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Thorax Nov 2023Fibrotic hypersensitivity pneumonitis (FHP) is an irreversible lung disease with high morbidity and mortality. We sought to evaluate the safety and effect of pirfenidone... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Fibrotic hypersensitivity pneumonitis (FHP) is an irreversible lung disease with high morbidity and mortality. We sought to evaluate the safety and effect of pirfenidone on disease progression in such patients.
METHODS
We conducted a single-centre, randomised, double-blinded, placebo-controlled trial in adults with FHP and disease progression. Patients were assigned in a 2:1 ratio to receive either oral pirfenidone (2403 mg/day) or placebo for 52 weeks. The primary end point was the mean absolute change in the per cent predicted forced vital capacity (FVC%). Secondary end points included progression-free survival (PFS, time to a relative decline ≥10% in FVC and/or diffusing capacity of the lung for carbon monoxide (DLCO), acute respiratory exacerbation, a decrease of ≥50 m in the 6 min walk distance, increase or introduction of immunosuppressive drugs or death), change in FVC slope and mean DLCO%, hospitalisations, radiological progression of lung fibrosis and safety.
RESULTS
After randomising 40 patients, enrolment was interrupted by the COVID-19 pandemic. There was no significant between-group difference in FVC% at week 52 (mean difference -0.76%, 95% CI -6.34 to 4.82). Pirfenidone resulted in a lower rate of decline in the adjusted FVC% at week 26 and improved PFS (HR 0.26, 95% CI 0.12 to 0.60). Results for other secondary end points showed no significant difference between groups. No deaths occurred in the pirfenidone group and one death (respiratory) occurred in the placebo group. There were no treatment-emergent serious adverse events.
CONCLUSIONS
The trial was underpowered to detect a difference in the primary end point. Pirfenidone was found to be safe and improved PFS in patients with FHP.
TRIAL REGISTRATION MUMBER
NCT02958917.
Topics: Adult; Humans; Idiopathic Pulmonary Fibrosis; Treatment Outcome; Pandemics; COVID-19; Vital Capacity; Pyridones; Double-Blind Method; Disease Progression; Alveolitis, Extrinsic Allergic
PubMed: 37028940
DOI: 10.1136/thorax-2022-219795 -
RSC Medicinal Chemistry Jun 2023In order to discover novel anti-pulmonary fibrosis agents, a series of novel pirfenidone derivatives were designed and synthesized. All compounds were investigated for...
In order to discover novel anti-pulmonary fibrosis agents, a series of novel pirfenidone derivatives were designed and synthesized. All compounds were investigated for their anti-pulmonary activity and characterized by C and H nuclear magnetic resonance and high-resolution mass spectrometry. Preliminary studies on their biological activity showed that all target compounds showed different degrees of inhibition on pulmonary fibrosis, and most of the derivatives were significantly better than pirfenidone.
PubMed: 37360397
DOI: 10.1039/d3md00072a -
MMW Fortschritte Der Medizin Feb 2023
Topics: Humans; Pyridones; Drugs, Generic
PubMed: 36849783
DOI: 10.1007/s15006-023-2384-3 -
Presse Medicale (Paris, France : 1983) Jun 2020Idiopathic pulmonary fibrosis (IPF) is characterized by relentlessly progressive lung function impairment that is consistently fatal in the absence of lung... (Review)
Review
Idiopathic pulmonary fibrosis (IPF) is characterized by relentlessly progressive lung function impairment that is consistently fatal in the absence of lung transplantation, as no curative pharmacological treatment exists. The pace of progression varies across patients, and acute life-threatening exacerbations occur unpredictably, causing further sharp drops in lung function. Recently introduced antifibrotic agents slow the pace of disease progression and may improve survival but fail to stop the fibrotic process. Moreover, the magnitude and kinetics of the response to these drugs cannot be predicted in the individual patient. These characteristics require that lung transplantation be considered early in the course of the disease. However, given the shortage of donor lungs, lung transplantation must be carefully targeted to those patients most likely to benefit. Current guidelines for lung transplantation listing may need reappraisal in the light of recent treatment advances. Patients with IPF often have multiple comorbidities such as coronary heart disease, frailty, and gastro-oesophageal reflux disease (GERD). Consequently, extensive screening for and effective treatment of concomitant conditions is crucial to appropriate candidate selection and outcome optimisation. A multidisciplinary approach is mandatory. Pulmonologists with expertise in IPF must work closely with lung transplant teams. Careful consideration must be given to preoperative optimisation, surgical technique, and pulmonary rehabilitation to produce the best post-transplantation outcomes.
Topics: Age Factors; Anti-Inflammatory Agents, Non-Steroidal; Cardiovascular Diseases; Comorbidity; Disease Progression; Frailty; Gastroesophageal Reflux; Humans; Hypertension, Pulmonary; Idiopathic Interstitial Pneumonias; Idiopathic Pulmonary Fibrosis; Indoles; Lung Neoplasms; Lung Transplantation; Prognosis; Pyridones; Telomere Shortening
PubMed: 32437844
DOI: 10.1016/j.lpm.2020.104026 -
European Journal of Pharmacology Jun 2024Idiopathic pulmonary fibrosis (IPF) associated to pulmonary hypertension (PH) portends a poor prognosis, characterized by lung parenchyma fibrosis and pulmonary artery...
Idiopathic pulmonary fibrosis (IPF) associated to pulmonary hypertension (PH) portends a poor prognosis, characterized by lung parenchyma fibrosis and pulmonary artery remodeling. Serum and parenchyma levels of Interleukin 11 (IL-11) are elevated in IPF-PH patients and contributes to pulmonary artery remodeling and PH. However, the effect of current approved therapies against IPF in pulmonary artery remodeling induced by IL-11 is unknown. The aim of this study is to analyze the effects of nintedanib and pirfenidone on pulmonary artery endothelial and smooth muscle cell remodeling induced by IL-11 in vitro. Our results show that nintedanib (NTD) and pirfenidone (PFD) ameliorates endothelial to mesenchymal transition (EnMT), pulmonary artery smooth muscle cell to myofibroblast-like transformation and pulmonary remodeling in precision lung cut slices. This study provided also evidence of the inhibitory effect of PFD and NTD on IL-11-induced endothelial and muscle cells proliferation and senescence. The inhibitory effect of these drugs on monocyte arrest and angiogenesis was also studied. Finally, we observed that IL-11 induced canonical signal transducer and activator of transcription 3 (STAT3) and non-canonical mitogen-activated protein kinase 1/2 (ERK1/2) phosphorylation, but, PFD and NTD only inhibited ERK1/2 phosphorylation. Therefore, this study provided evidence of the inhibitory effect of NTD and PFD on markers of pulmonary artery remodeling induced by IL-11.
Topics: Pulmonary Artery; Interleukin-11; Indoles; Animals; Myocytes, Smooth Muscle; STAT3 Transcription Factor; Endothelial Cells; Pyridones; Cell Proliferation; Rats; Humans; Male; Cellular Senescence; MAP Kinase Signaling System; Idiopathic Pulmonary Fibrosis; Monocytes; Vascular Remodeling
PubMed: 38561103
DOI: 10.1016/j.ejphar.2024.176547 -
Journal of Cardiovascular Medicine... Dec 2023An intense fibrotic response after myocardial infarction (MI) may lead to scar expansion and left ventricular (LV) remodeling. We investigated the effects of the...
BACKGROUND
An intense fibrotic response after myocardial infarction (MI) may lead to scar expansion and left ventricular (LV) remodeling. We investigated the effects of the antifibrotic drug pirfenidone in this setting.
METHODS
Male Wistar rats were randomized to: sham procedure (n = 13), reperfused MI-induced by ligating the left anterior descending artery (LAD) for 45 min (n = 17), reperfused MI plus standard therapy (aspirin, angiotensin-converting enzyme inhibitor, beta blocker, and mineralocorticoid receptor antagonist) (n = 17), reperfused MI plus pirfenidone alone (n = 17), or reperfused MI plus standard therapy and pirfenidone (n = 17). Rats surviving MI induction underwent cardiac magnetic resonance scans after 72 h and 30 days from MI, and were sacrificed on day 31.
RESULTS
Rats completing the whole protocol numbered 11 in the sham group, 9 in the untreated MI group, 8 in the standard treatment group, 9 in the pirfenidone alone group, and 9 in the standard treatment plus pirfenidone group. No significant differences emerged between LV volumes, ejection fraction or mass at 30 days or the differences from 72 h to 30 days. Small, nonsignificant differences between rats on pirfenidone alone vs. those on standard therapy emerged. The total extent of LV fibrosis, quantified as area and percentage of the tissue sample, did not differ significantly between rats on pirfenidone alone vs. those on standard therapy alone.
CONCLUSION
Pirfenidone does not have additional effects on LV remodeling or fibrosis compared with standard therapy, but its effects are similar to standard therapy alone.
Topics: Animals; Male; Rats; Cicatrix; Fibrosis; Myocardial Infarction; Rats, Wistar; Ventricular Remodeling; Random Allocation; Disease Models, Animal
PubMed: 37942789
DOI: 10.2459/JCM.0000000000001534 -
Heliyon Aug 2023Genetic variations in Idiopathic Pulmonary Fibrosis (IPF) affect survival and outcomes. Current antifibrotic agents are managed based on the patient's reported side...
BACKGROUND
Genetic variations in Idiopathic Pulmonary Fibrosis (IPF) affect survival and outcomes. Current antifibrotic agents are managed based on the patient's reported side effects, although certain single nucleotide polymorphisms (SNPs) might alter treatment response and survival depending on the antifibrotic administered. This study investigated variations in response and outcomes to pirfenidone based on patients-specific genetic profiles.
METHODS
Retrospective clinical data were collected from 56 IPF patients and had blood drawn for DNA extraction between 7/2013 and 3/2016, with the last patient followed until 10/2018. Nine SNPs were selected for pharmacogenetic investigation based on prior associations with IPF treatment outcomes or implications for pirfenidone metabolism. Genetic variants were examined in relation to clinical data and treatment outcomes.
RESULTS
Of the 56 patients, 38 were males (67.85%). The average age of IPF at diagnosis was 66.88 years. At the initiation of pirfenidone, the average percent predicted FVC was 70.7%, and the average DLCO percent predicted was 50.02% (IQR 40-61%). Among the genetic variants tested, the TOLLIP rs5743890 risk allele was significantly associated with improved survival, with increasing pirfenidone duration. This finding was observed with CC or CT genotype carriers but not for those with the TT genotype (p = 0.0457). Similarly, the TGF-B1 rs1800470 risk allele was also significantly associated with improved survival with longer pirfenidone therapy (p = 0.0395), even though it was associated with disease progression.
CONCLUSION
This pilot study suggests that in IPF patients, the TOLLIP rs5743890 genotypes CC and CT, as well as TGF-B1 rs 1800470 may be associated with increased survival when treated with pirfenidone.
PubMed: 37560683
DOI: 10.1016/j.heliyon.2023.e18573 -
Therapeutic Drug Monitoring May 2024Mutations in metabolic enzymes and co-administration of drugs may affect the blood concentration of pirfenidone effective in pulmonary fibrosis. To provide a basis for...
BACKGROUND
Mutations in metabolic enzymes and co-administration of drugs may affect the blood concentration of pirfenidone effective in pulmonary fibrosis. To provide a basis for the precise clinical use of pirfenidone, the authors analyzed the correlation between steady-state pirfenidone trough concentration and adverse drug reactions (ADRs) and examined the impact of CYP1A2*1C (rs2069514) and *1F (rs762551) variants and co-administration on pirfenidone blood concentrations and ADRs.
METHODS
Forty-four patients were enrolled. The blood concentration of pirfenidone was determined using high-performance liquid chromatography. CYP1A2*1C and *1F genotypes were determined using direct SNP sequencing. Additional information related to drug associations was collected to screen factors affecting drug metabolism.
RESULTS
The highest predictive value of ADRs was observed when the steady-state trough concentration of pirfenidone was 3.18 mcg·mL-1 and the area under the receiver operating characteristic curve was 0.701 (P = 0.024). The pirfenidone concentration-to-dose ratio (C/D) in CYP1A2*1F homozygous AA mutants was lower than that in C carriers (CC+AC) (1.28 ± 0.85 vs. 2.03 ± 1.28 mcg·mL-1; P = 0.036). Adverse drug reaction (ADR) incidence in the homozygous AA mutant group (28.0%) was significantly lower than that in the C carriers (CC+AC) (63.2%; P = 0.020), and ADR incidence in the A carriers (AC+AA) was considerably lower than that in the CC group (85.7%; P = 0.039). The C/D value of the combined lansoprazole/rabeprazole group was lower than that of the noncombination group (P < 0.05).
CONCLUSIONS
The ADR incidence was positively correlated with pirfenidone blood concentration. The CYP1A2 (rs762551) AA genotype is associated with lower pirfenidone concentrations and fewer ADRs. Lansoprazole/rabeprazole co-administration reduced pirfenidone concentrations. Randomized controlled trials should further explore personalized dosing of pirfenidone and combination therapies.
PubMed: 38723157
DOI: 10.1097/FTD.0000000000001208 -
Expert Opinion on Drug Safety Sep 2021The approval of antifibrotic agents nintedanib and pirfenidone revolutionized the management of idiopathic pulmonary fibrosis (IPF). These treatments showed acceptable... (Review)
Review
INTRODUCTION
The approval of antifibrotic agents nintedanib and pirfenidone revolutionized the management of idiopathic pulmonary fibrosis (IPF). These treatments showed acceptable tolerability in randomized-clinical trials; however, they have been associated with a spectrum of potential side effects which require careful assessment of risks and benefits in the individual patient before commencing and during antifibrotic therapy.
AREAS COVERED
The accrued evidence on safety of nintedanib and pirfenidone is summarized, from the first randomized clinical trials to the open-label extension studies and post-marketing clinical experiences which helped clarify the long-term tolerability of these drugs.
EXPERT OPINION
The data collected over the last years confirmed the comparable tolerability profile of nintedanib and pirfenidone. The physician's assessment of expected side effects may help decide the optimal first-line therapy for the individual patient. Patient's counseling during treatment remains essential to manage emerging adverse events and eventually inform the decision of drug discontinuation.
Topics: Anti-Inflammatory Agents, Non-Steroidal; Humans; Idiopathic Pulmonary Fibrosis; Indoles; Patient Education as Topic; Protein Kinase Inhibitors; Pyridones; Randomized Controlled Trials as Topic
PubMed: 33881959
DOI: 10.1080/14740338.2021.1921143 -
European Review For Medical and... Nov 2022The incidence of idiopathic pulmonary fibrosis is increasing year by year in the world, which has a greater impact on the quality of life of patients. In the past,... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
The incidence of idiopathic pulmonary fibrosis is increasing year by year in the world, which has a greater impact on the quality of life of patients. In the past, symptomatic treatment was used in clinical practice, but the overall effect is still not good. Multiple clinical studies have demonstrated the efficacy of pirfenidone in the treatment of idiopathic pulmonary fibrosis; however, adverse reactions have been reported. We, therefore, systematically evaluated the effectiveness and safety of pirfenidone in patients with idiopathic pulmonary fibrosis.
PATIENTS AND METHODS
Relevant studies were retrieved from the Embase, PubMed, Web of Science, Cochrane Library, China National Knowledge Infrastructure (CNKI), Chinese Biomedical Literature (CBM), Wanfang and Weipu databases between January 1999 and May 2020, including the keywords "pirfenidone" and "idiopathic pulmonary fibrosis", were included in our systematic review. Review Manager 5.4 software was used for data synthesis, and analyses of publication bias and sensitivity.
RESULTS
Our systematic review included 13 studies involving a total of 13247 patients with idiopathic pulmonary fibrosis. Pirfenidone was associated with reduced declines in vital capacity (VC) and forced vital capacity (FVC) from baseline in patients with hermansky-pudlak syndrome (HPS)-related pulmonary fibrosis and to moderate idiopathic pulmonary fibrosis (IPF). Pirfenidone treatment was associated with lower reductions in FVC, lower reductions in 6-minute walking test distance, lower decreases in minimum oxygen saturation during the 6-minute walking test, lower all-cause death, lower relative risk of IPF-related death and increased progression-free survival compared to placebo. Progression-free survival was significantly longer in the pirfenidone group. The incidence of gastrointestinal, skin, nervous system, and liver function-related adverse events was significantly higher in the pirfenidone group compared to the control group.
CONCLUSIONS
Pirfenidone has efficacy in delaying the progression of idiopathic pulmonary fibrosis. Pirfenidone is well-tolerated by the majority of patients; however, mild adverse reactions related to the gastrointestinal tract, skin, nervous system, and liver function are common. Overall, Pirfenidone may be an effective and well-tolerated treatment option for idiopathic pulmonary fibrosis.
Topics: Humans; Hermanski-Pudlak Syndrome; Quality of Life; Idiopathic Pulmonary Fibrosis; Vital Capacity; Skin
PubMed: 36459024
DOI: 10.26355/eurrev_202211_30377