Pirfenidone, sold under the brand name Esbriet among others, is a medication used for the treatment of idiopathic pulmonary fibrosis. It works by reducing lung fibrosis through downregulation of the production of growth factors and procollagens I and II. It was first approved in Japan for the treatment of people with idiopathic pulmonary fibrosis after clinical trials in 2008. It was approved for use in the European Union in 2011, in Canada in 2012, and in the United States in October 2014. It is available as a generic medication.
Medical uses In the European Union, pirfenidone is indicated for the treatment of mild-to-moderate idiopathic pulmonary fibrosis. It was approved by the European Medicines Agency in 2011. In October 2008, it was approved for use in Japan, in India in 2010, and in China in 2011 (commercial launch in 2014). In October 2014, it was approved for medical use in the United States. A tablet version was approved for use in the United States in January 2017. In Mexico it was approved as a gel for the treatment of scars and fibrotic tissue.
Adverse effects
Gastrointestinal Pirfenidone is frequently associated with gastrointestinal side effects such as dyspepsia, nausea, gastritis, gastroesophageal reflux disease and vomiting. To reduce the severity of these reactions, pirfenidone is to be taken after meals.
Skin Pirfenidone is known to cause photosensitivity reactions, rash, pruritus and dry skin. Patients are usually advised to avoid direct exposure to sunlight, including sun lamps, and to use protective clothing and sunscreening agents. Continuing photosensitivity reactions are usually managed by dose adjustment and temporary discontinuation of treatment if required, along with local symptomatic treatment.
Hepatic dysfunction Pirfenidone can increase hepatic enzyme levels, especially those of aspartate transaminase, alanine transaminase and gamma-glutamyl transpeptidase; periodic monitoring of hepatic enzyme levels is required during therapy: once before the initiation of therapy, monthly monitoring until 6 months after initiation of therapy, and 3 monthly thereafter. Extra precaution is required while prescribing the drug in patients with hepatic impairment and in patients who are concomitantly taking a CYP1A2 inhibitor. The drug is contraindicated in patients who have severe hepatic impairment.
Dizziness and fatigue Dizziness and fatigue have been reported in patients undergoing pirfenidone treatment. Dizziness typically resolves, although patients should know how they react to pirfenidone before undertaking activities that need mental alertness or coordination. If severe, dose adjustment or treatment discontinuation may be required.
Weight loss Weight loss has been reported in patients treated with pirfenidone. Doctors should monitor patients' weight and encourage increased caloric intake if necessary.
Interactions Most drug interactions are mediated by various cytochrome P450 enzymes.
CYP1A2 inhibitors Since Pirfenidone is metabolised through the CYP1A2 enzyme pathway, any drug which inhibits this enzyme is likely to precipitate the toxicity of pirfenidone: concomitant therapy is to be avoided. Fluvoxamine is contraindicated in patients who are on treatment with pirfenidone. Other inhibitors of CYP1A2 such as ciprofloxacin, amiodarone and propafenone should be used with caution.
Other CYP inhibitors Some pirfenidone is also metabolized by cytochrome P450 enzymes other than CYP1A2. Consequently, strong inhibitors of other cytochrome P450 enzymes such as fluconazole (CYP2C9), chloramphenicol (CYP2C19), fluoxetine and paroxetine (both CYP2D6) should be used with caution.
CYP1A2 inducers Moderate inducers of CYP1A2 such as omeprazole should be used with caution since they might reduce the circulating plasma levels of the drug.
Cigarette smoking Cigarette smoking causes increased clearance of pirfenidone by inducing CYP1A2, thereby decreasing exposure to the drug. Patients must be advised to abstain from cigarette smoking while on therapy with pirfenidone.
Pharmacology
Mechanism of action Pirfenidone has well-established antifibrotic and anti-inflammatory properties in various in vitro systems and animal models of fibrosis. A number of cell-based studies have shown that pirfenidone reduces fibroblast proliferation, inhibits transforming growth factor beta stimulated collagen production and reduces the production of fibrogenic mediators such as transforming growth factor beta. Pirfenidone has also been shown to reduce production of inflammatory mediators such as tumor necrosis factor alpha and IL-1β in both cultured cells and isolated human peripheral blood mononuclear cells. These activities are consistent with the broader antifibrotic and anti-inflammatory activities observed in animal models of fibrosis.
Pharmacokinetics Pirfenidone is administered orally. Though the presence of food significantly reduces the extent of absorption, the drug is to be taken after food, to reduce the nausea and dizziness associated with the drug. The drug is around 60% bound to plasma proteins, especially to albumin. Up to 50% of the drug is metabolized by hepatic CYP1A2 enzyme system to yield 5-carboxypirfenidone, the inactive metabolite. Almost 80% of the administered dose is excreted in the urine within 24 hours of intake.
History The drug was developed by several companies worldwide, including the original patent holder, Marnac, InterMune (now part of Roche), Shionogi, and GNI Group. In August 2023, Roche subsidiary Genentech sued Novartis in a New Jersey court. The lawsuit asserts that Novartis subsidiary Sandoz did not apply for a license when it began to sell pirfenidone in the U.S. market. Esbriet had a revenue of $740 million in the U.S. market (2021), and Genentech alleges that Sandoz's unlawful sale of pirfenidone has caused "significant financial harm."
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