Pirfenidone
|
| Systematic (IUPAC) name |
| 5-Methyl-1-phenylpyridin-2-one |
| Clinical data |
| Trade names |
Esbriet |
| AHFS/Drugs.com |
International Drug Names |
| Licence data |
EMA:Link |
| Legal status |
POM (UK) |
| Routes |
Oral |
| Pharmacokinetic data |
| Protein binding |
50–58%[1] |
| Metabolism |
Hepatic (70–80% CYP1A2-mediated; minor contributions from CYP2C9, CYP2C19, CYP2D6 and CYP2E1)[1] |
| Half-life |
2.4 hours[1] |
| Excretion |
Urine (80%)[1] |
| Identifiers |
| ATC code |
L04AX05 |
| PubChem |
CID 40632 |
| ChemSpider |
37115 |
| UNII |
D7NLD2JX7U N |
| KEGG |
D01583 Y |
| ChEMBL |
CHEMBL1256391 N |
| Chemical data |
| Formula |
C12H11NO |
| Mol. mass |
185.22 g/mol |
SMILES
- CC1=CN(C(=O)C=C1)C2=CC=CC=C2
|
InChI
-
InChI=1S/C12H11NO/c1-10-7-8-12(14)13(9-10)11-5-3-2-4-6-11/h2-9H,1H3
Key:ISWRGOKTTBVCFA-UHFFFAOYSA-N
|
| N (what is this?) (verify) |
Pirfenidone (INN, BAN) 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]
Contents
- 1 Mechanism of action
- 2 Preclinical studies
- 2.1 Studies in models of fibrosis
- 3 Pharmacokinetics
- 4 Clinical trials in Idiopathic Pulmonary Fibrosis (IPF)
- 5 Indication
- 6 Adverse effects
- 6.1 Gastrointestinal
- 6.2 Skin
- 6.3 Hepatic dysfunction
- 6.4 Dizziness and fatigue
- 6.5 Weight loss
- 7 Interactions
- 7.1 CYP1A2 inhibitors
- 7.2 Other CYP inhibitors
- 7.3 CYP1A2 inducers
- 7.4 Cigarette smoking
- 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.[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
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- ^ a b c "InterMune: Pirfenidone". InterMune.
- ^ "China SFDA Approves F647/pirfenidone for the Treatment of Idiopathic Pulmonary Fibrosis". Press Release. EvaluatePharma. 2011-09-22.
- ^ a b c Schaefer CJ, Ruhrmund DW, Pan L, Seiwert SD, Kossen K (June 2011). "Antifibrotic activities of pirfenidone in animal models". Eur Respir Rev 20 (120): 85–97. doi:10.1183/09059180.00001111. PMID 21632796.
- ^ 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 (November 2002). "Effect of pirfenidone on rat hepatic stellate cell proliferation and collagen production". J. Hepatol. 37 (5): 584–91. doi:10.1016/S0168-8278(02)00245-3. PMID 12399223.
- ^ 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.
- ^ a b Lin X, Yu M, Wu K, Yuan H, Zhong H (August 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.
- ^ Lee BS, Margolin SB, Nowak RA (January 1998). "Pirfenidone: a novel pharmacological agent that inhibits leiomyoma cell proliferation and collagen production". J. Clin. Endocrinol. Metab. 83 (1): 219–23. doi:10.1210/jc.83.1.219. PMID 9435445.
- ^ Ozes ON, Blatt LM (2006). "Development of a high throughput collagen assay using a cellular model of idiopathic pulmonary fibrosis". Chest 130: 230S. doi:10.1378/chest.130.4_meetingabstracts.230s-a.
- ^ 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.
- ^ Nakayama S, Mukae H, Sakamoto N, Kakugawa T, Yoshioka S, Soda H, Oku H, Urata Y, Kondo T, Kubota H, Nagata K, Kohno S (January 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.
- ^ 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. doi:10.1378/chest.128.4_meetingabstracts.169s-a.
- ^ Grattendick KJ, Nakashima JM, Feng L, Giri SN, Margolin SB (May 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.
- ^ a b c Kakugawa T, Mukae H, Hayashi T, Ishii H, Abe K, Fujii T, Oku H, Miyazaki M, Kadota J, Kohno S (July 2004). "Pirfenidone attenuates expression of HSP47 in murine bleomycin-induced pulmonary fibrosis". Eur. Respir. J. 24 (1): 57–65. doi:10.1183/09031936.04.00120803. PMID 15293605.
- ^ a b c Oku H, Shimizu T, Kawabata T, Nagira M, Hikita I, Ueyama A, Matsushima S, Torii M, Arimura A (August 2008). "Antifibrotic action of pirfenidone and prednisolone: different effects on pulmonary cytokines and growth factors in bleomycin-induced murine pulmonary fibrosis". Eur. J. Pharmacol. 590 (1–3): 400–8. doi:10.1016/j.ejphar.2008.06.046. PMID 18598692.
- ^ a b Card JW, Racz WJ, Brien JF, Margolin SB, Massey TE (September 2003). "Differential effects of pirfenidone on acute pulmonary injury and ensuing fibrosis in the hamster model of amiodarone-induced pulmonary toxicity". Toxicol. Sci. 75 (1): 169–80. doi:10.1093/toxsci/kfg167. PMID 12832656.
- ^ Liu H, Drew P, Gaugler AC, Cheng Y, Visner GA (June 2005). "Pirfenidone inhibits lung allograft fibrosis through L-arginine-arginase pathway". Am. J. Transplant. 5 (6): 1256–63. doi:10.1111/j.1600-6143.2005.00876.x. PMID 15888029.
- ^ a b Hirano A, Kanehiro A, Ono K, Ito W, Yoshida A, Okada C, Nakashima H, Tanimoto Y, Kataoka M, Gelfand EW, Tanimoto M (September 2006). "Pirfenidone modulates airway responsiveness, inflammation, and remodeling after repeated challenge". Am. J. Respir. Cell Mol. Biol. 35 (3): 366–77. doi:10.1165/rcmb.2005-0452OC. PMC 2643289. PMID 16675785.
- ^ Iyer SN, Wild JS, Schiedt MJ, Hyde DM, Margolin SB, Giri SN (June 1995). "Dietary intake of pirfenidone ameliorates bleomycin-induced lung fibrosis in hamsters". J. Lab. Clin. Med. 125 (6): 779–85. PMID 7539478.
- ^ Iyer SN, Margolin SB, Hyde DM, Giri SN (1998). "Lung fibrosis is ameliorated by pirfenidone fed in diet after the second dose in a three-dose bleomycin-hamster model". Exp. Lung Res. 24 (1): 119–32. doi:10.3109/01902149809046058. PMID 9457473.
- ^ Iyer SN, Gurujeyalakshmi G, Giri SN (April 1999). "Effects of pirfenidone on procollagen gene expression at the transcriptional level in bleomycin hamster model of lung fibrosis". J. Pharmacol. Exp. Ther. 289 (1): 211–8. PMID 10087006.
- ^ Lee KW, Everett TH, Rahmutula D, Guerra JM, Wilson E, Ding C, Olgin JE (October 2006). "Pirfenidone prevents the development of a vulnerable substrate for atrial fibrillation in a canine model of heart failure". Circulation 114 (16): 1703–12. doi:10.1161/CIRCULATIONAHA.106.624320. PMC 2129103. PMID 17030685.
- ^ Nguyen DT, Ding C, Wilson E, Marcus GM, Olgin JE (October 2010). "Pirfenidone mitigates left ventricular fibrosis and dysfunction after myocardial infarction and reduces arrhythmias". Heart Rhythm 7 (10): 1438–45. doi:10.1016/j.hrthm.2010.04.030. PMID 20433946.
- ^ Mirkovic S, Seymour AM, Fenning A, Strachan A, Margolin SB, Taylor SM, Brown L (February 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.
- ^ Shimizu T, Kuroda T, Hata S, Fukagawa M, Margolin SB, Kurokawa K (July 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.
- ^ Takakuta K, Fujimori A, Chikanishi T, Tanokura A, Iwatsuki Y, Yamamoto M, Nakajima H, Okada M, Itoh H (March 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.
- ^ Salazar-Montes A, Ruiz-Corro L, López-Reyes A, Castrejón-Gómez E, Armendáriz-Borunda J (October 2008). "Potent antioxidant role of pirfenidone in experimental cirrhosis". Eur. J. Pharmacol. 595 (1–3): 69–77. doi:10.1016/j.ejphar.2008.06.110. PMID 18652820.
- ^ García L, Hernández I, Sandoval A, Salazar A, Garcia J, Vera J, Grijalva G, Muriel P, Margolin S, Armendariz-Borunda J (December 2002). "Pirfenidone effectively reverses experimental liver fibrosis". J. Hepatol. 37 (6): 797–805. doi:10.1016/S0168-8278(02)00272-6. PMID 12445421.
- ^ a b c d e f g h i j k l "Esbriet 267 mg hard capsules". Summary of product characteristics. European Medicines Agency.
- ^ a b Taniguchi H, Ebina M, Kondoh Y, et al. (April 2010). "Pirfenidone in idiopathic pulmonary fibrosis". Eur. Respir. J. 35 (4): 821–9. doi:10.1183/09031936.00005209. PMID 19996196.
- ^ a b c d 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 (May 2011). "Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): two randomised trials". Lancet 377 (9779): 1760–9. doi:10.1016/S0140-6736(11)60405-4. PMID 21571362.
- ^ a b Spagnolo P, Del Giovane C, Luppi F, Cerri S, Balduzzi S, Walters EH, D'Amico R, Richeldi L (2010). "Non-steroid agents for idiopathic pulmonary fibrosis". Cochrane Database Syst Rev (9): CD003134. doi:10.1002/14651858.CD003134.pub2. PMID 20824834.
- ^ Frieden J (2010-05-10). "FDA Nixes Pirfenidone for Now, Wants New Trial". MedPage Today.
- ^ "Efficacy and Safety of Pirfenidone in Patients With Idiopathic Pulmonary Fibrosis (IPF) ]". NCT01366209. U.S. National Institutes of Health: ClinicalTrials.gov.
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