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Pirfenidone in idiopathic pulmonary fibrosis: Is there a role?
Egyptian Journal of Chest Diseases and Tuberculosis (2014) 63, 749–750
H O S T E D BY
Egyptian Journal of Chest Diseases and Tuberculosis
Egyptian Journal of Chest Diseases and Tuberculosis www.elsevier.com/locate/ejcdt www.sciencedirect.com
EDITORIAL
Pirfenidone in idiopathic pulmonary fibrosis: Is there a role? Pirfenidone, an orally active small molecule, is an immunosuppressant that is thought to have anti-inflammatory and antifibrotic effects both in vitro and in vivo [1–5]. Although various combinations of medications have been introduced over the past years for the treatment of idiopathic pulmonary fibrosis (IPF), yet no therapy has proven to improve survival. Following evaluation in Phase II and Phase III clinical trials in patients with IPF [6–8], pirfenidone was approved by the European Commission in February 2011. Its mechanism of action is not fully understood but it is likely that pirfenidone exerts its effects by suppressing fibroblast proliferation, reducing the production of fibrosis-associated proteins and cytokines and reducing the response to growth factors such as transforming growth factor-beta and platelet-derived growth factor [9]. In the lung, pirfenidone reduced fibrosis in response to bleomycin, lung transplant and repeated allergen exposure [5]. Pirfenidone is the first substance for which more than one positive phase III randomised, placebo-controlled trial has been reported with a statistically significant effect on a primary end-point in patients with IPF. A decline in both relative and absolute changes in the forced vital capacity (FVC) has been shown consistently to predict mortality in patients with IPF [10–12]. Pirfenidone has been shown to reduce the decline in FVC in patients with IPF. Therefore, it is recommended as an option for treating IPF only if the predicted FVC is between 50% and 80%. Treatment with pirfenidone should be discontinued if there is evidence of disease progression (a decline in percent predicted FVC of 10% or more within any 12 month period) [9]. It is noted that the most commonly reported (10% or greater) adverse effects of pirfenidone (2403 mg/day) compared with placebo were nausea (32.8% compared with 13.3%), rash (28.7% compared with 8.6%), fatigue (22.3% compared with 13.3%), diarrhoea (21.7% compared with 13.5%), dyspepsia (16.8% compared with 5.5%), and photosensitivity reaction (12.2% compared with 1.7%). These adverse events were consistent with the known safety profile of pirfenidone and were usually mild to moderate in severity [6]. The average annual cost of ongoing treatment with pirfenidone is £26,171.72 [9]. Thus, cost-benefit analysis and Peer review under responsibility of The Egyptian Society of Chest Diseases and Tuberculosis.
cost-effectiveness of using pirfenidone in IPF patients should be thoroughly evaluated before the start of treatment. Conflict of interest None declared. References [1] C.J. Schaefer, D.W. Ruhrmund, L. Pan, et al., Antifibrotic activities of pirfenidone in animal models, Eur. Respir. Rev. 20 (2011) 85–97. [2] S.N. Iyer, G. Gurujeyalakshmi, S.N. Giri, Effects of pirfenidone on transforming growth factor-beta gene expression at the transcriptional level in bleomycin hamster model of lung fibrosis, J. Pharmacol. Exp. Ther. 291 (1999) 367–373. [3] G. Gurujeyalakshmi, M.A. Hollinger, S.N. Giri, Pirfenidone inhibits PDGF isoforms in bleomycin hamster model of lung fibrosis at the translational level, Am. J. Physiol. 276 (1999) 311– 318. [4] S.N. Iyer, G. Gurujeyalakshmi, S.N. Giri, Effects of pirfenidone on procollagen gene expression at the transcriptional level in bleomycin hamster model of lung fibrosis, J. Pharmacol. Exp. Ther. 289 (1999) 211–218. [5] H. Oku, T. Shimizu, T. Kawabata, 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. 590 (2008) 400–408. [6] A. Azuma, T. Nukiwa, E. Tsuboi, et al., Double-blind, placebocontrolled trial of pirfenidone in patients with idiopathic pulmonary fibrosis, Am. J. Respir. Crit. Care Med. 171 (2005) 1040–1047. [7] H. Taniguchi, M. Ebina, Y. Kondoh, et al., Pirfenidone in idiopathic pulmonary fibrosis, Eur. Respir. J. 35 (2010) 821–829. [8] P.W. Noble, C. Albera, W.Z. Bradford, et al., Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): two randomised trials, Lancet 377 (2011) 1760–1769. [9] L.J. Landells, B. Naidoo, J. Robertson, et al., NICE guidance on pirfenidone for treating idiopathic pulmonary fibrosis, Lancet Respir. Med. 1 (3) (2013) 191–192, http://dx.doi.org/ 10.1016/S2213-2600(13)70065-1 (Epub 2013 Apr 24). [10] R.M. du Bois, D. Weycker, C. Albera, et al., Forced vital capacity in patients with idiopathic pulmonary fibrosis: test properties and minimal clinically important difference, Am. J. Respir. Crit. Care Med. 184 (12) (2011) 1382–1389.
http://dx.doi.org/10.1016/j.ejcdt.2014.06.013 0422-7638 ª 2014 The Egyptian Society of Chest Diseases and Tuberculosis. Production and hosting by Elsevier B.V. Open access under CC BY-NC-ND license.
750 [11] R.M. Du Bois, D. Weycker, C. Albera, et al., Ascertainment of individual risk of mortality for patients with idiopathic pulmonary fibrosis, Am. J. Respir. Crit. Care Med. 184 (2011) 459–466. [12] L. Richeldi, C.J. Ryerson, J.S. Lee, et al., Interstitial lung disease: original article: relative versus absolute change in forced vital capacity in idiopathic pulmonary fibrosis, Thorax 67 (2012) 407–411.
Editorial I. Galal Ain Shams University Hospital, Department of Chest Diseases, Cairo, Egypt Tel.: +20 101001502179. E-mail address: [email protected] Available online 28 August 2014
H O S T E D BY
Egyptian Journal of Chest Diseases and Tuberculosis
Egyptian Journal of Chest Diseases and Tuberculosis www.elsevier.com/locate/ejcdt www.sciencedirect.com
EDITORIAL
Pirfenidone in idiopathic pulmonary fibrosis: Is there a role? Pirfenidone, an orally active small molecule, is an immunosuppressant that is thought to have anti-inflammatory and antifibrotic effects both in vitro and in vivo [1–5]. Although various combinations of medications have been introduced over the past years for the treatment of idiopathic pulmonary fibrosis (IPF), yet no therapy has proven to improve survival. Following evaluation in Phase II and Phase III clinical trials in patients with IPF [6–8], pirfenidone was approved by the European Commission in February 2011. Its mechanism of action is not fully understood but it is likely that pirfenidone exerts its effects by suppressing fibroblast proliferation, reducing the production of fibrosis-associated proteins and cytokines and reducing the response to growth factors such as transforming growth factor-beta and platelet-derived growth factor [9]. In the lung, pirfenidone reduced fibrosis in response to bleomycin, lung transplant and repeated allergen exposure [5]. Pirfenidone is the first substance for which more than one positive phase III randomised, placebo-controlled trial has been reported with a statistically significant effect on a primary end-point in patients with IPF. A decline in both relative and absolute changes in the forced vital capacity (FVC) has been shown consistently to predict mortality in patients with IPF [10–12]. Pirfenidone has been shown to reduce the decline in FVC in patients with IPF. Therefore, it is recommended as an option for treating IPF only if the predicted FVC is between 50% and 80%. Treatment with pirfenidone should be discontinued if there is evidence of disease progression (a decline in percent predicted FVC of 10% or more within any 12 month period) [9]. It is noted that the most commonly reported (10% or greater) adverse effects of pirfenidone (2403 mg/day) compared with placebo were nausea (32.8% compared with 13.3%), rash (28.7% compared with 8.6%), fatigue (22.3% compared with 13.3%), diarrhoea (21.7% compared with 13.5%), dyspepsia (16.8% compared with 5.5%), and photosensitivity reaction (12.2% compared with 1.7%). These adverse events were consistent with the known safety profile of pirfenidone and were usually mild to moderate in severity [6]. The average annual cost of ongoing treatment with pirfenidone is £26,171.72 [9]. Thus, cost-benefit analysis and Peer review under responsibility of The Egyptian Society of Chest Diseases and Tuberculosis.
cost-effectiveness of using pirfenidone in IPF patients should be thoroughly evaluated before the start of treatment. Conflict of interest None declared. References [1] C.J. Schaefer, D.W. Ruhrmund, L. Pan, et al., Antifibrotic activities of pirfenidone in animal models, Eur. Respir. Rev. 20 (2011) 85–97. [2] S.N. Iyer, G. Gurujeyalakshmi, S.N. Giri, Effects of pirfenidone on transforming growth factor-beta gene expression at the transcriptional level in bleomycin hamster model of lung fibrosis, J. Pharmacol. Exp. Ther. 291 (1999) 367–373. [3] G. Gurujeyalakshmi, M.A. Hollinger, S.N. Giri, Pirfenidone inhibits PDGF isoforms in bleomycin hamster model of lung fibrosis at the translational level, Am. J. Physiol. 276 (1999) 311– 318. [4] S.N. Iyer, G. Gurujeyalakshmi, S.N. Giri, Effects of pirfenidone on procollagen gene expression at the transcriptional level in bleomycin hamster model of lung fibrosis, J. Pharmacol. Exp. Ther. 289 (1999) 211–218. [5] H. Oku, T. Shimizu, T. Kawabata, 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. 590 (2008) 400–408. [6] A. Azuma, T. Nukiwa, E. Tsuboi, et al., Double-blind, placebocontrolled trial of pirfenidone in patients with idiopathic pulmonary fibrosis, Am. J. Respir. Crit. Care Med. 171 (2005) 1040–1047. [7] H. Taniguchi, M. Ebina, Y. Kondoh, et al., Pirfenidone in idiopathic pulmonary fibrosis, Eur. Respir. J. 35 (2010) 821–829. [8] P.W. Noble, C. Albera, W.Z. Bradford, et al., Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): two randomised trials, Lancet 377 (2011) 1760–1769. [9] L.J. Landells, B. Naidoo, J. Robertson, et al., NICE guidance on pirfenidone for treating idiopathic pulmonary fibrosis, Lancet Respir. Med. 1 (3) (2013) 191–192, http://dx.doi.org/ 10.1016/S2213-2600(13)70065-1 (Epub 2013 Apr 24). [10] R.M. du Bois, D. Weycker, C. Albera, et al., Forced vital capacity in patients with idiopathic pulmonary fibrosis: test properties and minimal clinically important difference, Am. J. Respir. Crit. Care Med. 184 (12) (2011) 1382–1389.
http://dx.doi.org/10.1016/j.ejcdt.2014.06.013 0422-7638 ª 2014 The Egyptian Society of Chest Diseases and Tuberculosis. Production and hosting by Elsevier B.V. Open access under CC BY-NC-ND license.
750 [11] R.M. Du Bois, D. Weycker, C. Albera, et al., Ascertainment of individual risk of mortality for patients with idiopathic pulmonary fibrosis, Am. J. Respir. Crit. Care Med. 184 (2011) 459–466. [12] L. Richeldi, C.J. Ryerson, J.S. Lee, et al., Interstitial lung disease: original article: relative versus absolute change in forced vital capacity in idiopathic pulmonary fibrosis, Thorax 67 (2012) 407–411.
Editorial I. Galal Ain Shams University Hospital, Department of Chest Diseases, Cairo, Egypt Tel.: +20 101001502179. E-mail address: [email protected] Available online 28 August 2014