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Pharmaceuticals (Basel, Switzerland) May 2024Pirfenidone and Nintedanib are specific drugs used against idiopathic pulmonary fibrosis (IPF) that showed efficacy in non-IPF fibrosing interstitial lung diseases... (Review)
Review
Pirfenidone and Nintedanib are specific drugs used against idiopathic pulmonary fibrosis (IPF) that showed efficacy in non-IPF fibrosing interstitial lung diseases (ILD). Both drugs have side effects that affect patients in different ways and have different levels of severity, making treatment even more challenging for patients and clinicians. The present review aims to assess the effectiveness and potential complications of Pirfenidone and Nintedanib treatment regimens across various ILD diseases. A detailed search was performed in relevant articles published between 2018 and 2023 listed in PubMed, UpToDate, Google Scholar, and ResearchGate, supplemented with manual research. The following keywords were searched in the databases in all possible combinations: Nintedanib; Pirfenidone, interstitial lung disease, and idiopathic pulmonary fibrosis. The most widely accepted method for evaluating the progression of ILD is through the decline in forced vital capacity (FVC), as determined by respiratory function tests. Specifically, a decrease in FVC over a 6-12-month period correlates directly with increased mortality rates. Antifibrotic drugs Pirfenidone and Nintedanib have been extensively validated; however, some patients reported several side effects, predominantly gastrointestinal symptoms (such as diarrhea, dyspepsia, and vomiting), as well as photosensitivity and skin rashes, particularly associated with Pirfenidone. In cases where the side effects are extremely severe and are more threatening than the disease itself, the treatment has to be discontinued. However, further research is needed to optimize the use of antifibrotic agents in patients with PF-ILDs, which could slow disease progression and decrease all-cause mortality. Finally, other studies are requested to establish the treatments that can stop ILD progression.
PubMed: 38931376
DOI: 10.3390/ph17060709 -
Expert Opinion on Investigational Drugs Aug 2020The two available therapies for idiopathic pulmonary fibrosis (IPF), pirfenidone and nintedanib, slow down but do not halt IPF progression. As such, in the last few... (Review)
Review
INTRODUCTION
The two available therapies for idiopathic pulmonary fibrosis (IPF), pirfenidone and nintedanib, slow down but do not halt IPF progression. As such, in the last few years several agents with specific molecular targets have been investigated to find a cure forIPF. Pamrevlumab, a recombinant human antibody that binds to connective tissue growth factor (CTGF) has emerged as a potential therapy for IPF and has advanced to phase 3 clinical trials.
AREAS COVERED
The authors offer a backdrop to the current IPF treatment market and describe the chemistry, pharmacokinetics and pharmacodynamics of pamrevlumab. They summarize the preclinical and early clinical evidence on pamrevlumab and propose ways of progressing this agent further as a potential IPF treatment.
EXPERT OPINION
Pamrevlumab was effective and safe in patients in a placebo-controlled phase 2 trial, demonstrating its potential to become an alternative therapeutic option for IPF; however, the feasibility of intravenous administration in clinical practice may be a hurdle to its use as a first-line treatment. Further studies are necessary to assess its effects when administered with pirfenidone or nintedanib and this could open up a new era of combined therapeutic approaches for IPF.
Topics: Animals; Antibodies, Monoclonal, Humanized; Connective Tissue Growth Factor; Disease Progression; Humans; Idiopathic Pulmonary Fibrosis; Indoles; Pyridones; Treatment Outcome
PubMed: 32447983
DOI: 10.1080/13543784.2020.1773790 -
The Annals of Pharmacotherapy Dec 2019Provide information for pharmacists on idiopathic pulmonary fibrosis (IPF) and its treatment. All articles with data from randomized controlled trials of nintedanib or... (Review)
Review
Provide information for pharmacists on idiopathic pulmonary fibrosis (IPF) and its treatment. All articles with data from randomized controlled trials of nintedanib or pirfenidone were reviewed. IPF is a progressive and ultimately fatal interstitial lung disease characterized by decline in lung function and worsening dyspnea. It is uncommon and mainly occurs in individuals aged >60 years, particularly men with a history of smoking. Nintedanib and pirfenidone were approved in the United States for the treatment of IPF in 2014 and received conditional recommendations in the 2015 American Thoracic Society/European Respiratory Society/Japanese Respiratory Society/Latin American Thoracic Association treatment guidelines. These drugs slow the progression of IPF by reducing the rate of decline in lung function. Their adverse event profile is characterized mainly by gastrointestinal events, which can be managed through dose adjustment and symptom management. Management of IPF should also include smoking cessation, vaccinations, and supportive care such as patient education, pulmonary rehabilitation, and the use of supplemental oxygen as well as optimizing the management of comorbidities. This review provides clinical pharmacists with information on the course of IPF, what can be expected of current treatments, and how to help patients manage their drug therapy. IPF is a progressive disease, but treatments are available that can slow the progression of the disease. Clinical pharmacists can play an important role in the care of patients with IPF through patient education, monitoring medication compliance and safety, ensuring drugs for comorbidities are optimized, and preventive strategies such as immunizations.
Topics: Comorbidity; Disease Progression; Female; Humans; Idiopathic Pulmonary Fibrosis; Indoles; Male; Medication Adherence; Middle Aged; Patient Education as Topic; Pharmacists; Pyridones
PubMed: 31280590
DOI: 10.1177/1060028019862497 -
Scientific Reports Nov 2022Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease of unknown etiology. Currently, pirfenidone and nintedanib are the only FDA-approved drugs...
Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease of unknown etiology. Currently, pirfenidone and nintedanib are the only FDA-approved drugs for the treatment of IPF and are now the standard of care. This is a significant step in slowing down the progression of the disease. However, the drugs are unable to stop or reverse established fibrosis. Several retrospective clinical studies indicate that proton pump inhibitors (PPIs; FDA-approved to treat gastroesophageal reflux) are associated with favorable outcomes in patients with IPF, and emerging preclinical studies report that PPIs possess antifibrotic activity. In this study, we evaluated the antifibrotic efficacy of the PPI esomeprazole when combined with pirfenidone in vitro and in vivo. In cell culture studies of IPF lung fibroblasts, we assessed the effect of the combination on several fibrosis-related biological processes including TGFβ-induced cell proliferation, cell migration, cell contraction, and collagen production. In an in vivo study, we used mouse model of TGFβ-induced lung fibrosis to evaluate the antifibrotic efficacy of esomeprazole/pirfenidone combination. We also performed computational studies to understand the molecular mechanisms by which esomeprazole and/or pirfenidone regulate lung fibrosis. We found that esomeprazole significantly enhanced the anti-proliferative effect of pirfenidone and favorably modulated TGFβ-induced cell migration and contraction of collagen gels. We also found that the combination significantly suppressed collagen production in response to TGFβ in comparison to pirfenidone monotherapy. In addition, our animal study demonstrated that the combination therapy effectively inhibited the differentiation of lung fibroblasts into alpha smooth muscle actin (αSMA)-expressing myofibroblasts to attenuate the progression of lung fibrosis. Finally, our bioinformatics study of cells treated with esomeprazole or pirfenidone revealed that the drugs target several extracellular matrix (ECM) related pathways with esomeprazole preferentially targeting collagen family members while pirfenidone targets the keratins. In conclusion, our cell biological, computational, and in vivo studies show that the PPI esomeprazole enhances the antifibrotic efficacy of pirfenidone through complementary molecular mechanisms. This data supports the initiation of prospective clinical studies aimed at repurposing PPIs for the treatment of IPF and other fibrotic lung diseases where pirfenidone is prescribed.
Topics: Animals; Mice; Esomeprazole; Transforming Growth Factor beta; Prospective Studies; Retrospective Studies; Proton Pump Inhibitors; Idiopathic Pulmonary Fibrosis; Disease Models, Animal
PubMed: 36450789
DOI: 10.1038/s41598-022-24985-x -
The European Respiratory Journal Apr 2023
Topics: Humans; Fibrosis; Pyridones
PubMed: 37105587
DOI: 10.1183/13993003.00240-2023 -
Nature Medicine Aug 2021In heart failure with preserved ejection fraction (HFpEF), the occurrence of myocardial fibrosis is associated with adverse outcome. Whether pirfenidone, an oral... (Randomized Controlled Trial)
Randomized Controlled Trial
In heart failure with preserved ejection fraction (HFpEF), the occurrence of myocardial fibrosis is associated with adverse outcome. Whether pirfenidone, an oral antifibrotic agent without hemodynamic effect, is efficacious and safe for the treatment of HFpEF is unknown. In this double-blind, phase 2 trial ( NCT02932566 ), we enrolled patients with heart failure, an ejection fraction of 45% or higher and elevated levels of natriuretic peptides. Eligible patients underwent cardiovascular magnetic resonance and those with evidence of myocardial fibrosis, defined as a myocardial extracellular volume of 27% or greater, were randomly assigned to receive pirfenidone or placebo for 52 weeks. Forty-seven patients were randomized to each of the pirfenidone and placebo groups. The primary outcome was change in myocardial extracellular volume, from baseline to 52 weeks. In comparison to placebo, pirfenidone reduced myocardial extracellular volume (between-group difference, -1.21%; 95% confidence interval, -2.12 to -0.31; P = 0.009), meeting the predefined primary outcome. Twelve patients (26%) in the pirfenidone group and 14 patients (30%) in the placebo group experienced one or more serious adverse events. The most common adverse events in the pirfenidone group were nausea, insomnia and rash. In conclusion, among patients with HFpEF and myocardial fibrosis, administration of pirfenidone for 52 weeks reduced myocardial fibrosis. The favorable effects of pirfenidone in patients with HFpEF will need to be confirmed in future trials.
Topics: Aged; Female; Heart Failure; Humans; Male; Pyridones; Time Factors; Treatment Outcome
PubMed: 34385704
DOI: 10.1038/s41591-021-01452-0 -
Therapeutic Delivery Aug 2023Idiopathic pulmonary fibrosis is a rare disease with few efficient drugs in the market. The consequences of this disease are mainly respiratory failure and pulmonary...
Idiopathic pulmonary fibrosis is a rare disease with few efficient drugs in the market. The consequences of this disease are mainly respiratory failure and pulmonary hypertension. In our experiment we used the drugs pirfenidone, nintetanib and macitentan. We performed nebulization experiments with three jet nebulizers and three ultrasound nebulizers with different combinations of residual cup designs, and residual cup loadings in order to identify which combination produces droplets of less than 5 μm in mass median aerodynamic diameter. Pirfenidone versus nintetanib had smaller droplet size formation at both inhaled technologies (1.37 < 2.23 and 1.92 < 3.11, jet and ultrasound respectively). Pirfenidone and nintetanib can be administered as aerosol in any type of nebulization system.
Topics: Humans; Pulmonary Fibrosis; Respiratory Aerosols and Droplets; Nebulizers and Vaporizers; Particle Size
PubMed: 37584210
DOI: 10.4155/tde-2023-0045 -
Frontiers in Pharmacology 2023Recent studies have suggested that combination therapy with pirfenidone and nintedanib is safe and tolerable in patients with idiopathic pulmonary fibrosis (IPF)....
Recent studies have suggested that combination therapy with pirfenidone and nintedanib is safe and tolerable in patients with idiopathic pulmonary fibrosis (IPF). However, data from real-world practice are limited. Thus, we aimed to investigate the safety and efficacy of this combination therapy in patients with IPF in a real-world setting. A multicenter retrospective cohort study was conducted to investigate the safety and efficacy of combination therapy with pirfenidone and nintedanib in 45 patients with IPF. Incidences of adverse events and rates of lung function decline were compared before and after the combination therapy. Propensity score matching was performed to compare the outcomes between the combination and monotherapy groups. The mean age of the patients was 68.8 years, and 82.2% of them were male. The median follow-up duration after combination therapy was 12.1 months. The majority of the patients (97.8%) received nintedanib as an add-on to pirfenidone. The most common adverse events after the combination therapy were diarrhea and anorexia. Pirfenidone or nintedanib was stopped in 12 patients owing to gastrointestinal AEs, lung transplantation, or financial problems. In patients with serial lung function data, the rate of decline in the forced vital capacity was significantly reduced after the combination therapy. In the matched analysis, the combination group had a higher incidence of diarrhea than the monotherapy group without an increase in serious adverse events; however, the two groups had similar changes in forced vital capacity (FVC). The combination of pirfenidone and nintedanib in patients with IPF has the potential to reduce the rate of FVC decline. However, in the matched analysis, FVC decline was comparable between the patients on combination therapy and those on monotherapy. The incidence of certain adverse events, particularly diarrhea, was higher with combination therapy, but serious adverse events were similar between the groups.
PubMed: 38192410
DOI: 10.3389/fphar.2023.1301923 -
Medicina Clinica Jun 2023Although pulmonary fibrosis secondary to COVID-19 infection is uncommon, it can lead to problems if not treated effectively in the early period. This study aimed to... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Although pulmonary fibrosis secondary to COVID-19 infection is uncommon, it can lead to problems if not treated effectively in the early period. This study aimed to compare the effects of treatment with nintedanib and pirfenidone in patients with COVID-19-related fibrosis.
METHODS
Thirty patients who presented to the post-COVID outpatient clinic between May 2021 and April 2022 with a history of COVID-19 pneumonia and exhibited persistent cough, dyspnea, exertional dyspnea, and low oxygen saturation at least 12 weeks after diagnosis were included. The patients were randomized to receive off-label treatment with nintedanib or pirfenidone and were followed up for 12 weeks.
RESULTS
After 12 weeks of treatment, all pulmonary function test (PFT) parameters, 6MWT distance, and oxygen saturation were increased compared to baseline in both the pirfenidone group and nintedanib groups, while heart rate and radiological score levels were decreased (p<0.05 for all). The changes in 6MWT distance and oxygen saturation were significantly greater in the nintedanib group than in the pirfenidone group (p=0.02 and 0.005, respectively). Adverse drug effects were more frequent with nintedanib than pirfenidone, with the most common being diarrhea, nausea, and vomiting.
CONCLUSION
In patients with interstitial fibrosis after COVID-19 pneumonia, both nintedanib and pirfenidone were observed to be effective in improving radiological score and PFT parameters. Nintedanib was more effective than pirfenidone in increasing exercise capacity and saturation values but caused more adverse drug effects.
Topics: Adult; Aged; Female; Humans; Male; Middle Aged; Antifibrotic Agents; Follow-Up Studies; Post-Acute COVID-19 Syndrome; Prospective Studies; Pulmonary Fibrosis; Pyridones; Treatment Outcome
PubMed: 37055254
DOI: 10.1016/j.medcli.2022.12.021 -
Advances in Therapy Sep 2023In the European Union (EU), the indication for the antifibrotic pirfenidone prior to April 2023 did not include patients with advanced idiopathic pulmonary fibrosis... (Clinical Trial)
Clinical Trial
INTRODUCTION
In the European Union (EU), the indication for the antifibrotic pirfenidone prior to April 2023 did not include patients with advanced idiopathic pulmonary fibrosis (IPF). This analysis compared the efficacy and safety of pirfenidone in advanced IPF versus non-advanced IPF.
METHODS
Data were included from the following studies of pirfenidone: ASCEND (NCT01366209); CAPACITY (004 [NCT00287716] and 006 [NCT00287729]); RECAP (NCT00662038; advanced IPF defined as percent predicted forced vital capacity [%FVC] < 50% and/or percent predicted carbon monoxide diffusing capacity [%DLco] < 35% at baseline); PASSPORT (NCT02699879; advanced IPF defined as baseline %FVC < 50%); and SP-IPF (NCT02951429; patients with advanced IPF [defined as %DLco ≤ 40% at screening] at risk of group 3 pulmonary hypertension).
RESULTS
In the pooled ASCEND/CAPACITY studies, the annual mean rate of FVC decline from baseline to Week 52 was significantly lower for pirfenidone versus placebo in advanced (p = 0.0035) and non-advanced IPF (p = 0.0001). Rate of all-cause mortality over 52 weeks was numerically lower for pirfenidone versus placebo in advanced and non-advanced IPF. In RECAP, the mean annual rate of FVC decline from baseline to Week 180 of pirfenidone treatment was similar in patients with advanced (- 141.5 mL) and non-advanced IPF (- 153.5 mL). In SP-IPF, the mean annual rate of FVC decline and rate of all-cause mortality from baseline to Week 52 in patients treated with placebo + pirfenidone were - 93.0 mL and 20.2%, respectively. No new safety signals were identified, and the safety profile of pirfenidone in patients with advanced IPF was generally consistent with that of non-advanced IPF.
CONCLUSIONS
These results highlight the benefit of pirfenidone treatment in patients with advanced and non-advanced IPF. As such, the indication for pirfenidone in the EU has now been updated to include the treatment of adult patients with advanced IPF.
TRIAL REGISTRATIONS
ASCEND (NCT01366209), CAPACITY 004 (NCT00287716), CAPACITY 006 (NCT00287729), RECAP (NCT00662038), PASSPORT (NCT02699879), and SP-IPF (NCT02951429).
Topics: Adult; Humans; Anti-Inflammatory Agents, Non-Steroidal; Idiopathic Pulmonary Fibrosis; Pyridones; Treatment Outcome; Vital Capacity
PubMed: 37391667
DOI: 10.1007/s12325-023-02565-3