Long-Term Safety of Antifibrotic Drugs in IPF: A Real-World Experience

Abstract

Pirfenidone and nintedanib are the only two drugs approved for the treatment of idiopathic pulmonary fibrosis (IPF). Both proved to be safe and well-tolerated in clinical trials, but real-world data and direct comparisons are scarce. This real-life study explored the safety profile of pirfenidone and nintedanib with a prolonged follow-up. We retrospectively collected clinical status, adverse events (AEs), and treatment changes from IPF patients who had started an antifibrotic treatment at our centre from December 2011 to December 2020, including 192 patients treated with pirfenidone and 89 with nintedanib. The majority of patients in both groups experienced one or more AEs during the follow-up. A higher proportion of AEs in the nintedanib group were effectively treated with behavioural modifications or additional medications compared with the pirfenidone group (52.5% vs. 40.6%, p = 0.04). Overall, a difference in the impact of AEs due to nintedanib versus pirfenidone resulted in a lower permanent discontinuation of therapy (8.3% vs. 18.3%, p = 0.02), with the latter being associated with a higher risk of drug discontinuation at 48 months after initiation (OR =2.52, p = 0.03). Our study confirms the safety profile of antifibrotic drugs in IPF but highlights that AEs due to nintedanib are usually easier to manage and lead to fewer cases of permanent discontinuation of therapy.

Clinical course of mild-to-moderate idiopathic pulmonary fibrosis during therapy with pirfenidone: Results of the non-interventional study AERplus

“…The percentage of non-smokers comprised only one third in the previous studies and more than 50 % in the present study. The incidence of adverse events was similar to that observed by Bonella and coworkers [23] and an Italian long-term safety study [30], and thus lower compared to the CAPACITY [12] and PASSPORT [18] studies as well as the German and Japanese retrospective studies [22,31]. Compared to the pan-European 2-year PASSPORT study, a smaller proportion of patients discontinued treatment due to ADRs [18], which may be a consequence of the shorter follow-up period.…”

Antifibrotic treatment adherence, efficacy and outcomes for patients with idiopathic pulmonary fibrosis in Spain: a real-world evidence study

“…This is not surprising as the study populations of RCTs tend to differ from those of RWE studies, which tend to include older patients with more comorbidities and more concomitant pharmacological treatments. Many authors have reported higher rates of drug discontinuation in populations with IPF, with pirfenidone showing a more favourable safety profile 9 17–23. However, we have to acknowledge that some of these RWE studies have shown a better safety profile for nintedanib, which could be explained by different study populations or different susceptibility to side effects among study participants.…”

Pirfenidone and Nintedanib in Pulmonary Fibrosis: Lights and Shadows

“…In addition, AEs were, in almost all the patients, easily manageable with therapy adjustments or additional treatments for the symptom; for example, the administration of anti-diarrheals and probiotics seemed to increase Nintedanib therapy tolerance in patients who had diarrhea as a main side effect [25]. These two drugs potentially have similar efficacy in slowing down IPF progression, while adverse events are different, and the main reasons that lead patients to permanently stop the therapy may depend on which drug is chosen [26][27][28]. In Pirfenidone Pharmaceuticals 2024, 17, 709 10 of 20 treatment cohorts, it has been highlighted that firstly, skin adverse events, especially photosensitivity reactions, and secondly, gastrointestinal intolerance (mainly nausea), are the main AEs in Pirfenidone cohorts and most likely led to therapy adjustments, as shown in Table 1.…”

“…This strategy usually allows the drug to be tolerated and treatment to continue, resulting in a lower percentage of patients having to discontinue therapy. Importantly, the dose reduction made to manage ADRs seems to not reduce the benefits of treatment in decreasing lung function decline [ 28 ].…”

“…When the lung is exposed to innumerable injuries, it enacts a series of repair and recovery processes that are finely synchronized with each other. However, in some cases, especially in predisposed individuals, continuous alveolar epithelial injury can lead to several consequences, including profibrotic epigenetic reprogramming, premature senescence, excessive production of profibrotic factors, and the activation of mesenchymal cells, which could lead to the development of pulmonary fibrosis [ 5 , 26 , 27 , 28 , 29 ]. The fibrosis process that characterizes ILDs and the associated hypoxemia led to pulmonary vasoconstriction and a reduction in angiogenesis through various pathological mechanisms, which result in, among other things, a reduction in capillary density.…”