Pirfenidone
Clinical data | |
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Trade names | Esbriet, Pirespa, Etuary |
AHFS/Drugs.com | Monograph |
MedlinePlus | a615008 |
License data |
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Pregnancy category |
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Routes of administration | By mouth |
ATC code | |
Legal status | |
Legal status | |
Pharmacokinetic data | |
Protein binding | 50–58%[7] |
Metabolism | Liver (70–80% CYP1A2-mediated; minor contributions from CYP2C9, CYP2C19, CYP2D6 and CYP2E1)[7] |
Elimination half-life | 2.4 hours[7] |
Excretion | Urine (80%)[7] |
Identifiers | |
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JSmol) | |
Solubility in water | 10mg/mL at 60 °C |
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Pirfenidone, sold under the brand name Pirespa among others, is a
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,[8][6] in Canada in 2012,[4] and in the United States in October 2014.[5][9]
It is available as a
Medical uses
In the European Union, pirfenidone is
In Mexico it was approved as a gel[12] for the treatment of scars and fibrotic tissue.[13]
Adverse effects
Gastrointestinal
Pirfenidone is frequently associated with gastrointestinal side effects such as
Skin
Pirfenidone is known to cause
Hepatic dysfunction
Pirfenidone can increase hepatic enzyme levels, especially those of
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.[14]
Weight loss
Weight loss has been reported in patients treated with pirfenidone. Doctors should monitor patients’ weight and encourage increased caloric intake if necessary.[14]
Interactions
Most drug interactions are mediated by various cytochrome P450 enzymes.[14]
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.[14]
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.[14]
CYP1A2 inducers
Moderate
Cigarette smoking
Cigarette smoking causes increased
Pharmacology
Mechanism of action
Pirfenidone has well-established
Pharmacokinetics
Pirfenidone is administered orally. Though the presence of food significantly reduces the extent of
History
The drug was developed by several companies worldwide, including the original patent holder,
.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."[26]
Preclinical studies in models of fibrosis
In animal models, pirfenidone displays a systemic antifibrotic activity and has been shown to reduce
Pirfenidone demonstrates a consistent antifibrotic effect in several animal models of
The antifibrotic effect of pirfenidone has been further established in animal models of
Pirfenidone has also been shown to inhibit spondyloarthritis fibroblast-like synoviocytes and osteoblasts in vitro.[43]
Clinical trials in idiopathic pulmonary fibrosis
The clinical efficacy of pirfenidone has been studied in three
The first Phase III clinical trial to evaluate the efficacy and safety of pirfenidone for the treatment of patients with idiopathic pulmonary fibrosis was conducted in Japan. This was a multicentre, randomised, double-blind, trial, in which 275 patients with idiopathic pulmonary fibrosis were randomly assigned to receive pirfenidone 1800 mg/day (110 patients), pirfenidone 1200 mg/day (56 patients), or placebo (109 patients), for 52 weeks. Pirfenidone 1800 or 1200 mg/day reduced the mean decline in vital capacity from baseline to week 52 compared with placebo. Progression-free survival was also improved with pirfenidone compared with placebo.[44]
Two randomized, double-blind, placebo-controlled Phase III studies in eleven countries across Europe, North America, and Australia.
In May 2014, the results of another randomized, double-blind, placebo-controlled trial that enrolled 555 patients were published. They confirmed observations from previous clinical studies that pirfenidone significantly reduced the progression of idiopathic pulmonary fibrosis as measured by change in percent predicted forced vital capacity from baseline to week 52. In addition, significant treatment effects were shown on both of the key secondary endpoints of six-minute walk test distance change and progression-free survival. A pre-specified analysis of the pooled population of 1,247 subjects from three studies showed that the risk of all-cause mortality was reduced by 48% in the pirfenidone group compared to the placebo group.[46]
A review by the
Regulatory progress
In May 2010, the U.S. Food and Drug Administration (FDA) declined to approve the use of pirfenidone for the treatment of idiopathic pulmonary fibrosis, requesting additional clinical trials.[48] In December 2010, an advisory panel to the European Medicines Agency (EMA) recommended approval of the drug.[8] In February 2011, the European Commission granted marketing authorisation in all 27 EU member states and the China Food and Drug Administration granted approval in September 2011. Afterwards, a randomised, Phase III trial was completed in the U.S. in 2014,[49] with regulatory approval in U.S. following shortly after.
In October 2010, the Indian Company
In 2014, it was approved in Mexico under the name KitosCell LP, indicated for pulmonary fibrosis and liver fibrosis.[52] In Mexico it has also been approved in gel for the treatment of chronic wounds and skin injuries and the oral form it is approved for the treatment of pulmonary fibrosis and liver fibrosis.[citation needed]
Research
Other research shows that pirfenidone may be an effective anti-fibrotic treatment
References
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{{cite web}}
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- ^ A controlled clinical trial with pirfenidone in the treatment of pathological skin scarring caused by burns in pediatric patients, annals of plastic surgery, volume 68, number 1, January 2012
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