|Jmol-3D images||Image 1|
|Molar mass||185.22 g mol−1|
|Solubility in water||10 mg/mL at 60 °C|
|Solubility in DMSO||20 mg/mL|
| (what is: / ?)
Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa)
Pirfenidone is a drug developed by InterMune Inc. for the treatment of idiopathic pulmonary fibrosis (IPF). In 2011 it was approved for use in Europe for IPF under the trade name Esbriet. The proposed trade name in the US is also Esbriet.
In Japan it is marketed as Pirespa by Shionogi & Co. In October 2010, the Indian Company Cipla launched it as Pirfenex. In September 2011, the Chinese State Food and Drug Administration provided GNI Group Ltd with approval of pirfenidone in China.
- 1 Mechanism of action
- 2 Preclinical studies
- 3 Pharmacokinetics
- 4 Clinical trials in Idiopathic Pulmonary Fibrosis (IPF)
- 5 Indication
- 6 Adverse effects
- 7 Interactions
- 8 Regulatory progress
- 9 References
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 TGF-β stimulated collagen production and reduces the production of fibrogenic mediators such as TGF-β. Pirfenidone has also been shown to reduce production of inflammatory mediators such as TNF-α 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.
Studies in models of fibrosis
Pirfenidone demonstrates a consistent antifibrotic effect in several animal models of pulmonary fibrosis. Of these, the bleomycin model is the most widely used model of pulmonary fibrosis. In this model, bleomycin administration results in oxidative stress and acute inflammation, with the subsequent onset of pulmonary fibrosis in a number of animal species including the mouse and hamster. Numerous studies have demonstrated that pirfenidone attenuates bleomycin-induced pulmonary fibrosis. One study investigated the effect of pirfenidone over a 42-day period after repeated bleomycin administration. Administration of pirfenidone minimised early lung oedema and pulmonary fibrosis when treatment was initiated concurrently with lung damage. This study evaluated pulmonary protein expression and found pirfenidone treatment normalised expression of pro-inflammatory and fibrogenic proteins. Similar reductions in pulmonary fibrosis were observed when pirfenidone treatment was delayed until pulmonary fibrosis was established and progressing, i.e. when administered in a therapeutic as opposed to a prophylactic treatment regimen.
The antifibrotic effect of pirfenidone has been further established in animal models of cardiac, renal, and hepatic fibrosis. In these models, pirfenidone demonstrated a consistent ability to reduce fibrosis and the expression of fibrogenic mediators.
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.
Clinical trials in Idiopathic Pulmonary Fibrosis (IPF)
The clinical efficacy of pirfenidone has been studied in three Phase III, randomized, double-blind, placebo-controlled studies in patients with IPF. The first Phase III clinical trial to evaluate the efficacy and safety of pirfenidone for the treatment of patients with IPF was conducted in Japan. This was a multicentre, randomised, double-blind, trial, in which 275 patients with IPF 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. The CAPACITY (004 & 006) studies were randomized, double-blind, placebo-controlled Phase III trials in eleven countries across Europe, North America, and Australia. Patients with IPF were randomly assigned to treatment with oral pirfenidone or placebo for a minimum of 72 weeks. In study 004, pirfenidone reduced decline in forced vital capacity (FVC) (p=0.001). Mean change in FVC at week 72 was –8.0% (SD 16.5) in the pirfenidone 2403 mg/day group and –12.4% (SD 18.5) in the placebo group, a difference of 4.4% (95% CI 0.7 to 9.1). Thirty-five (20%) of 174 versus 60 (35%) of 174 patients, respectively, had an FVC decline of at least 10%. In study 006, the difference between groups in FVC change at week 72 was not significant (p=0.501). Mean change in FVC at week 72 was –9.0% (SD 19.6) in the pirfenidone group and –9.6% (19.1) in the placebo group. The difference between groups in change in predicted FVC at week 72 was not significant (0.6%, 95% CI –3.5 to 4.7).
A recent review by the Cochrane Collaboration concluded that pirfenidone appears to improve progression-free survival and, to a lesser effect, pulmonary function in patients with IPF. Randomised studies comparing non-steroid drugs with placebo or steroids in adult patients with IPF were included. Four placebo-controlled trials of pirfenidone treatment were reviewed, involving a total of 1155 patients. The result of the meta-analysis showed that pirfenidone significantly reduces the risk of disease progression by 30%. In addition, meta-analysis of the two Japanese studies confirmed the beneficial effect of pirfenidone on the change in VC from baseline compared with placebo.
In Europe, pirfenidone is indicated for the treatment of mild-to-moderate idiopathic pulmonary fibrosis. It was approved by the European Medicines Agency (EMA) in 2011. In October 2008 it was approved for use in Japan, and in India in 2010.
Pirfenidone is frequently associated with gastrointestinal side effects such as dyspepsia, nausea, gastritis, gastroesophageal reflux disease (GERD) and vomiting.To reduce the severity of these reactions, pirfenidone is to be taken after meals.
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 sunscreen agents. Continuing photosensitivity reactions are usually managed by dose adjustment and temporary discontinuation of treatment if required, along with local symptomatic treatment.
Pirfenidone can increase hepatic enzyme levels, especially those of aspartate transaminase (AST), alanine transaminase (ALT) and gamma-glutamyl transpeptidase (GGT); 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 has been reported in patients treated with pirfenidone. Doctors should monitor patients’ weight and encourage increased calorific intake if necessary.
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 CYP enzymes other than CYP1A2. Consequently, strong inhibitors of other CYP systems such as fluconazole (CYP2C9), chloramphenicol (CYP2C19), fluoxetine and paroxetine (both CYP2D6) should be used with caution.
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.
In May 2010, the U.S. Food and Drug Administration declined to approve the use of pirfenidone for the treatment of idiopathic pulmonary fibrosis, requesting additional clinical trials. A randomised, Phase III trial (the ASCEND study) is currently underway in the U.S. In December 2010 an advisory panel to the European Medicines Agency recommended approval of the drug. In February 2011 the European Commission (EC) has granted marketing authorisation in all 27 EU member states.
- Pirfenidone at Sigma-Aldrich
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