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Case 20
Published in Andrew Solomon, Julia Anstey, Liora Wittner, Priti Dutta, Clinical Cases, 2021
Andrew Solomon, Julia Anstey, Liora Wittner, Priti Dutta
There are two new agents whose mechanism of action suggests promising potential for efficacy to treat these conditions; nintedanib and pirfenidone. Nintedanib inhibits tyrosine kinase receptors and thus seems to interfere with vascular endothelial growth factor (VEGF) and fibroblast growth factor action thus reducing fibrosis. Pirfenidone appears to have anti-inflammatory and fibrotic-reducing activity.
Pulmonary fibrosis
Published in Anthony J. Hickey, Heidi M. Mansour, Inhalation Aerosols, 2019
Priya Muralidharan, Don Hayes, Heidi M. Mansour
Among the currently available drugs, pirfenidone is an antifibrotic with anti-inflammatory properties, which inhibits the synthesis of growth factors responsible for fibrogenesis. The therapeutic dose given orally is a high dose of 801 mg three times daily. This has been shown to have some gastrointestinal (GI) side effects, including nausea, abdominal pain, dyspepsia, and diarrhea in addition to photosensitivity and rash (14). Nintedanib is a tyrosine kinase receptor inhibitor targeting growth factors that eventually attenuates fibrosis development (15). It is given as 150 mg capsules twice daily orally. Nintedanib is also known to cause GI side effects such as diarrhea, nausea, abdominal pain, and vomiting and liver enzyme elevation. Although nintedanib received a conditional recommendation for its clinical use, the other tyrosine kinase receptor inhibitor imatinib was not recommended for IPF treatment. The committee has strongly recommended against the use of imatinib due to the high cost incurred and the lack of effective benefit from the clinical trial involving 119 patients (16). The use of corticosteroids is also limited due to the reduced clinical benefit. It is recommended only for acute disease exacerbations (15). Anti-GER therapies such as proton pump inhibitors or histamine 2 blocker receptor antagonists are commonly prescribed for IPF patients since GER is commonly seen in IPF patients.
Interstitial lung disease associated with connective tissue disorders
Published in Muhunthan Thillai, David R Moller, Keith C Meyer, Clinical Handbook of Interstitial Lung Disease, 2017
Deborah Assayag, Aryeh Fischer
With the recent approval of two novel anti-fibrotic agents (pirfenidone and nintedanib) for the treatment of idiopathic pulmonary fibrosis (IPF), there is a pressing need to evaluate their efficacy in fibrotic forms of CTD-ILD. Studies of these agents in SSc-ILD are already underway. The safety and tolerability of pirfenidone was tested in the LOTUSS (Safety and Tolerability of Pirfenidone in Patients with Systemic Sclerosis-Associated Interstitial Lung Disease) study (120). This open-label, phase II, 16-week study enrolled 63 patients, and 64% of the study participants were on background MMF. Pirfenidone was found to be safe and generally well tolerated. However, LOTUSS was not designed to determine whether the drug is effective in treating SSc-ILD. A double-blind, randomized, placebo-controlled trial evaluating efficacy and safety of oral nintedanib treatment for at least 52 weeks in patients with SSc-ILD is actively enrolling (ClinicalTrials.gov Identifier: NCT02597933) and should help determine whether nintedanib has a role in the management of SSc-ILD. Beyond SSc-ILD, other forms of fibrotic CTD-ILD need to be studied.
Idiopathic pulmonary fibrosis and lung cancer: targeting the complexity of the pharmacological interconnection
Published in Expert Review of Respiratory Medicine, 2022
Fabio Perrotta, Vittorio Chino, Valentino Allocca, Vito D’Agnano, Chandra Bortolotto, Andrea Bianco, Angelo Guido Corsico, Giulia Maria Stella
The other antifibrotic agent used in IPF is Pirfenidone (5-methyl-1-phenyl-2-[1 H]-pyridone), a synthetic molecule orally administered, that regulates the activity of TGF-β and TNF-α, cytokines with a crucial role in interstitial pulmonary fibrosis (IPF). In most studies pirfenidone have shown the properties to reduce lung markers of fibrosis, the fibroblasts proliferation and collagen synthesis [33–35]. In the CAPACITY study, pirfenidone administered at dose of 2403 mg/die, significantly reduced decline of mean FVC predicted in percentage and reduced, in addition, the percentage of patients with a FVC decline ≥ 10%. The effect of the pirfenidone was major at 24 weeks of treatment and persisted until 72 weeks [28]. In the same work pirfenidone prolonged survival with a 36% reduction in risk of death or disease progression [28]. These data are confirmed by ASCEND trial in which pirfenidone (2403 mg/die) reduced disease progression, improved exercise tolerance, and progression-free survival in patients with idiopathic pulmonary fibrosis. Treatment was well-tolerated with acceptable side effects [36].
Pirfenidone 5-hydroxylation is mainly catalysed by CYP1A2 and partly catalysed by CYP2C19 and CYP2D6 in the human liver
Published in Xenobiotica, 2021
Yongjie Zhang, Rei Sato, Tatsuki Fukami, Masataka Nakano, Miki Nakajima
Pirfenidone is a first-line drug for the treatment of idiopathic pulmonary fibrosis. It has pronounced antifibrotic and anti-inflammatory efficacy and is generally well tolerated in patients with idiopathic pulmonary fibrosis (Taniguchi et al. 2010). Nevertheless, several adverse reactions, including liver injury, photosensitivity reaction/rash, and gastrointestinal injuries (Cottin et al. 2018), could be an obstacle to the rational usage of pirfenidone. The severity of adverse drug reactions varies greatly, from autorecovery to even death in extreme cases (Verma et al. 2018). The mechanisms underlying these adverse drug reactions to pirfenidone have been largely unknown until now, although toxic or immunogenic metabolite(s) and/or drug–drug interactions have been postulated as the causes of pirfenidone-induced toxicities (LiverTox website: https://www.ncbi.nlm.nih.gov/books/NBK548769/). However, concrete evidence is lacking.
An updated safety review of the drug treatments for idiopathic pulmonary fibrosis
Published in Expert Opinion on Drug Safety, 2021
Giacomo Sgalla, Alessia Comes, Luca Richeldi
The expanded access program in the US, an open-label study of 1620 patients with IPF [22], corroborated the safety profile of pirfenidone. In addition, several studies conducted in order to evaluate the tolerability and the efficacy of pirfenidone in a real setting have confirmed the known safety profile of pirfenidone with no new safety signals emerged [23–27]. In particular, 138 patients with IPF, diagnosed at Asan Medical Center, Seoul, Republic of Korea, treated with pirfenidone between January 2010 and December 2015 were included in a retrospective study to evaluate the safety and the efficacy of pirfenidone in advanced and non-advanced disease groups [26]. Advanced IPF was defined as FVC<50% predicted or DLCO<30% predicted. The authors endorsed the safety profile of pirfenidone in advanced and non-advanced IPF patients; anorexia, nausea and photosensitivity were the more frequent events (39%, 23%, and 21%, respectively). In another real-life observation study conducted in Turkey between January and September 2017, dyspepsia (36.4%), nausea (27.3%), and rash/photosensitivity (24.2%) were the most frequent side effects reported [25]. A real-world, retrospective study conducted from 2014 to 2016 to evaluate the tolerability of pirfenidone and nintedanib in non-clinical trial patients with IPF, showed a comparable safety profile of the two drugs in clinical practice with subjects enrolled in clinical trials [28]. In particular, nausea was the most common side effect (26%) in patients taking pirfenidone followed by rash/photosensitivity (14.7%).