Pirfenidone
Encyclopedia
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. In October 2010, the Indian Company Cipla launched it as Pirfenex.
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. It is also shown to slow tumor cell proliferation by inhibiting fibroblast growth factor
, epidermal growth factor
and platelet-derived growth factor
.
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.
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
.
, nausea
, diarrhea
, gastroesophageal reflux disease
(GERD) and vomiting
. To reduce the severity of these reactions, pirfenidone is to be taken after meals.
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.
(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.
and fatigue
are very frequently reported adverse drug reactions with pirfenidone.The severity of these reactions may be reduced if the drug is taken after food. If severe, treatment discontinuation may be required.
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.
(CYP2C9
), chloramphenicol
(CYP2C19
), fluoxetine
and paroxetine
(both CYP2D6
) should be used with caution.
should be used with caution since they might reduce the circulating plasma levels of the drug.
of pirfenidone by inducing CYP1A2. Patients must be advised to abstain from cigarette
smoking
while on therapy with pirfenidone.
In December 2010 an advisory panel to the European Medicines Agency
recommended approval of the drug. In March 2011 the European Commission
(EC) has granted marketing authorization in all 27 EU member states.
Idiopathic pulmonary fibrosis
Idiopathic pulmonary fibrosis is a chronic, progressive form of lung disease characterized by fibrosis of the supporting framework of the lungs...
. In 2011 it was approved for use in Europe for idiopathic pulmonary fibrosis
Idiopathic pulmonary fibrosis
Idiopathic pulmonary fibrosis is a chronic, progressive form of lung disease characterized by fibrosis of the supporting framework of the lungs...
(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.
Mechanism of action
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 fibroblastFibroblast
A fibroblast is a type of cell that synthesizes the extracellular matrix and collagen, the structural framework for animal tissues, and plays a critical role in wound healing...
proliferation, production of fibrosis-associated proteins and cytokines, and the increased biosynthesis and accumulation of extracellular matrix
Extracellular matrix
In biology, the extracellular matrix is the extracellular part of animal tissue that usually provides structural support to the animal cells in addition to performing various other important functions. The extracellular matrix is the defining feature of connective tissue in animals.Extracellular...
in response to cytokines such as transforming growth factor-β. It is also shown to slow tumor cell proliferation by inhibiting fibroblast growth factor
Fibroblast growth factor
Fibroblast growth factors, or FGFs, are a family of growth factors involved in angiogenesis, wound healing, and embryonic development. The FGFs are heparin-binding proteins and interactions with cell-surface associated heparan sulfate proteoglycans have been shown to be essential for FGF signal...
, epidermal growth factor
Epidermal growth factor
Epidermal growth factor or EGF is a growth factor that plays an important role in the regulation of cell growth, proliferation, and differentiation by binding to its receptor EGFR...
and platelet-derived growth factor
Platelet-derived growth factor
In molecular biology, platelet-derived growth factor is one of the numerous growth factors, or proteins that regulate cell growth and division. In particular, it plays a significant role in blood vessel formation , the growth of blood vessels from already-existing blood vessel tissue. Uncontrolled...
.
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 CYP1A2CYP1A2
Cytochrome P450 1A2 , a member of the cytochrome P450 mixed-function oxidase system, is involved in the metabolism of xenobiotics in the body...
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.
Contraindications
Pirfenidone is contraindicated in patients who have documented hypersensitivityHypersensitivity
Hypersensitivity refers to undesirable reactions produced by the normal immune system, including allergies and autoimmunity. These reactions may be damaging, uncomfortable, or occasionally fatal. Hypersensitivity reactions require a pre-sensitized state of the host. The four-group classification...
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
Fluvoxamine
Fluvoxamine is an antidepressant which functions as a selective serotonin reuptake inhibitor . Fluvoxamine was first approved by the U.S. Food and Drug Administration in 1993 for the treatment of obsessive compulsive disorder . Fluvoxamine CR is approved to treat social anxiety disorder...
.
Gastrointestinal
Pirfenidone is frequently associated with gastrointestinal side effects such as dyspepsiaDyspepsia
Dyspepsia , also known as upset stomach or indigestion, refers to a condition of impaired digestion. It is a medical condition characterized by chronic or recurrent pain in the upper abdomen, upper abdominal fullness and feeling full earlier than expected when eating...
, nausea
Nausea
Nausea , is a sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit. It often, but not always, precedes vomiting...
, diarrhea
Diarrhea
Diarrhea , also spelled diarrhoea, is the condition of having three or more loose or liquid bowel movements per day. It is a common cause of death in developing countries and the second most common cause of infant deaths worldwide. The loss of fluids through diarrhea can cause dehydration and...
, gastroesophageal reflux disease
Gastroesophageal reflux disease
Gastroesophageal reflux disease , gastro-oesophageal reflux disease , gastric reflux disease, or acid reflux disease is chronic symptoms or mucosal damage caused by stomach acid coming up from the stomach into the esophagus...
(GERD) and vomiting
Vomiting
Vomiting is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose...
. To reduce the severity of these reactions, pirfenidone is to be taken after meals.
Skin
Pirfenidone is known to cause photosensitivityPhotosensitivity
Photosensitivity is the amount to which an object reacts upon receiving photons, especially visible light.- Human medicine :Sensitivity of the skin to a light source can take various forms. People with particular skin types are more sensitive to sunburn...
reactions, rash
Rash
A rash is a change of the skin which affects its color, appearance or texture. A rash may be localized in one part of the body, or affect all the skin. Rashes may cause the skin to change color, itch, become warm, bumpy, chapped, dry, cracked or blistered, swell and may be painful. The causes, and...
, 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
Sunscreen
Sunblock is a lotion, spray, gel or other topical product that absorbs or reflects some of the sun's ultraviolet radiation on the skin exposed to sunlight and thus helps protect against sunburn...
agents. When developed, photosensitivity reactions are usually managed by dose adjustment and temporary discontinuation of treatment if required, along with local symptomatic treatment.
Hepatic dysfunction
Pirfenidone is known to increase hepatic enzyme levels, esecially those of aspartate transaminaseAspartate transaminase
Aspartate transaminase , also called aspartate aminotransferase or serum glutamic oxaloacetic transaminase , is a pyridoxal phosphate -dependent transaminase enzyme . AST catalyzes the reversible transfer of an α-amino group between aspartate and glutamate and, as such, is an important enzyme in...
(AST), alanine transaminase
Alanine transaminase
Alanine transaminase or ALT is a transaminase enzyme . It is also called serum glutamic pyruvic transaminase or alanine aminotransferase ....
(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
CYP1A2
Cytochrome P450 1A2 , a member of the cytochrome P450 mixed-function oxidase system, is involved in the metabolism of xenobiotics in the body...
inhibitors. The drug is contraindicated in patients who have severe hepatic impairment.
Dizziness and fatigue
DizzinessDizziness
Dizziness refers to an impairment in spatial perception and stability. The term is somewhat imprecise. It can be used to mean vertigo, presyncope, disequilibrium, or a non-specific feeling such as giddiness or foolishness....
and fatigue
Fatigue
Fatigue may refer to:*Fatigue , structural damage from repeated loading*Fatigue , a state of physical and/or mental weakness*Fatigue , safety implications of tiredness...
are very frequently reported adverse drug reactions with pirfenidone.The severity of these reactions may be reduced if the drug is taken after food. If severe, treatment discontinuation may be required.
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. FluvoxamineFluvoxamine
Fluvoxamine is an antidepressant which functions as a selective serotonin reuptake inhibitor . Fluvoxamine was first approved by the U.S. Food and Drug Administration in 1993 for the treatment of obsessive compulsive disorder . Fluvoxamine CR is approved to treat social anxiety disorder...
being one such drug is in fact contraindicated in patients who are on treatment with pirfenidone. Other inhibitors of CYP1A2 such as ciprofloxacin
Ciprofloxacin
Ciprofloxacin is a synthetic chemotherapeutic antibiotic of the fluoroquinolone drug class.It is a second-generation fluoroquinolone antibacterial. It kills bacteria by interfering with the enzymes that cause DNA to rewind after being copied, which stops synthesis of DNA and of...
, amiodarone
Amiodarone
Amiodarone is an antiarrhythmic agent used for various types of tachyarrhythmias , both ventricular and supraventricular arrhythmias. Discovered in 1961, it was not approved for use in the United States until 1985...
and propafenone
Propafenone
Propafenone is a class Ic anti-arrhythmic medication, which treats illnesses associated with rapid heart beats such as atrial and ventricular arrhythmias.-Mechanism of action:...
should be used with caution.
Other CYP inhibitors
Some amount of pirfenidone is also metabolized by CYP enzymes other than CYP1A2. Consequently, strong inhibitors of other CYP systems such as fluconazoleFluconazole
Fluconazole is a triazole antifungal drug used in the treatment and prevention of superficial and systemic fungal infections. In a bulk powder form, it appears as a white crystalline powder, and it is very slightly soluble in water and soluble in alcohol. It is commonly marketed under the trade...
(CYP2C9
CYP2C9
Cytochrome P450 2C9 is a protein that in humans is encoded by the CYP2C9 gene.- Function :CYP2C9 is an important cytochrome P450 enzyme with a major role in the oxidation of both xenobiotic and endogenous compounds. CYP2C9 makes up about 18% of the cytochrome P450 protein in liver microsomes...
), chloramphenicol
Chloramphenicol
Chloramphenicol is a bacteriostatic antimicrobial that became available in 1949. It is considered a prototypical broad-spectrum antibiotic, alongside the tetracyclines, and as it is both cheap and easy to manufacture it is frequently found as a drug of choice in the third world.Chloramphenicol is...
(CYP2C19
CYP2C19
Cytochrome P450 2C19 , a member of the cytochrome P450 mixed-function oxidase system, is involved in the metabolism of xenobiotics in the body. It is involved in the metabolism of several...
), fluoxetine
Fluoxetine
Fluoxetine is an antidepressant of the selective serotonin reuptake inhibitor class. It is manufactured and marketed by Eli Lilly and Company...
and paroxetine
Paroxetine
Paroxetine is an SSRI antidepressant. Marketing of the drug began in 1992 by the pharmaceutical company SmithKline Beecham, now GlaxoSmithKline...
(both CYP2D6
CYP2D6
Cytochrome P450 2D6 , a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. Also, many substances are bioactivated by CYP2D6 to form their active compounds...
) should be used with caution.
CYP1A2 inducers
Moderate inducers of CYP1A2 such as omeprazoleOmeprazole
Omeprazole is a proton pump inhibitor used in the treatment of dyspepsia, peptic ulcer disease , gastroesophageal reflux disease , laryngopharyngeal reflux and Zollinger–Ellison syndrome...
should be used with caution since they might reduce the circulating plasma levels of the drug.
Cigarette smoking
Cigarette smoking causes increased clearanceClearance (medicine)
In medicine, the clearance is a measurement of the renal excretion ability. Although clearance may also involve other organs than the kidney, it is almost synonymous with renal clearance or renal plasma clearance. Each substance has a specific clearance that depends on its filtration characteristics...
of pirfenidone by inducing CYP1A2. Patients must be advised to abstain from cigarette
Cigarette
A cigarette is a small roll of finely cut tobacco leaves wrapped in a cylinder of thin paper for smoking. The cigarette is ignited at one end and allowed to smoulder; its smoke is inhaled from the other end, which is held in or to the mouth and in some cases a cigarette holder may be used as well...
smoking
Smoking
Smoking is a practice in which a substance, most commonly tobacco or cannabis, is burned and the smoke is tasted or inhaled. This is primarily practised as a route of administration for recreational drug use, as combustion releases the active substances in drugs such as nicotine and makes them...
while on therapy with pirfenidone.
Regulatory progress
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.In December 2010 an advisory panel to the European Medicines Agency
European Medicines Agency
The European Medicines Agency is a European agency for the evaluation of medicinal products. From 1995 to 2004, the European Medicines Agency was known as European Agency for the Evaluation of Medicinal Products.Roughly parallel to the U.S...
recommended approval of the drug. In March 2011 the European Commission
European Commission
The European Commission is the executive body of the European Union. The body is responsible for proposing legislation, implementing decisions, upholding the Union's treaties and the general day-to-day running of the Union....
(EC) has granted marketing authorization in all 27 EU member states.