Treatment of Idiopathic Pulmonary Fibrosis with a New Antifibrotic Agent, Pirfenidone

Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive clinical syndrome of unknown etiology and fatal outcome. Currently available therapies are ineffective and associated with significant adverse effects. Pirfenidone, a new, investigational antifibrotic agent, was evaluated for its tolerability and usefulness in terminally ill patients with advanced IPF. Consecutive patients with IPF and deterioration despite conventional therapy or who were unable to tolerate or unwilling to try conventional therapy were treated with oral pirfenidone. Treatment was administered on a compassionate basis (open-label). Fifty-four patients were followed for mortality, change in lung function, and adverse effects. Their mean age was 62, mean duration of symptoms 4.6 yr, and time since lung biopsy was 3.2 yr. Conventional therapy was discontinued in 38 of 46 patients; the other eight were able to decrease their prednisone dosage and eight had no previous conventional treatment. One- and 2-yr survival was 78% (95% CI 66%, 89%) and 63% (95% CI 50%, 76%), respectively. Patients whose lung functions had deteriorated prior to enrollment appeared to stabilize after beginning treatment. Adverse effects were relatively minor. The results of this study are encouraging. Pirfenidone is a promising new treatment for IPF that is well tolerated.

High-Dose Acetylcysteine in Idiopathic Pulmonary Fibrosis

“…It was not our aim to examine whether the therapeutic effect of the activity of acetylcysteine is in accordance with the current hypothesis that persistent lung injury from fibrosis, and not from inflammation, is the primary pathogenetic mechanism in idiopathic pulmonary fibrosis. [6][7][8][9] On the basis of this hypothesis, there has been particular interest in antifibrotic drugs, 7 such as pirfenidone, 43,44 and in immune modulators, especially interferon gamma-1b. [45][46][47] In a recent double-blind study, pirfenidone was shown to improve vital capacity and to prevent acute exacerbations of idiopathic pulmonary fibrosis.…”

The bleomycin animal model: A useful tool to investigate treatment options for idiopathic pulmonary fibrosis?

“…Among the drugs tried or on trial are Etanercept, Imatinib, Prednisone (Daniil et al, 1999;Douglas et al, 1997;Douglas, Ryu, & Schroeder, 2000;Douglas et al, 1998;Nicholson AG, 2000;Riha et al, 2002;Ziesche, Hofbauer, Wittmann, Petkov, & Block, 1999), N-Acetylcysteine (Demedts et al, 2005), TGF-β antibody (Genzyme, 2007), Interferon-γ (Antoniou et al, 2006;Raghu et al, 2004;Raghu R, 2001), Interferon-β (Raghu, Bozic, & Brown, 2001), Pirfenidone (Azuma, Nukiwa et al, 2005;S. Nagai et al, 2002;Raghu, Johnson, Lockhart, & Mageto, 1999), Colchicine (Douglas, Ryu, & Schroeder, 2000;Douglas et al, 1998;Selman et al, 1998), Bosentan, Cyclosporin-A (Alton, Johnson, & Turner-Warwick, 1989;Moolman, Bardin, Rossouw, & Joubert, 1991), D-Penicillamin (Chapela, Zuniga, & Selman, 1986;Selman et al, 1998), Heparin (Kubo et al, 2005), Relaxin (ATS, 2002), Angiotensin converting enzyme (ACE) inhibitors (Nadrous, Ryu, Douglas, Decker, & Olson, 2004), and CTGF antibodies (Mageto Y, 2004). Interestingly, azathioprine and cyclophosphamide, two drugs that are still in the current ATS/ERS guidelines for IPF treatment (ATS, 2002), have never been evaluated in the bleomycin model as far as we know.…”

Interstitial fibrosis and growth factors.

“…This causes a stiff lung with concomitant abnormalities of gas exchange as the alveolar-capillary membranes widen from increased deposition of extracellular matrix, as the microvascular bed is destroyed by the fibrotic process, and as abnormalities in ventilation-perfusion matching occur (15). As the fibrogenesis progresses, scarring becomes more obvious by radiographic studies, and the disease tends to be even more refractory to successful therapeutic intervention (16).…”