receptors in the gastrointestinal tract, blood vessels, and respiratory tract.

Pharmacokinetics

• Absorption: Absorbed from the gastrointestinal tract. Decreased absorption with food. Time to peak plasma concentration: 30 minutes to 4 hours.

• Distribution: Volume of distribution: Approx 59-71 L. Plasma protein binding: 50-58% mainly to albumin.

• Metabolism: Metabolised in the liver mainly by CYP1A2 and to a lesser extent by CYP2C9, 2C19, 2D6 and 2E1 into metabolites including 5-carboxy-pirfenidone.

• Excretion: Mainly via urine (approx 80%; >95% as 5-carboxy-pirfenidone and <1% as unchanged drug). Terminal elimination half-life: Approx 3 hours.

1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1364710/
2. https://reference.medscape.com/drug/colestid-Pirfenidone -342452
3. https://go.drugbank.com/drugs/DB00375
4. https://www.sciencedirect.com/topics/medicine-and-dentistry/Pirfenidone
5. https://europepmc.org/article/med/6988203