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In animal models, pirfenidone displays a systemic [[antifibrotic]] activity and has been shown to reduce [[biochemical]] and [[histopathological]] indices of fibrosis of the lung, liver, heart and kidney.<ref name=Schaefer />
In animal models, pirfenidone displays a systemic [[antifibrotic]] activity and has been shown to reduce [[biochemical]] and [[histopathological]] indices of fibrosis of the lung, liver, heart and kidney.<ref name=Schaefer />


Pirfenidone demonstrates a consistent [[antifibrotic]] effect in several animal models of [[pulmonary fibrosis]].<ref name=Kakugawa>Kakugawa T, et al., ["Pirfenidone attenuates expression of HSP47 in murine bleomycin-induced pulmonary fibrosis"], ''Eur Respir J.'', 2004;24:57-65.</ref><ref name=Oku>Oku H, et al., ["Antifibrotic action of pirfenidone and prednisolone: different effects on pulmonary cytokines and growth factors in bleomycin-induced murine pulmonary fibrosis"], ''Eur J Pharmacol.'', 2008;590:400-408.</ref><ref name=Card>Card JW, et al., ["Differential effects of pirfenidone on acute pulmonary injury and ensuing fibrosis in the hamster model of amiodarone-induced pulmonary toxicity"], ''Toxicol Sci.'', 2003;75:169-80.</ref><ref name=Liu>Liu H, et al., ["Pirfenidone inhibits lung allograft fibrosis through L-arginine-arginase pathway "], ''Eur J Pharmacol.'', 2005;5:1256-1263.</ref><ref name=Zhou>Zhou H, et al., ["Pirfenidone inhibits obliterative airway disease in mouse tracheal allografts."], “J Heart Lung Transplant.'', 2005;24:1577-1585.</ref><ref name=Hirano>Hirano A, et al., ["Pirfenidone modulates airway responsiveness, inflammation, and remodeling after repeated challenge."], “Am J Respir Cell Mol Biol.'', 2006;35:366-377.</ref> 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.<ref name=Schaefer /><ref name=Card /> Numerous studies have demonstrated that pirfenidone attenuates bleomycin-induced [[pulmonary fibrosis]].<ref name=Kakugawa /><ref name=Oku /><ref name=Hirano /><ref name=Iyera>Iyer SN, et al., ["Dietary intake of pirfenidone ameliorates bleomycin-induced lung fibrosis in hamsters."], "J Lab Clin Med.'', 1995;125:779-785.</ref><ref name=Iyerb>Iyer SN, et al., ["Lung fibrosis is ameliorated by pirfenidone fed in diet after the second dose in a three-dose bleomycin-hamster model. "], '' Exp Lung Res.'', 1998;24:119-132.</ref><ref name=Iyerc>Iyer SN, et al., ["Effects of pirfenidone on procollagen gene expression at the transcriptional level in bleomycin hamster model of lung fibrosis."], '' J Pharmacol Exp Ther.'', 1999;289:211-218.</ref> One study investigated the effect of pirfenidone over a 42-day period after repeated [[bleomycin]] administration.<ref name=Oku /> 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,<ref name=Kakugawa /> i.e. when administered in a therapeutic as opposed to a prophylactic treatment regimen.
Pirfenidone demonstrates a consistent [[antifibrotic]] effect in several animal models of [[pulmonary fibrosis]].<ref name=Kakugawa>{{cite journal | author = Kakugawa T, Mukae H, Hayashi T, Ishii H, Abe K, Fujii T, Oku H, Miyazaki M, Kadota J, Kohno S | title = Pirfenidone attenuates expression of HSP47 in murine bleomycin-induced pulmonary fibrosis | journal = Eur. Respir. J. | volume = 24 | issue = 1 | pages = 57–65 | year = 2004 | month = July | pmid = 15293605 | doi = }}</ref><ref name=Oku>{{cite journal | author = Oku H, Shimizu T, Kawabata T, Nagira M, Hikita I, Ueyama A, Matsushima S, Torii M, Arimura A | title = Antifibrotic action of pirfenidone and prednisolone: different effects on pulmonary cytokines and growth factors in bleomycin-induced murine pulmonary fibrosis | journal = Eur. J. Pharmacol. | volume = 590 | issue = 1-3 | pages = 400–8 | year = 2008 | month = August | pmid = 18598692 | doi = 10.1016/j.ejphar.2008.06.046 }}</ref><ref name=Card>{{cite journal | author = Card JW, Racz WJ, Brien JF, Margolin SB, Massey TE | title = Differential effects of pirfenidone on acute pulmonary injury and ensuing fibrosis in the hamster model of amiodarone-induced pulmonary toxicity | journal = Toxicol. Sci. | volume = 75 | issue = 1 | pages = 169–80 | year = 2003 | month = September | pmid = 12832656 | doi = 10.1093/toxsci/kfg167 }}</ref><ref name=Liu>{{cite journal | author = Liu H, Drew P, Gaugler AC, Cheng Y, Visner GA | title = Pirfenidone inhibits lung allograft fibrosis through L-arginine-arginase pathway | journal = Am. J. Transplant. | volume = 5 | issue = 6 | pages = 1256–63 | year = 2005 | month = June | pmid = 15888029 | doi = 10.1111/j.1600-6143.2005.00876.x }}</ref><ref name=Hirano>{{cite journal | author = Hirano A, Kanehiro A, Ono K, Ito W, Yoshida A, Okada C, Nakashima H, Tanimoto Y, Kataoka M, Gelfand EW, Tanimoto M | title = Pirfenidone modulates airway responsiveness, inflammation, and remodeling after repeated challenge | journal = Am. J. Respir. Cell Mol. Biol. | volume = 35 | issue = 3 | pages = 366–77 | year = 2006 | month = September | pmid = 16675785 | pmc = 2643289 | doi = 10.1165/rcmb.2005-0452OC }}</ref> 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.<ref name=Schaefer /><ref name=Card /> Numerous studies have demonstrated that pirfenidone attenuates bleomycin-induced [[pulmonary fibrosis]].<ref name=Kakugawa /><ref name=Oku /><ref name=Hirano /><ref name=Iyera>{{cite journal | author = Iyer SN, Wild JS, Schiedt MJ, Hyde DM, Margolin SB, Giri SN | title = Dietary intake of pirfenidone ameliorates bleomycin-induced lung fibrosis in hamsters | journal = J. Lab. Clin. Med. | volume = 125 | issue = 6 | pages = 779–85 | year = 1995 | month = June | pmid = 7539478 | doi = }}</ref><ref name=Iyerb>{{cite journal | author = Iyer SN, Margolin SB, Hyde DM, Giri SN | title = Lung fibrosis is ameliorated by pirfenidone fed in diet after the second dose in a three-dose bleomycin-hamster model | journal = Exp. Lung Res. | volume = 24 | issue = 1 | pages = 119–32 | year = 1998 | pmid = 9457473 | doi = 10.3109/01902149809046058 }}</ref><ref name=Iyerc>{{cite journal | author = Iyer SN, Gurujeyalakshmi G, Giri SN | title = Effects of pirfenidone on procollagen gene expression at the transcriptional level in bleomycin hamster model of lung fibrosis | journal = J. Pharmacol. Exp. Ther. | volume = 289 | issue = 1 | pages = 211–8 | year = 1999 | month = April | pmid = 10087006 | doi = }}</ref> One study investigated the effect of pirfenidone over a 42-day period after repeated [[bleomycin]] administration.<ref name=Oku /> 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,<ref name=Kakugawa /> 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,<ref name=Leeb>Lee KWT, et al., ["Pirfenidone prevents the development of a vulnerable substrate for atrial fibrillation in a canine model of heart failure "], ''Circulation.'', 2006;114:1703-1712.</ref><ref name=Nguyen>Nguyen GT et al., ["Pirfenidone mitigates left ventricular fibrosis and dysfunction after myocardial infarction and reduces arrhythmias. "], ''Heart Rhythm.'', 2010;7:1438-1445.</ref><ref name=Mirkovic>Mirkovic S, et al., ["Attenuation of cardiac fibrosis by pirfenidone and amiloride in DOCA-salt hypertensive rats"], ''Br J Pharmacol.'', 2002;135:961-968.</ref> renal,<ref name=Shimizu>Shimizu T, et al., ["Pirfenidone improves renal function and fibrosis in the post-obstructed kidney "], '' Kidney Int.'', 1998;54:99-109.</ref><ref name=Takakuta>Takakuta K, et al., ["Renoprotective properties of pirfenidone in subtotally nephrectomized rats."], '' Eur J Pharmacol.'', 2010;629:118-24.</ref> and hepatic<ref name=DiSario /><ref name=Salazar-Montes>Salazar Montes A, et al., ["Potent antioxidant role of pirfenidone in experimental cirrhosis."], '' Eur J Pharmacol.'', 2008;595:69-77.</ref><ref name=Garcia>Garcia L et al., ["Pirfenidone effectively reverses experimental liver fibrosis ."], '' J Hepatol. '', 2002;37:797-805.</ref> fibrosis. In these models, pirfenidone demonstrated a consistent ability to reduce [[fibrosis]] and the expression of [[fibrogenic mediators]].
The [[antifibrotic]] effect of pirfenidone has been further established in animal models of cardiac,<ref name=Leeb>{{cite journal | author = Lee KW, Everett TH, Rahmutula D, Guerra JM, Wilson E, Ding C, Olgin JE | title = Pirfenidone prevents the development of a vulnerable substrate for atrial fibrillation in a canine model of heart failure | journal = Circulation | volume = 114 | issue = 16 | pages = 1703–12 | year = 2006 | month = October | pmid = 17030685 | pmc = 2129103 | doi = 10.1161/CIRCULATIONAHA.106.624320 }}</ref><ref name=Nguyen>{{cite journal | author = Nguyen DT, Ding C, Wilson E, Marcus GM, Olgin JE | title = Pirfenidone mitigates left ventricular fibrosis and dysfunction after myocardial infarction and reduces arrhythmias | journal = Heart Rhythm | volume = 7 | issue = 10 | pages = 1438–45 | year = 2010 | month = October | pmid = 20433946 | doi = 10.1016/j.hrthm.2010.04.030 }}</ref><ref name=Mirkovic>{{cite journal | author = Mirkovic S, Seymour AM, Fenning A, Strachan A, Margolin SB, Taylor SM, Brown L | title = Attenuation of cardiac fibrosis by pirfenidone and amiloride in DOCA-salt hypertensive rats | journal = Br. J. Pharmacol. | volume = 135 | issue = 4 | pages = 961–8 | year = 2002 | month = February | pmid = 11861324 | pmc = 1573203 | doi = 10.1038/sj.bjp.0704539 }}</ref> renal,<ref name=Shimizu>{{cite journal | author = Shimizu T, Kuroda T, Hata S, Fukagawa M, Margolin SB, Kurokawa K | title = Pirfenidone improves renal function and fibrosis in the post-obstructed kidney | journal = Kidney Int. | volume = 54 | issue = 1 | pages = 99–109 | year = 1998 | month = July | pmid = 9648068 | doi = 10.1046/j.1523-1755.1998.00XXX.x }}</ref><ref name=Takakuta>{{cite journal | author = Takakuta K, Fujimori A, Chikanishi T, Tanokura A, Iwatsuki Y, Yamamoto M, Nakajima H, Okada M, Itoh H | title = Renoprotective properties of pirfenidone in subtotally nephrectomized rats | journal = Eur. J. Pharmacol. | volume = 629 | issue = 1-3 | pages = 118–24 | year = 2010 | month = March | pmid = 20006961 | doi = 10.1016/j.ejphar.2009.12.011 }}</ref> and hepatic<ref name=DiSario /><ref name=Salazar-Montes>{{cite journal | author = Salazar-Montes A, Ruiz-Corro L, López-Reyes A, Castrejón-Gómez E, Armendáriz-Borunda J | title = Potent antioxidant role of pirfenidone in experimental cirrhosis | journal = Eur. J. Pharmacol. | volume = 595 | issue = 1-3 | pages = 69–77 | year = 2008 | month = October | pmid = 18652820 | doi = 10.1016/j.ejphar.2008.06.110 }}</ref><ref name=Garcia>{{cite journal | author = García L, Hernández I, Sandoval A, Salazar A, Garcia J, Vera J, Grijalva G, Muriel P, Margolin S, Armendariz-Borunda J | title = Pirfenidone effectively reverses experimental liver fibrosis | journal = J. Hepatol. | volume = 37 | issue = 6 | pages = 797–805 | year = 2002 | month = December | pmid = 12445421 | doi = }}</ref> fibrosis. In these models, pirfenidone demonstrated a consistent ability to reduce [[fibrosis]] and the expression of [[fibrogenic mediators]].


==Pharmacokinetics==
==Pharmacokinetics==
Line 60: Line 60:


==Clinical trials in Idiopathic Pulmonary Fibrosis (IPF)==
==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 [[Idiopathic pulmonary fibrosis|IPF]].<ref name=Taniguchi>Taniguchi H, et al., ["Pirfenidone in idiopathic pulmonary fibrosis."], '' Eur Respir J.'', 2010;35:821-829</ref><ref name=Noble>Noble PW, et al., ["Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY: two randomized trials. Lancet. '', 2011;377:1760-9.</ref>
The clinical efficacy of pirfenidone has been studied in three [[Phase III]], [[randomized]], [[double-blind]], [[placebo-controlled]] studies in patients with [[Idiopathic pulmonary fibrosis|IPF]].<ref name=Taniguchi>{{cite journal | author = Taniguchi H, Ebina M, Kondoh Y, ''et al.'' | title = Pirfenidone in idiopathic pulmonary fibrosis | journal = Eur. Respir. J. | volume = 35 | issue = 4 | pages = 821–9 | year = 2010 | month = April | pmid = 19996196 | doi = 10.1183/09031936.00005209 }}</ref><ref name=Noble>{{cite journal | author = Noble PW, Albera C, Bradford WZ, Costabel U, Glassberg MK, Kardatzke D, King TE, Lancaster L, Sahn SA, Szwarcberg J, Valeyre D, du Bois RM | title = Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): two randomised trials | journal = Lancet | volume = 377 | issue = 9779 | pages = 1760–9 | year = 2011 | month = May | pmid = 21571362 | doi = 10.1016/S0140-6736(11)60405-4 }}</ref>
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&nbsp;mg/day (110 patients), pirfenidone 1200&nbsp;mg/day (56 patients), or [[placebo]] (109 patients), for 52 weeks. Pirfenidone 1800 or 1200&nbsp;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.<ref name=Taniguchi />
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&nbsp;mg/day (110 patients), pirfenidone 1200&nbsp;mg/day (56 patients), or [[placebo]] (109 patients), for 52 weeks. Pirfenidone 1800 or 1200&nbsp;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.<ref name=Taniguchi />
The CAPACITY (004 & 006) studies were [[randomized]], [[double-blind]], [[placebo-controlled]] [[Phase III]] trials in eleven countries across Europe, North America, and Australia.<ref name=Noble /> Patients with IPF were randomly assigned to treatment with oral pirfenidone or [[placebo]] for a minimum of 72 weeks.<ref name=Noble />
The CAPACITY (004 & 006) studies were [[randomized]], [[double-blind]], [[placebo-controlled]] [[Phase III]] trials in eleven countries across Europe, North America, and Australia.<ref name=Noble /> Patients with IPF were randomly assigned to treatment with oral pirfenidone or [[placebo]] for a minimum of 72 weeks.<ref name=Noble />

Revision as of 14:56, 16 March 2013

Pirfenidone[1]
Names
IUPAC name
5-Methyl-1-phenylpyridin-2-one
Identifiers
3D model (JSmol)
ChEMBL
ECHA InfoCard 100.150.129 Edit this at Wikidata
KEGG
  • CC1=CN(C(=O)C=C1)C2=CC=CC=C2
Properties
C12H11NO
Molar mass 185.226 g·mol−1
10 mg/mL at 60 °C
Solubility in DMSO 20 mg/mL
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
☒N verify (what is checkY☒N ?)

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.[2] 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.[3]

Mechanism of action

Pirfenidone has well-established antifibrotic and anti-inflammatory properties in various in vitro systems and animal models of fibrosis.[4] A number of cell-based studies have shown that pirfenidone reduces fibroblast proliferation,[5][6][7][8] inhibits TGF-β stimulated collagen production[5][6][9][10][11] and reduces the production of fibrogenic mediators such as TGF-β.[7][10] 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.[12][13] These activities are consistent with the broader antifibrotic and anti-inflammatory activities observed in animal models of fibrosis.

Preclinical studies

Studies in models of fibrosis

In animal models, pirfenidone displays a systemic antifibrotic activity and has been shown to reduce biochemical and histopathological indices of fibrosis of the lung, liver, heart and kidney.[4]

Pirfenidone demonstrates a consistent antifibrotic effect in several animal models of pulmonary fibrosis.[14][15][16][17][18] 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.[4][16] Numerous studies have demonstrated that pirfenidone attenuates bleomycin-induced pulmonary fibrosis.[14][15][18][19][20][21] One study investigated the effect of pirfenidone over a 42-day period after repeated bleomycin administration.[15] 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,[14] 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,[22][23][24] renal,[25][26] and hepatic[5][27][28] fibrosis. In these models, pirfenidone demonstrated a consistent ability to reduce fibrosis and the expression of fibrogenic mediators.

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.[29] 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.[29]

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.[30][31] 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.[30] The CAPACITY (004 & 006) studies were randomized, double-blind, placebo-controlled Phase III trials in eleven countries across Europe, North America, and Australia.[31] Patients with IPF were randomly assigned to treatment with oral pirfenidone or placebo for a minimum of 72 weeks.[31] 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).[31]

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.[32] 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.[32]

Indication

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.[2] In October 2008 it was approved for use in Japan, and in India in 2010.

Adverse effects

Gastrointestinal

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.[29]

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 sunscreen agents. Continuing photosensitivity reactions are usually managed by dose adjustment and temporary discontinuation of treatment if required, along with local symptomatic treatment.[29]

Hepatic dysfunction

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.[29]

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.[29]

Weight loss

Weight loss has been reported in patients treated with pirfenidone. Doctors should monitor patients’ weight and encourage increased calorific intake if necessary.[29]

Interactions

Most drug interactions are mediated by various cytochrome P450 (CYP) enzymes.[29]

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.[29]

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.[29]

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.[29]

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.[29]

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.[33] A randomised, Phase III trial (the ASCEND study) is currently underway in the U.S.[34] In December 2010 an advisory panel to the European Medicines Agency recommended approval of the drug.[2] In February 2011 the European Commission (EC) has granted marketing authorisation in all 27 EU member states.

References

  1. ^ Pirfenidone at Sigma-Aldrich
  2. ^ a b c http://www.intermune.com/Pirfenidone
  3. ^ [1]
  4. ^ a b c Schaefer CJ, Ruhrmund DW, Pan L, Seiwert SD, Kossen K (2011). "Antifibrotic activities of pirfenidone in animal models". Eur Respir Rev. 20 (120): 85–97. doi:10.1183/09059180.00001111. PMID 21632796. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  5. ^ a b c Di Sario A, Bendia E, Svegliati Baroni G, Ridolfi F, Casini A, Ceni E, Saccomanno S, Marzioni M, Trozzi L, Sterpetti P, Taffetani S, Benedetti A (2002). "Effect of pirfenidone on rat hepatic stellate cell proliferation and collagen production". J. Hepatol. 37 (5): 584–91. PMID 12399223. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  6. ^ a b Hewitson TD, Kelynack KJ, Tait MG, Martic M, Jones CL, Margolin SB, Becker GJ (2001). "Pirfenidone reduces in vitro rat renal fibroblast activation and mitogenesis". J. Nephrol. 14 (6): 453–60. PMID 11783601.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  7. ^ a b Lin X, Yu M, Wu K, Yuan H, Zhong H (2009). "Effects of pirfenidone on proliferation, migration, and collagen contraction of human Tenon's fibroblasts in vitro". Invest. Ophthalmol. Vis. Sci. 50 (8): 3763–70. doi:10.1167/iovs.08-2815. PMID 19264889. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  8. ^ Lee BS, Margolin SB, Nowak RA (1998). "Pirfenidone: a novel pharmacological agent that inhibits leiomyoma cell proliferation and collagen production". J. Clin. Endocrinol. Metab. 83 (1): 219–23. PMID 9435445. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  9. ^ Ozes ON, Blatt LM (2006). "Development of a high throughput collagen assay using a cellular model of idiopathic pulmonary fibrosis". Chest. 130: 230S.
  10. ^ a b Sulfab M (2007). "The effects of pirfenidone and IFN-inducible T-cell alpha chemoattractant (ITAC) on transforming-growth factor-beta 1-mediated synthesis of extracellular matrix proteins in endothelial cells". Am J Respir Crit Care Med. 175: A730.
  11. ^ Nakayama S, Mukae H, Sakamoto N, Kakugawa T, Yoshioka S, Soda H, Oku H, Urata Y, Kondo T, Kubota H, Nagata K, Kohno S (2008). "Pirfenidone inhibits the expression of HSP47 in TGF-beta1-stimulated human lung fibroblasts". Life Sci. 82 (3–4): 210–7. doi:10.1016/j.lfs.2007.11.003. PMID 18093617. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  12. ^ Phillips R, Wang T, Blatt LM, Seiwert S (2005). "Pirfenidone mediates differential effects on lipopolysaccharide-induced cytokine expression in human peripheral mononuclear cells". Chest. 128. {{cite journal}}: Cite has empty unknown parameter: |month= (help)CS1 maint: multiple names: authors list (link)
  13. ^ Grattendick KJ, Nakashima JM, Feng L, Giri SN, Margolin SB (2008). "Effects of three anti-TNF-alpha drugs: etanercept, infliximab and pirfenidone on release of TNF-alpha in medium and TNF-alpha associated with the cell in vitro". Int. Immunopharmacol. 8 (5): 679–87. doi:10.1016/j.intimp.2008.01.013. PMID 18387510. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  14. ^ a b c Kakugawa T, Mukae H, Hayashi T, Ishii H, Abe K, Fujii T, Oku H, Miyazaki M, Kadota J, Kohno S (2004). "Pirfenidone attenuates expression of HSP47 in murine bleomycin-induced pulmonary fibrosis". Eur. Respir. J. 24 (1): 57–65. PMID 15293605. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
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  24. ^ Mirkovic S, Seymour AM, Fenning A, Strachan A, Margolin SB, Taylor SM, Brown L (2002). "Attenuation of cardiac fibrosis by pirfenidone and amiloride in DOCA-salt hypertensive rats". Br. J. Pharmacol. 135 (4): 961–8. doi:10.1038/sj.bjp.0704539. PMC 1573203. PMID 11861324. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  25. ^ Shimizu T, Kuroda T, Hata S, Fukagawa M, Margolin SB, Kurokawa K (1998). "Pirfenidone improves renal function and fibrosis in the post-obstructed kidney". Kidney Int. 54 (1): 99–109. doi:10.1046/j.1523-1755.1998.00XXX.x. PMID 9648068. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  26. ^ Takakuta K, Fujimori A, Chikanishi T, Tanokura A, Iwatsuki Y, Yamamoto M, Nakajima H, Okada M, Itoh H (2010). "Renoprotective properties of pirfenidone in subtotally nephrectomized rats". Eur. J. Pharmacol. 629 (1–3): 118–24. doi:10.1016/j.ejphar.2009.12.011. PMID 20006961. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
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  28. ^ García L, Hernández I, Sandoval A, Salazar A, Garcia J, Vera J, Grijalva G, Muriel P, Margolin S, Armendariz-Borunda J (2002). "Pirfenidone effectively reverses experimental liver fibrosis". J. Hepatol. 37 (6): 797–805. PMID 12445421. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
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  33. ^ http://www.medpagetoday.com/PublicHealthPolicy/FDAGeneral/19933.
  34. ^ http://clinicaltrials.gov/ct2/show/NCT01366209?term=pirfenidone&rank=4
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