A pilot study in patients with established advanced liver fibrosis using pirfenidone

Armendáriz‐Borunda, Juan; Islas-Carbajal, María Cristina; Meza-García, Eduardo; Rincón, Ana Rosa; Lucano, S; Sandoval, Ana; Salazar, Andrea; Berumen, Jaime; A, Alvarez Prechous; Covarrubias, A; Arechiga, G; García, L. Sarmiento

doi:10.1136/gut.2006.107136

Cited by 74 publications

(61 citation statements)

References 7 publications

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“…Pirfenidone, an orally available pyridine derivative, inhibits TGF-␤ production and has been subjected to a small uncontrolled pilot study in HCV-related fibrosis, in which it improved liver inflammation and fibrosis in some patients after 12 mo of treatment (1).…”

Section: Reducing Fibrogenesismentioning

confidence: 99%

Therapeutic targets in liver fibrosis

Fallowfield

2011

American Journal of Physiology-Gastrointestinal and Liver Physi

116

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Detailed analysis of the cellular and molecular mechanisms that mediate liver fibrosis has provided a framework for therapeutic approaches to prevent, slow down, or even reverse fibrosis and cirrhosis. A pivotal event in the development of liver fibrosis is the activation of quiescent hepatic stellate cells (HSCs) to scar-forming myofibroblast-like cells. Consequently, HSCs and the factors that regulate HSC activation, proliferation, and function represent important antifibrotic targets. Drugs currently licensed in the US and Europe for other indications target HSC-related components of the fibrotic cascade. Their deployment in the near future looks likely. Ultimately, treatment strategies for liver fibrosis may vary on an individual basis according to etiology, risk of fibrosis progression, and the prevailing pathogenic milieu, meaning that a multiagent approach could be required. The field continues to develop rapidly and starts to identify exciting potential targets in proof-of-concept preclinical studies. Despite this, no antifibrotics are currently licensed for use in humans. With epidemiological predictions for the future prevalence of viral, obesity-related, and alcohol-related cirrhosis painting an increasingly gloomy picture, and a shortfall in donors for liver transplantation, the clinical urgency for new therapies is high. There is growing interest from stakeholders keen to exploit the market potential for antifibrotics. However, the design of future trials for agents in the developmental pipeline will depend on strategies that enable equal patient stratification, techniques to reliably monitor changes in fibrosis over time, and the definition of clinically meaningful end points. antifibrotic therapy; hepatic stellate cell MECHANISMS AND MEDIATORS OF LIVER FIBROGENESIS AND FIBROSIS REGRESSIONAs our understanding of the complex biological processes that regulate liver scarring increases, points of intervention in the fibrotic cascade are relentlessly uncovered. Key mechanisms and mediators are outlined below, to highlight emerging therapeutic targets (Fig. 1). Liver Fibrogenesis and the Role of the Hepatic Stellate Cell-MyofibroblastLiver fibrogenesis is orchestrated by a heterogeneous population of profibrogenic myofibroblasts (MFBs), the majority originating from hepatic stellate cells (HSCs), following a process termed "activation." Other sources of fibrogenic cells have recently been implicated, including portal fibroblasts and cells derived from the bone marrow (including fibrocytes) (7). A more controversial phenomenon is epithelial-to-mesenchymal transition, whereby epithelial cells (hepatocytes or cholangiocytes) undergo transdifferentiation to MFBs driven by bone morphogenic protein 7 and the hedgehog pathway, respectively, as well as a series of proinflammatory mediators. The relative contribution of these diverse precursors to fibrogenesis and the timing of their recruitment are unclear but may vary by disease etiology. In normal liver, quiescent HSCs store vitamin A in lipid droplets, but i...

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Section: Reducing Fibrogenesismentioning

confidence: 99%

Therapeutic targets in liver fibrosis

Fallowfield

2011

American Journal of Physiology-Gastrointestinal and Liver Physi

116

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“…Clinical trials that have evaluated safety and efficacy of pirfenidone in various fibrotic diseases have also been encouraging. In a pilot study of 15 patients with hepatitis C-associated cirrhosis, pirfenidone therapy was associated with a significant improvement of liver histology in Ͼ50% of patients (16). A double-blind, randomized, controlled study of pirfenidone for treatment of secondary multiple sclerosis revealed a marked improvement in bladder dysfunction and a significantly decreased relapse rate (17).…”

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confidence: 99%

Pirfenidone Slows Renal Function Decline in Patients with Focal Segmental Glomerulosclerosis

Cho¹,

Smith²,

Branton³

et al. 2007

Clinical Journal of the American Society of Nephrology

190

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Background and Objectives: Pirfenidone is an orally available antifibrotic agent that has shown benefit in animal models of pulmonary and renal fibrosis and in clinical trials of pulmonary fibrosis, multiple sclerosis, and hepatic cirrhosis. Our objective was to determine whether pirfenidone slows the loss of renal function in focal segmental glomerulosclerosis.Design, Setting, Participants, & Measurements: An open-label trial was performed to evaluate the safety and efficacy of pirfenidone in patients with idiopathic and postadaptive focal segmental glomerulosclerosis. The monthly change in estimated GFR, expressed as ml/min per 1.73 m 2 , was compared between the baseline period and the treatment period. During both periods, patients received angiotensin antagonist therapy if tolerated. Twenty-one patients were enrolled, and 18 patients completed a median of 13 mo of pirfenidone treatment.Results: The monthly change in GFR improved from a median of ؊0.61 ml/min per 1.73 m 2 (interquartile range ؊1.31 to ؊0.41) during the baseline period to ؊0.45 ml/min per 1.73 m 2 (interquartile range ؊0.78 to ؊0.16) with pirfenidone therapy. This change represents a median of 25% improvement in the rate of decline (P < 0.01). Pirfenidone had no effect on BP or proteinuria. Adverse events attributed to therapy included dyspepsia, sedation, and photosensitive dermatitis.Conclusions: It is concluded that pirfenidone is an attractive candidate for placebo-controlled trials in patients with progressive chronic kidney disease.

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“…Initially used as an antihelminthic and antipyretic, it is currently approved as an antifibrotic drug for use in patients with IPF. It has also been shown to reduce liver fibrosis in animal models and improve fibrosis in patients with chronic hepatitis C 3, 4, 11. In large randomized control trials, hepatotoxicity has been reported in about 4% of patients, with mild to moderate asymptomatic serum aminotransferase elevations requiring termination of the drug in up to 1% of cases 11.…”

Section: Discussionmentioning

confidence: 99%

“…Pirfenidone is an anti‐inflammatory and antifibrotic drug used for the treatment of idiopathic pulmonary fibrosis (IPF) 2. It has been shown to reduce liver fibrosis 3, 4. Hepatotoxicity with its use is rare and manifests as a mild rise in aminotransferases.…”

Section: Introductionmentioning

confidence: 99%

Drug idiosyncrasy due to pirfenidone presenting as acute liver failure: Case report and mini‐review of the literature

Verma

Kumar

Mitra

et al. 2017

Hepatology Communications

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Idiosyncratic drug‐induced liver injury (DILI) is ranked among the top most common etiologies of acute liver failure (ALF). It carries poor transplant‐free survival. Pirfenidone is an anti‐inflammatory and antifibrotic drug that is commonly used for the treatment of idiopathic pulmonary fibrosis (IPF). Hepatotoxicity due to pirfenidone is rare and generally manifests as a mild rise in serum aminotransferases. In this mini‐review, we report an unusual case of idiosyncratic DILI due to pirfenidone presenting as ALF, with emphasis on the definition, classification, diagnostic criteria, histopathology, molecular markers, and treatment options for DILI and related ALF. A 77‐year‐old man with known Parkinson's disease and IPF presented with jaundice for 7 days and altered mental status for 4 days. His long‐term medications included a levodopa/carbidopa combination with a recent addition of pirfenidone over the previous 1 month; there was no monitoring of liver function tests. The evaluation suggested features of acute liver failure with grade III hepatic encephalopathy, acute kidney injury, and metabolic acidosis. The diagnostic workup ruled out viral, toxic, ischemic, and other etiologies for acute liver failure. Based on a Roussel Uclaf Causality Assessment Method score of 7 and possible DILI‐ALF, pirfenidone was withdrawn. He was evaluated for liver transplantation but was declined. Despite all supportive measures in intensive care, organ failure progressed and he succumbed to the illness on day 4. Postmortem liver biopsy revealed findings consistent with DILI (final Roussel Uclaf Causality Assessment score, 10). Conclusion: DILI‐ALF carries poor prognosis, and liver transplantation should be considered early in the course. Characterization, reporting, monitoring, and labeling of pirfenidone‐related hepatotoxicity is vital given its common use in IPF. (Hepatology Communications 2018;2:142–147)

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A pilot study in patients with established advanced liver fibrosis using pirfenidone

Cited by 74 publications

References 7 publications

Therapeutic targets in liver fibrosis

Therapeutic targets in liver fibrosis

Pirfenidone Slows Renal Function Decline in Patients with Focal Segmental Glomerulosclerosis

Drug idiosyncrasy due to pirfenidone presenting as acute liver failure: Case report and mini‐review of the literature

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