Pirfenidone (Synonyms: AMR 69)

Pirfenidone,an oral antifibrotic agent, has a broad-spectrum of antifibroticand anti-inflammatory effects. Pirfenidonehas beneficial effects for the treatment of certain fibrotic diseases, and is under clinical trials in patients with idiopathic pulmonary fibrosis.

In vitro: In RAW264.7 cells, Pirfenidone (< 300 μg/mL) suppressed the proinflammatory cytokine tumor necrosis factor-α (TNF-α) through a translational mechanism, which was independent of activation of the mitogen-activated protein kinase (MAPK)2, p38 MAP kinase, and c-Jun N-terminal kinase (JNK)[1]. In LN-18, T98G, LNT-229 and LN-308 cell lines, Pirfenidone (< 10 mM) reduced glioma cell density in a concentration-dependent manner. In CCL-64 cells, Pirfenidone (< 5 mM) reduced TGF-β bioactivity by affecting TGF-β2 mRNA expression and processing of pro-TGF-β. Pirfenidone (< 8.3 mM) inhibited the activity of recombinant furin and downregulated the expression of MMP-11 in a dose-dependent manner in LN-308 cells[2].In cultured myometrial and leiomyoma smooth muscle cells, pirfenidone inhibited serum-stimulated increases in DNA synthesis and cell proliferation in a dose-dependent manner[3].

In vivo: In animals, pirfenidone treatment significantly decreased gene expression of collagens I, III and IV, transforming growth factor β-1, Smad-7, TIMP-1 and PAI-1 [4]. Pirfenidone at a dose of 30 mg/kg/day t.i.d. attenuated the bleomycin-induced pulmonary fibrosi. Pirfenidone (30, 100 mg/kg/day t.i.d) suppressed lung inflammatory edema and pulmonary fibrosis. Pirfenidone suppressed the bleomycin-induced increase in lung interleukin (IL)-1β, IL-6, IL-12\p40 and monocyte chemoattractant protein (MCP)-1 levels and prevented the bleomycin-induced decrease in lung interferon (IFN)-γ levels. Furthermore, pirfenidone suppressed elevation of lung basic-fibroblast growth factor (bFGF), transforming growth factor (TGF)-β1 levels, lung stroma cell derived factor (SDF)-1α and IL-18[5].

Pirfenidoneat (250 mg/kg) potently inhibited the production of the proinflammatory cytokines, TNF-α, interferon-gamma, and interleukin-6, but enhanced the production of the anti-inflammatory cytokine, interleukin-10 in mice [1]. Pirfenidone (250 mg/kg/day) ameliorated cyclosporine-induced fibrosis by about 50% and improved CsA-induced decrease in creatinine clearance. PFD treatment also decreased the TGF-β1 protein expression by 80% in salt-depleted Sprague-Dawley rats [6]. Pirfenidone (400 mg/kg/day) inhibited heat shock protein 47-positive cells and myofibroblasts, the principal cells responsible for the accumulation and deposition of extracellular matrix seen in pulmonary fibrosis in ICR mice intravenously injected with bleomycin [7].

In rats treated with dimethylnitrosamine (10 mg/kg) for 5 weeks, 0.5% pirfenidonereduced the degree of liver injury. Administration of pirfenidone(0.5%, liquid diet)downregulated the elevated levels of those transcripts by 50-60%, and this was associated with a 70% reduction in collagen deposition[8].

Clinical Trials: Pirfenidone is a promising agent for individuals with overt diabetic nephropathy. In the pirfenidone 1200-mg/d group, the mean eGFR increased (+3.3 ± 8.5 ml/min per 1.73 m2) while the mean eGFR decreased in the placebo group (2.2 ± 4.8 ml/min per 1.73 m2;P= 0.026). In the pirfenidone 2400-mg/d group, the dropout rate was high (11 of 25) and the change in eGFR was not significantly different from placebo (1.9 ± 6.7 ml/min per 1.73 m2)[9].

Pirfenidone has entered three Phase III, randomized,double-blind, placebo-controlledstudies in patients withidiopathic pulmonary fibrosis(IPF)[10,11]. In the pirfenidone group, as compared with the placebo group, there was a relative reduction of 47.9% in the proportion of patients who had an absolute decline of 10 percentage points and a relative increase of 132.5% in the proportion of patients with no decline in FVC (P < 0.001). Pirfenidonealso reduced the decline in the 6-minute walk distance (P = 0.04) and improved progression-free survival (P < 0.001). The most common adverse events were gastrointestinal and skin-related diseases [11].

References:
[1].  Nakazato H, Oku H, Yamane S, et al. A novel anti-fibrotic agent pirfenidone suppresses tumor necrosis factor-α at the translational level[J]. European journal of pharmacology, 2002, 446(1): 177-185.
[2].  Burghardt I, Tritschler F, Opitz C A, et al. Pirfenidone inhibits TGF-β expression in malignant glioma cells[J]. Biochemical and biophysical research communications, 2007, 354(2): 542-547.
[3].  Lee B S, Margolin S B, Nowak R A. Pirfenidone: a novel pharmacological agent that inhibits leiomyoma cell proliferation and collagen production[J]. The Journal of Clinical Endocrinology & Metabolism, 1998, 83(1): 219-223.
[4].  Garca L, Hernández I, Sandoval A, et al. Pirfenidone effectively reverses experimental liver fibrosis[J]. Journal of hepatology, 2002, 37(6): 797-805.
[5].  Oku H, Shimizu T, Kawabata T, et al. Antifibrotic action of pirfenidone and prednisolone: different effects on pulmonary cytokines and growth factors in bleomycin-induced murine pulmonary fibrosis[J]. European journal of pharmacology, 2008, 590(1): 400-408.
[6].  Shihab F S, Bennett W M, Yi H, et al. Pirfenidone Treatment Decreases Transforming Growth Factor‐β1 and Matrix Proteins and Ameliorates Fibrosis in Chronic Cyclosporine Nephrotoxicity[J]. American Journal of Transplantation, 2002, 2(2): 111-119.
[7].  Kakugawa T, Mukae H, Hayashi T, et al. Pirfenidone attenuates expression of HSP47 in murine bleomycin-induced pulmonary fibrosis[J]. European Respiratory Journal, 2004, 24(1): 57-65.
[8].  Di Sario A, Bendia E, Macarri G, et al. The anti-fibrotic effect of pirfenidone in rat liver fibrosis is mediated by downregulation of procollagen α1 (I), TIMP-1 and MMP-2[J]. Digestive and liver disease, 2004, 36(11): 744-751.
[9].  Sharma K, Ix J H, Mathew A V, et al. Pirfenidone for diabetic nephropathy[J]. Journal of the American Society of Nephrology, 2011, 22(6): 1144-1151.
[10].  Azuma A, Nukiwa T, Tsuboi E, et al. Double-blind, placebo-controlled trial of pirfenidone in patients with idiopathic pulmonary fibrosis[J]. American journal of respiratory and critical care medicine, 2005, 171(9): 1040-1047.
[11].  King Jr T E, Bradford W Z, Castro-Bernardini S, et al. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis[J]. New England Journal of Medicine, 2014, 370(22): 2083-2092.