| Pirfenidone[1] | |
|---|---|
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5-Methyl-1-phenylpyridin-2-one |
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| Identifiers | |
| CAS number | 53179-13-8 |
| PubChem | 40632 |
| KEGG | D01583 |
| ChEMBL | CHEMBL1256391 |
| ATC code | L04 |
| Jmol-3D images | Image 1 |
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| Properties | |
| Molecular formula | C12H11NO |
| Molar mass | 185.22 g mol−1 |
| Solubility in water | 10 mg/mL at 60 °C |
| Solubility in DMSO | 20 mg/mL |
| Hazards | |
| R-phrases | R22 |
| S-phrases | S36 |
| (verify) (what is: /?) Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa) |
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| Infobox references | |
Pirfenidone is a drug developed by InterMune Inc. for the treatment of idiopathic pulmonary fibrosis. In 2011 it was approved for use in Europe for idiopathic pulmonary fibrosis (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.[2] In October 2010, the Indian Company Cipla launched it as Pirfenex.
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Pirfenidone has proven antifibrotic and anti-inflammatory properties in various in vitro systems and animal models of pulmonary fibrosis, although its precise mechanism of action remains unclear. It attenuates fibroblast proliferation, production of fibrosis-associated proteins and cytokines, and the increased biosynthesis and accumulation of extracellular matrix in response to cytokines such as transforming growth factor-β.[3] It is also shown to slow tumor cell proliferation by inhibiting fibroblast growth factor, epidermal growth factor and platelet-derived growth factor.[4]
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.[5]
Pirfenidone is indicated in the treatment of idiopathic pulmonary fibrosis.
Pirfenidone is contraindicated in patients who have documented hypersensitivity to pirfenidone. It is also contraindicated in patients with severe hepatic impairment and renal impairment. Pirfenidone is contraindicated in patients who are on concomitant therapy with any of the CYP1A2 inhibitors such as fluvoxamine.[5]
Pirfenidone is frequently associated with gastrointestinal side effects such as dyspepsia, nausea, diarrhea, 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. The photosensitivity reactions can be troublesome; there is also the risk of carcinogenic transformation of skin after direct exposure to sunlight. Patients are usually advised to avoid direct exposure to sunlight, including sun lamps, by using protective clothing and sunscreen agents. When developed, photosensitivity reactions are usually managed by dose adjustment and temporary discontinuation of treatment if required, along with local symptomatic treatment.[5]
Pirfenidone is known to increase hepatic enzyme levels, esecially 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 upto 6 months after initiation of therapy, and 3 monthly therearter. Extra precaution is required while prescribing the drug in patients with hepatic impairment and in patients who are on concomitant therapy with CYP1A2 inhibitors. The drug is contraindicated in patients who have severe hepatic impairment.
Dizziness and fatigue are very frequently reported adverse drug reactions with pirfenidone.The severity of these reactions may be reduced if the drug is taken with food. If severe, treatment discontinuation may be required.[5]
Pirfenidone is reported to cause weight loss in various clinical trials.
Most drug interactions are mediated by various cytochrome P450 (CYP) enzymes.[5]
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 being one such drug is in fact contraindicated in patients who are on treatment with pirfenidone. Other inhibitors of CYP1A2 such as ciprofloxacin, amiodarone and propafenone should be used with caution.
Some amount of 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.
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 causes increased clearance of pirfenidone by inducing CYP1A2. 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.[6]
In December 2010 an advisory panel to the European Medicines Agency recommended approval of the drug.[7] In March 2011 the European Commission (EC) has granted marketing authorization in all 27 EU member states.[8]
This compound is also being studied to treat end stage kidney disease through its blocking action on transforming growth factor beta.[9]