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Giulianelli G, Cocconcelli E, Fiorentù G, Bernardinello N, Balestro E, Spagnolo P. Idiopathic Pulmonary Fibrosis, Today and Tomorrow: Certainties and New Therapeutic Horizons. Pulm Ther 2025; 11:195-234. [PMID: 40323570 PMCID: PMC12102415 DOI: 10.1007/s41030-025-00296-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2025] [Accepted: 04/02/2025] [Indexed: 05/24/2025] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) represents a clinical and therapeutic challenge characterized by progressive fibrosis and destruction of the lung architecture. The pathogenesis of IPF has been long debated; while it is generally believed that repeated lung injury and abnormal wound repair are the main pathogenetic mechanisms, clear understanding of disease development and efficacious treatment remain important unmet needs. Indeed, current standard of care (i.e., the antifibrotic drugs pirfenidone and nintedanib) can slow down lung function decline and disease progression without halting the disease. In the last 2 decades, several clinical trials in IPF have been completed mostly with negative results. Yet, unprecedented numbers of clinical trials of pharmacological interventions are currently being conducted. In this review, we summarize and critically discuss the current and future treatment landscape of IPF, with emphasis on the most promising developmental molecules.
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Affiliation(s)
- Giacomo Giulianelli
- Respiratory Disease Unit, Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padova, Padova, Italy.
| | - Elisabetta Cocconcelli
- Respiratory Disease Unit, Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padova, Padova, Italy
| | - Giordano Fiorentù
- Respiratory Disease Unit, Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padova, Padova, Italy
| | - Nicol Bernardinello
- Respiratory Disease Unit, Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padova, Padova, Italy
| | - Elisabetta Balestro
- Respiratory Disease Unit, Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padova, Padova, Italy
| | - Paolo Spagnolo
- Respiratory Disease Unit, Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padova, Padova, Italy
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Wang T, Cui Z, Ou Y, Lou S, Chen H, Zhu C, Zhou L, Zou F. Post-marketing safety concerns with pirfenidone and nintedanib: an analysis of individual case safety reports from the FDA adverse event reporting system database and the Japanese adverse drug event report databases. Front Pharmacol 2025; 16:1530697. [PMID: 40356972 PMCID: PMC12067420 DOI: 10.3389/fphar.2025.1530697] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2024] [Accepted: 04/08/2025] [Indexed: 05/15/2025] Open
Abstract
Introduction To date, only two drugs, pirfenidone and nintedanib, are approved for the treatment of patients with idiopathic pulmonary fibrosis (IPF). In addition, very few studies have reported on the safety profile of either drug in large populations. This study aims to identify and compare adverse drug events (ADEs) associated with pirfenidone and nintedanib in real-world settings by analyzing data from the US Food and Drug Administration Adverse Event Reporting System (FAERS). In addition, we utilized data from the Japanese Adverse Drug Event Report (JADER) database for external validation. Methods The ADE reports on both drugs from 2014 Q3 to 2024 Q2 in FAERS and from 2008 Q1 to 2024 Q1 in JADER were collected. After deduplication, Bayesian and non-Bayesian methods for disproportionality analysis, including Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Multiple Gamma Poisson Shrinkers (MGPS), were used for signal detection. Additionally, time to onset (TTO) analysis were performed. Results In total, 35,804 and 20,486 ADE reports were identified from the FAERS database for pirfenidone and nintedanib, respectively. At the system organ class (SOC) level, both drugs have a positive signal value for "gastrointestinal disorders," "respiratory, thoracic, and mediastinal disorders," and "metabolism and nutrition disorders." Other positive signals for pirfenidone include "general disorders and administration site conditions," and "skin and subcutaneous tissue disorders," while for nintedanib, they were "investigations," "infections and infestations," and "hepatobiliary disorders." Some positive signals were consistent with the drug labels, including nausea, decreased appetite, and weight decreased identified in pirfenidone, as well as diarrhea, decreased appetite, abdominal pain upper, and epistaxis identified in nintedanib. We also identified unexpected signals not listed on the drug label, such as decreased gastric pH, and pneumothorax for pirfenidone, and constipation, flatulence for nintedanib. The median onset time for ADEs was 146 days for pirfenidone and 45 days for nintedanib, respectively. Although the two antifibrotics differed in the proportion of periods in which the ADEs occurred, these ADEs were likely to continue even after a year of treatment. In the external validation of JADER, the number of reports for pirfenidone and nintedanib were 265, and 1,327, respectively. The disproportionality analysis at the SOC and preferred term (PT) levels supports the FAERS results. Conclusion This study systematically investigates and compares the ADEs and their onset times at the SOC and specific PT levels for pirfenidone and nintedanib. Our results provide valuable pharmacological insights for the similarities and differences between the safety profiles of the two drugs and highlight the importance of monitoring and managing the toxicity profile associated with antifibrotic drugs.
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Affiliation(s)
- Tao Wang
- Department of Respiratory and Critical Care Medicine, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Zhiwei Cui
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Yingyong Ou
- Department of Respiratory and Critical Care Medicine, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Siyu Lou
- Department of Respiratory and Critical Care Medicine, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Huayou Chen
- The Second Affiliated Hospital of Hainan Medical University, Haikou, Hainan, China
| | - Chengyu Zhu
- Department of Respiratory and Critical Care Medicine, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Linmei Zhou
- Department of Respiratory and Critical Care Medicine, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Fan Zou
- Department of Respiratory and Critical Care Medicine, Affiliated Hospital of Zunyi Medical University, Zunyi, China
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Kuo PH, Tu CY, Chen CH, Kao KC, Hsu JY, Lin MC, Chong IW, Sheu CC. Real-World Experience in the Clinical Use of Pirfenidone in Patients with Idiopathic Pulmonary Fibrosis in Taiwan: A Post-Marketing Surveillance Study. Biomedicines 2024; 12:2348. [PMID: 39457660 PMCID: PMC11504274 DOI: 10.3390/biomedicines12102348] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2024] [Revised: 10/02/2024] [Accepted: 10/09/2024] [Indexed: 10/28/2024] Open
Abstract
BACKGROUND Idiopathic pulmonary fibrosis (IPF) is a serious, progressive lung disease for which treatments are scarce. Pirfenidone has been approved for the treatment of IPF in Taiwan since 2016. This study aimed to gain a better insight into pirfenidone's real-world safety and effectiveness in adult IPF patients in Taiwan. METHODS We conducted a prospective, multicenter, post-marketing surveillance study, and analyzed data from a small sample of 50 IPF patients treated with pirfenidone. RESULTS Most patients were men, with a mean age of 72.8 years (±10.3). They were in physiology stage I or II with a baseline mean forced vital capacity (FVC) of 2.236 L (73.8% of predicted value). After treatment with pirfenidone, the mean FVC decreased by 0.088 L at week 24 and 0.127 L at week 52. The mean 6 min walk test was 325.5 m at baseline, increased by 8.1 m at week 24, but then decreased by 23.0 m at week 52. These changes from baseline did not reach statistical significance. Pirfenidone prevented worsening of cough but did not stabilize dyspnea. During 52 weeks of treatment, the incidence of total adverse drug reactions was 62.0%, with decreased appetite (32.0%) and pruritis (10.0%) being the most common. The adverse events leading to treatment discontinuation were decreased appetite (8.0%), nausea (4.0%), and respiratory failure (4.0%). No safety concern was raised by the study. Treatment with pirfenidone stabilized both FVC and the subjective symptom of cough in most patients. CONCLUSIONS This post-marketing surveillance study demonstrated that pirfenidone is an effective, safe, and well-tolerated treatment in patients with IPF in Taiwan.
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Affiliation(s)
- Ping-Hung Kuo
- Department of Internal Medicine, National Taiwan University Hospital, Taipei 100225, Taiwan;
| | - Chih-Yen Tu
- Division of Pulmonary and Critical Care, Department of Internal Medicine, China Medical University Hospital, Taichung 404327, Taiwan; (C.-Y.T.); (C.-H.C.)
- School of Medicine, College of Medicine, China Medical University, Taichung 406040, Taiwan
| | - Chia-Hung Chen
- Division of Pulmonary and Critical Care, Department of Internal Medicine, China Medical University Hospital, Taichung 404327, Taiwan; (C.-Y.T.); (C.-H.C.)
- School of Medicine, College of Medicine, China Medical University, Taichung 406040, Taiwan
| | - Kuo-Chin Kao
- Department of Thoracic Medicine, Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan;
- Department of Respiratory Therapy, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
| | - Jeng-Yuan Hsu
- Division of Chest Medicine, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung 407219, Taiwan;
| | - Meng-Chih Lin
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan;
| | - Inn-Wen Chong
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 80756, Taiwan;
- Department of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Chau-Chyun Sheu
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 80756, Taiwan;
- Department of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
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Kou M, Jiao Y, Li Z, Wei B, Li Y, Cai Y, Wei W. Real-world safety and effectiveness of pirfenidone and nintedanib in the treatment of idiopathic pulmonary fibrosis: a systematic review and meta-analysis. Eur J Clin Pharmacol 2024; 80:1445-1460. [PMID: 38963453 DOI: 10.1007/s00228-024-03720-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Accepted: 06/23/2024] [Indexed: 07/05/2024]
Abstract
BACKGROUND AND OBJECTIVE Multiple randomized controlled studies have shown that pirfenidone and nintedanib are effective and safe for treating idiopathic pulmonary fibrosis. This study aimed to evaluate their efficacy, safety, and tolerability in a real-world setting. METHODS We searched PubMed, Embase, Cochrane Library, and ClinicalTrials.gov databases for real-world studies published up to March 3, 2023, on pirfenidone and nintedanib for idiopathic pulmonary fibrosis. RESULTS A total of 74 studies with 23,119 participants were included. After 12 months of treatment, the change from baseline in percent predicted FVC (%FVC) was - 0.75% for pirfenidone and - 1.43% for nintedanib. The change from baseline in percent predicted DLCO (%DCLO) was - 2.32% for pirfenidone and - 3.95% for nintedanib. The incidence of acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) was 12.5% for pirfenidone and 14.4% for nintedanib. The IPF-related mortality rates of pirfenidone and nintedanib were 13.4% and 7.2%, respectively. The all-cause mortality was 20.1% for pirfenidone and 16.6% for nintedanib. In the pirfenidone group, 16.6% of patients discontinued treatment because of adverse events, and in the nintedanib group, 16.2% of patients discontinued treatment because of adverse events. The incidence of adverse events was 56.4% and 69.7% for pirfenidone and nintedanib, respectively. CONCLUSION The results of this study indicate that pirfenidone and nintedanib are both effective in slowing down the decline of lung function in IPF patients in real-world settings. The incidence of adverse events with pirfenidone is lower than that with nintedanib, but both are below the clinical trial data, and no new major adverse events have been observed. The discontinuation rates due to adverse reactions of the two drugs are consistent with clinical trial data, indicating good tolerability. However, the mortality rates and AE-IPF incidence rates of these two drugs in real-world settings are higher than those in previous clinical trials, with pirfenidone patients showing a higher mortality rate. Further large-sample studies are needed to investigate the risks of these drugs in these aspects. Additionally, we recommend that future real-world studies pay more attention to patients' subjective symptoms and conduct stratified analyses of the efficacy and safety of pirfenidone and nintedanib based on factors such as patients' baseline lung function, comorbidities, and age, in order to provide more personalized medication advice for IPF patients in clinical practice.
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Affiliation(s)
- Mengjia Kou
- Graduate School, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Yang Jiao
- Department of Respiration, Dongfang Hospital Affiliated to Beijing University of Chinese Medicine, Beijing, 100078, China
| | - Zhipeng Li
- Graduate School, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Bin Wei
- Graduate School, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Yang Li
- Graduate School, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Yaodong Cai
- Graduate School, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Wan Wei
- Department of Respiration, Dongfang Hospital Affiliated to Beijing University of Chinese Medicine, Beijing, 100078, China.
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Behr J, Bonella F, Frye BC, Günther A, Hagmeyer L, Henes J, Klemm P, Koschel D, Kreuter M, Leuschner G, Nowak D, Prasse A, Quadder B, Sitter H, Costabel U. Pharmacological Treatment of Idiopathic Pulmonary Fibrosis (Update) and Progressive Pulmonary Fibroses: S2k Guideline of the German Respiratory Society. Respiration 2024; 103:782-810. [PMID: 39250885 DOI: 10.1159/000540856] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2024] [Accepted: 07/24/2024] [Indexed: 09/11/2024] Open
Affiliation(s)
- Jürgen Behr
- Department of Medicine V, Comprehensice Pneumology Center Munich, German Center for Lung Research Munich, LMU University Hospital, LMU Munich, Munich, Germany
| | - Francesco Bonella
- Pneumology Department, Center for Interstitial and Rare Lung Diseases, Ruhrlandklinik, University of Duisburg-Essen, Essen, Germany
| | - Björn Christian Frye
- Department for Pneumology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, Germany
| | - Andreas Günther
- Center for Interstitial and Rare Lung Diseases, Agaplesion Evangelisches Krankenhaus Mittelhessen, University Hospital Giessen Marburg, Giessen, Germany
| | - Lars Hagmeyer
- Clinic for Pulmonology and Allergology, Center for Sleep Medicine and Respiratory Care, Bethanien Hospital Solingen, Institute for Pulmonology with the University of Cologne, Cologne, Germany
| | - Jörg Henes
- Department for Internal Medicine II (Hematology, Oncology, Rheumatology and Clinical Immunology), University Hospital Tuebingen, Tuebingen, Germany
| | - Philipp Klemm
- Deptartment of Rheumatology and Clinical Immunology, Campus Kerckhoff, Kerckhoff Clinic, Justus-Liebig-University Giessen, Bad Nauheim, Germany
| | - Dirk Koschel
- Fachkrankenhaus Coswig, Lung Center Coswig, and Medical Department I, University Hospital Carl Gustav Carus, TU Dresden, Dresden, Germany
| | - Michael Kreuter
- Department of Pneumology, Mainz University Medical Center, Mainz, Germany
- Department of Pulmonary, Critical Care and Sleep Medicine, Marienhaus Clinic Mainz, Mainz, Germany
| | - Gabriela Leuschner
- Department of Medicine V, Comprehensice Pneumology Center Munich, German Center for Lung Research Munich, LMU University Hospital, LMU Munich, Munich, Germany
| | - Dennis Nowak
- Institute and Policlinic for Occupational, Social and Environmental Medicine, Omprehensive Pulmonology Center (CPC) Munich, Member of the German Lung Research Center, Munich, Germany
| | - Antje Prasse
- Department of Pulmonology and Infectiology, German DZL BREATH and Fibrosis Research Department, Hannover Medical School, Fraunhofer ITEM, Hannover, Germany
| | | | - Helmut Sitter
- Institute for Surgical Research, Philipps University Marburg, Marburg, Germany
| | - Ulrich Costabel
- Pneumology Department, Center for Interstitial and Rare Lung Diseases, Ruhrlandklinik, University of Duisburg-Essen, Essen, Germany
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Kang J, Lee KH, Lee JH, Jeong YY, Choi SM, Kim HC, Park JH, Lee HK, Yong SJ, Choi HS, Kim HR, Jegal Y, Choi WI, Lee EJ, Song JW. Safety, effectiveness, and usefulness of higher-dose tablets of generic pirfenidone in patients with IPF: a nationwide observational study in South Korea. Front Pharmacol 2024; 15:1451447. [PMID: 39185314 PMCID: PMC11341391 DOI: 10.3389/fphar.2024.1451447] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2024] [Accepted: 07/29/2024] [Indexed: 08/27/2024] Open
Abstract
BACKGROUND Pirfenidone is an antifibrotic medication approved for idiopathic pulmonary fibrosis (IPF). Fybro®, a generic version of pirfenidone developed in South Korea, gained approval and is available in 200 mg and in higher-dose formulations of 400 and 600 mg. This real-world prospective cohort study investigated the safety and effectiveness of Fybro®. METHODS A nationwide observational study was conducted in patients with IPF. Patients were followed up for 6 months, with a subset of patients being followed up for 12 months. Data on lung function and adverse events were collected. Patient adherence to fewer-pill (400 and/or 600 mg tablets) and multiple-pill (200 mg tablets) regimens were compared. RESULTS Of the 359 enrolled patients, 352 received pirfenidone (Fybro®) at least once and were included in the analysis. The mean age was 69.0 years and 82.4% of patients were male. The median treatment duration was 186.0 days. A total of 253 patients (71.9%) experienced adverse events, with decreased appetite being the most common (16.5%). The adjusted decline rates in lung function were -1.5% and -2.2% predicted per year for forced vital capacity and diffusing capacity, respectively. No significant differences were observed based on the pirfenidone dose. For a daily intake of 1,200 or 1800 mg of pirfenidone, a significantly longer duration of drug administration was observed with the fewer-pill regimen than with multiple-pill regimen. CONCLUSION The safety and effectiveness of Fybro® observed in this real-world cohort study are consistent with previous studies. Using higher-strength tablets to reduce pill burden may improve medication adherence.
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Affiliation(s)
- Jieun Kang
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Ilsan Paik Hospital, Inje University College of Medicine, Goyang, Republic of Korea
| | - Kwan Ho Lee
- Division of Pulmonology and Allergy, Department of Internal Medicine, Yeungnam University Medical Center, Yeungnam University College of Medicine, Daegu, Republic of Korea
| | - Jae Ha Lee
- Division of Pulmonology, Department of Internal Medicine, Haeundae Paik Hospital, Inje University College of Medicine, Busan, Republic of Korea
| | - Yi Yeong Jeong
- Division of Pulmonology and Allergy, Department of Internal Medicine, Gyeongsang National University Hospital, Gyeongsang National University College of Medicine, Jinju, Republic of Korea
| | - Sun Mi Choi
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Ho Cheol Kim
- Department of Internal Medicine, Gyeongsang National University Changwon Hospital, Gyeongsang National University College of Medicine, Changwon, Republic of Korea
| | - Joo Hun Park
- Department of Pulmonary and Critical Care Medicine, Ajou University Hospital, Ajou University School of Medicine, Suwon, Republic of Korea
| | - Hyun-Kyung Lee
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Internal Medicine, Busan Paik Hospital, Inje University College of Medicine, Busan, Republic of Korea
| | - Suk Joong Yong
- Department of Internal Medicine, Wonju Severance Christian Hospital, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea
| | - Hye Sook Choi
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Internal Medicine, Kyung Hee University Medical Center, Kyung Hee University School of Medicine, Seoul, Republic of Korea
| | - Hak Ryul Kim
- Department of Internal Medicine, Institute of Wonkwang Medical Science, Wonkwang University School of Medicine, Iksan, Republic of Korea
| | - Yangjin Jegal
- Division of Pulmonary and Critical Medicine, Department of Internal Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Republic of Korea
| | - Won-il Choi
- Department of Internal Medicine, Myongji Hospital, Hanyang University College of Medicine, Goyang, Republic of Korea
| | - Eun Joo Lee
- Division of Respiratory and Critical Care Medicine, Department of Internal Medicine, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Republic of Korea
| | - Jin Woo Song
- Department of Pulmonary and Critical Care Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
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Lee C, Kwak SH, Han J, Shin JH, Yoo B, Lee YS, Park JS, Lim BJ, Lee JG, Kim YS, Kim SY, Bae SH. Repositioning of ezetimibe for the treatment of idiopathic pulmonary fibrosis. Eur Respir J 2024; 63:2300580. [PMID: 38359963 PMCID: PMC11096666 DOI: 10.1183/13993003.00580-2023] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Accepted: 02/05/2024] [Indexed: 02/17/2024]
Abstract
BACKGROUND We previously identified ezetimibe, an inhibitor of Niemann-Pick C1-like intracellular cholesterol transporter 1 and European Medicines Agency-approved lipid-lowering agent, as a potent autophagy activator. However, its efficacy against pulmonary fibrosis has not yet been evaluated. This study aimed to determine whether ezetimibe has therapeutic potential against idiopathic pulmonary fibrosis. METHODS Primary lung fibroblasts isolated from both humans and mice were employed for mechanistic in vitro experiments. mRNA sequencing of human lung fibroblasts and gene set enrichment analysis were performed to explore the therapeutic mechanism of ezetimibe. A bleomycin-induced pulmonary fibrosis mouse model was used to examine in vivo efficacy of the drug. Tandem fluorescent-tagged microtubule-associated protein 1 light chain 3 transgenic mice were used to measure autophagic flux. Finally, the medical records of patients with idiopathic pulmonary fibrosis from three different hospitals were reviewed retrospectively, and analyses on survival and lung function were conducted to determine the benefits of ezetimibe. RESULTS Ezetimibe inhibited myofibroblast differentiation by restoring the mechanistic target of rapamycin complex 1-autophagy axis with fine control of intracellular cholesterol distribution. Serum response factor, a potential autophagic substrate, was identified as a primary downstream effector in this process. Similarly, ezetimibe ameliorated bleomycin-induced pulmonary fibrosis in mice by inhibiting mechanistic target of rapamycin complex 1 activity and increasing autophagic flux, as observed in mouse lung samples. Patients with idiopathic pulmonary fibrosis who regularly used ezetimibe showed decreased rates of all-cause mortality and lung function decline. CONCLUSION Our study presents ezetimibe as a potential novel therapeutic for idiopathic pulmonary fibrosis.
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Affiliation(s)
- Chanho Lee
- Department of Biomedical Sciences, Yonsei University College of Medicine, Seoul, Republic of Korea
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
- These authors contributed equally to this work
| | - Se Hyun Kwak
- Division of Pulmonology, Allergy and Critical Care Medicine, Department of Internal Medicine, Yongin Severance Hospital, Yonsei University College of Medicine, Yongin, Republic of Korea
- These authors contributed equally to this work
| | - Jisu Han
- Department of Biomedical Sciences, Yonsei University College of Medicine, Seoul, Republic of Korea
- Department of Biomedical Sciences, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Ju Hye Shin
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Byunghun Yoo
- Department of Biomedical Sciences, Yonsei University College of Medicine, Seoul, Republic of Korea
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Yu Seol Lee
- Department of Biomedical Sciences, Yonsei University College of Medicine, Seoul, Republic of Korea
- Department of Biomedical Sciences, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Jeong Su Park
- Department of Biomedical Sciences, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Beom Jin Lim
- Department of Pathology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Jin Gu Lee
- Department of Thoracic and Cardiovascular Surgery, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Young Sam Kim
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Song Yee Kim
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
- These authors contributed equally to this work
| | - Soo Han Bae
- Department of Biomedical Sciences, Yonsei University College of Medicine, Seoul, Republic of Korea
- Department of Biomedical Sciences, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, Republic of Korea
- These authors contributed equally to this work
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Sofia C, Comes A, Sgalla G, Richeldi L. Promising advances in treatments for the management of idiopathic pulmonary fibrosis. Expert Opin Pharmacother 2024; 25:717-725. [PMID: 38832823 DOI: 10.1080/14656566.2024.2354460] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Accepted: 05/08/2024] [Indexed: 06/06/2024]
Abstract
INTRODUCTION Following the INPULSIS and ASCEND studies, leading to the first two approved antifibrotic therapies for patients with IPF, ongoing investigations are firmly exploring novel agents for a targeted effective and better tolerated therapy able to improve the natural history of the disease. AREAS COVERED This review aims to analyze recent advances in pharmacological research of IPF, discussing the currently available treatments and the novel drugs under investigation in phase 3 trials, with particular emphasis on BI 1015550 and inhaled treprostinil. The literature search utilized Medline and Clinicaltrials.org databases. Critical aspects of clinical trial design in IPF are discussed in light of recently completed phase III studies. EXPERT OPINION While randomized clinical trials in IPF are currently underway, future objectives should explore potential synergistic benefits when combining novel molecules with the existing therapies and identify more specific molecular targets. Moreover, refining the study design represent another crucial goal. The aim of the pharmacological research will be not only stabilizing but also potentially reversing the fibrotic changes in IPF.
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Affiliation(s)
- Carmelo Sofia
- Facoltà di Medicina e Chirurgia, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Alessia Comes
- Facoltà di Medicina e Chirurgia, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Giacomo Sgalla
- Facoltà di Medicina e Chirurgia, Università Cattolica del Sacro Cuore, Rome, Italy
- Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Luca Richeldi
- Facoltà di Medicina e Chirurgia, Università Cattolica del Sacro Cuore, Rome, Italy
- Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
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Liao KM, Chen CY. Risk of potential hepatotoxicity from pirfenidone or nintedanib in patients with idiopathic pulmonary fibrosis: results of a retrospective analysis of a large insurance database in Taiwan. Front Pharmacol 2024; 15:1309712. [PMID: 38384288 PMCID: PMC10879927 DOI: 10.3389/fphar.2024.1309712] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2023] [Accepted: 01/23/2024] [Indexed: 02/23/2024] Open
Abstract
Background: A growing population of individuals diagnosed with idiopathic pulmonary fibrosis (IPF) are receiving treatment with nintedanib and pirfenidone. The aim of our study was to assess the incidence of drug-induced liver injury (DILI) associated with the use of pirfenidone and nintedanib in patients with IPF in Taiwan. Methods: We collected a cohort of adult patients diagnosed with IPF between 2017 and 2020. The research outcomes involved assessing the incidence of DILI in patients treated with nintedanib or pirfenidone. Poisson regression analysis was employed to estimate incidence rates, with and without adjustments for covariates, to calculate and present both unadjusted and adjusted incidence rate ratios (IRRs). Results: The risk of DILI was greater in patients who received nintedanib than in those who received pirfenidone during the 1-year follow-up. Patients treated with nintedanib exhibited a heightened risk of DILI based on inpatient diagnoses using specific codes after adjusting for variables such as gender, age group, comorbidities and concomitant medications, with an adjusted incidence rate ratio (aIRR) of 3.62 (95% confidence interval (CI) 1.11-11.78). Similarly, the risk of DILI was elevated in patients treated with nintedanib according to a per-protocol Poisson regression analysis of outcomes identified from inpatient diagnoses using specific codes. This was observed after adjusting for variables including gender, age group, comorbidities, and concomitant medications, with an aIRR of 3.60 (95% CI 1.11-11.72). Conclusion: Data from postmarketing surveillance in Taiwan indicate that patients who received nintedanib have a greater risk of DILI than do those who received pirfenidone.
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Affiliation(s)
- Kuang-Ming Liao
- Department of Internal Medicine, Chi Mei Medical Center, Chiali, Taiwan
| | - Chung-Yu Chen
- Master Program in Clinical Pharmacy, School of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Pharmacy, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
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10
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Bonella F, Spagnolo P, Ryerson C. Current and Future Treatment Landscape for Idiopathic Pulmonary Fibrosis. Drugs 2023; 83:1581-1593. [PMID: 37882943 PMCID: PMC10693523 DOI: 10.1007/s40265-023-01950-0] [Citation(s) in RCA: 48] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/17/2023] [Indexed: 10/27/2023]
Abstract
Idiopathic pulmonary fibrosis (IPF) remains a disease with poor survival. The pathogenesis is complex and encompasses multiple molecular pathways. The first-generation antifibrotics pirfenidone and nintedanib, approved more than 10 years ago, have been shown to reduce the rate of progression, increase the length of life for patients with IPF, and work for other fibrotic lung diseases. In the last two decades, most clinical trials on IPF have failed to meet the primary endpoint and an urgent unmet need remains to identify agents or treatment strategies that can stop disease progression. The pharmacotherapeutic landscape for IPF is moving forward with a number of new drugs currently in clinical development, mostly in phase I and II trials, while only a few phase III trials are running. Since our understanding of IPF pathogenesis is still limited, we should keep focusing our efforts to deeper understand the mechanisms underlying this complex disease and their reflection on clinical phenotypes. This review discusses the key pathogenetic concepts for the development of new antifibrotic agents, presents the newest data on approved therapies, and summarizes new compounds currently in clinical development. Finally, future directions in antifibrotics development are discussed.
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Affiliation(s)
- Francesco Bonella
- Pneumology Department, Center for Interstitial and Rare Lung Diseases, Ruhrlandklinik University Hospital, University of Duisburg Essen, Essen, Germany.
| | - Paolo Spagnolo
- Cardiac, Thoracic and Vascular, Sciences and Public Health, University of Padova School of Medicine and Surgery, Padua, Italy
| | - Chris Ryerson
- Department of Medicine, The University of British Columbia, Vancouver, BC, Canada
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11
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Lee HY, Jung SY, Jang JH, Ko J, Kim DW, Her M, Lee JH. Efficacy of Pirfenidone According to Dose in Patients with Idiopathic Pulmonary Fibrosis: A Prospective, Observational, Single-Center Cohort Study. Life (Basel) 2023; 13:2118. [PMID: 38004258 PMCID: PMC10672649 DOI: 10.3390/life13112118] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Revised: 10/24/2023] [Accepted: 10/24/2023] [Indexed: 11/26/2023] Open
Abstract
BACKGROUND Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease with a poor prognosis. Pirfenidone is approved and widely used for the treatment of IPF and reduces lung function decline. The aim of this study was to evaluate the efficacy of different doses of pirfenidone for the prevention of disease progression in patients with IPF. METHODS This was a prospective, observational, single-center cohort study conducted in Haeundae Paik Hospital, Republic of Korea, from April 2021 to March 2023. IPF patients were assigned to three groups according to the dose of pirfenidone (600 mg, 1200 mg, 1800 mg). Disease progression was defined as an absolute decline to ≥5% of forced vital capacity (FVC) (% predicted value) or an absolute decline to ≥10% of diffusing capacity of the lung for carbon monoxide (DLco) (% predicted value) over 12 months. The primary endpoint was to evaluate the clinical effects of pirfenidone of each dosage on disease progression in IPF patients by comparing the FVC (% predicted value) and DLco (% predicted value) values over 12 months. The secondary endpoint was to evaluate the prognostic value of Krebs von den Lungen-6 (KL-6) in the disease progression in IPF patients using the baseline KL-6 value and the change in KL-6 values between the baseline and 12 months. RESULTS A total of 44 patients were enrolled, of whom 39 completed the study, with 13 patients assigned to each of the three groups. The median age was 71.7 years, and 79.5% of patients were men. The baseline characteristics were similar across groups, except the 600 mg group was older (75.9 vs. 69.2 vs. 68.2 years, p = 0.016). The overall median change in FVC and DLco over 12 months was -2.7% (IQR: -9.1%, -1.2%) and -3.8% (IQR: -13.6%, -3.7%), respectively. There was no difference in the decline in FVC (change in FVC, % predicted value: -3.23 vs. -4.08 vs. -1.54, p = 0.621) and DLco (change in DLco, % predicted value: 0.00 vs. -3.62 vs. -3.15, p = 0.437) among the three groups. Fourteen patients (35.9%) suffered disease progression. The rate of disease progression did not differ according to the dose of pirfenidone (38.5 vs. 38.5 vs. 30.8%, p = 1.000). In multivariable logistic regression analysis, KL-6 was not a statistically significant predictor of disease progression. CONCLUSIONS In our study, regardless of dose, consistent pirfenidone use for 12 months resulted in similar efficacy for the prevention of disease progression in patients with IPF. Large-scale, randomized, double-blind, placebo-controlled clinical trials are needed.
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Affiliation(s)
- Ho Young Lee
- Division of Pulmonology, Department of Internal Medicine, Inje University Busan Paik Hospital, Inje University College of Medicine, Busan 47392, Republic of Korea;
| | - So Young Jung
- Division of Dermatology, Inje University Haeundae Paik Hospital, Inje University College of Medicine, Busan 48108, Republic of Korea;
| | - Ji Hoon Jang
- Division of Pulmonology and Critical Care Medicine, Department of Internal Medicine, Inje University Haeundae Paik Hospital, Inje University College of Medicine, Busan 48108, Republic of Korea;
| | - Junghae Ko
- Division of Endocrinology, Department of Internal Medicine, Inje University Haeundae Paik Hospital, Inje University College of Medicine, Busan 48108, Republic of Korea;
| | - Dae-Wook Kim
- Department of Orthopedic Surgery, Inje University Haeundae Paik Hospital, Inje University College of Medicine, Busan 48108, Republic of Korea;
| | - Minyoung Her
- Division of Rheumatology, Department of Internal Medicine, Inje University Haeundae Paik Hospital, Inje University College of Medicine, Busan 48108, Republic of Korea;
| | - Jae Ha Lee
- Division of Pulmonology and Critical Care Medicine, Department of Internal Medicine, Inje University Haeundae Paik Hospital, Inje University College of Medicine, Busan 48108, Republic of Korea;
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12
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Wang R, Yang YM. Identification of potential biomarkers for idiopathic pulmonary fibrosis and validation of TDO2 as a potential therapeutic target. World J Cardiol 2023; 15:293-308. [PMID: 37397828 PMCID: PMC10308271 DOI: 10.4330/wjc.v15.i6.293] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2023] [Revised: 06/01/2023] [Accepted: 06/13/2023] [Indexed: 06/26/2023] Open
Abstract
BACKGROUND Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease with a high mortality rate. On this basis, exploring potential therapeutic targets to meet the unmet needs of IPF patients is important.
AIM To explore novel hub genes for IPF therapy.
METHODS Here, we used public datasets to identify differentially expressed genes between IPF patients and healthy donors. Potential targets were considered based on multiple bioinformatics analyses, especially the correlation between hub genes and carbon monoxide diffusing capacity of carbon monoxide, forced vital capacity, and patient survival rate. The mRNA levels of the hub genes were determined through quantitative real-time polymerase chain reaction.
RESULTS We found that TDO2 was upregulated in IPF patients and predicted poor prognosis. Surprisingly, single-cell RNA sequencing data analysis revealed significant enrichment of TDO2 in alveolar fibroblasts, indicating that TDO2 may participate in the regulation of proliferation and survival. Therefore, we verified the upregulated expression of TDO2 in an experimental mouse model of transforming growth factor-β (TGF-β)-induced pulmonary fibrosis. Furthermore, the results showed that a TDO2 inhibitor effectively suppressed TGF-β-induced fibroblast activation. These findings suggest that TDO2 may be a potential target for IPF treatment. Based on transcription factors-microRNA prediction and scRNA-seq analysis, elevated TDO2 promoted the IPF proliferation of fibroblasts and may be involved in the P53 pathway and aggravate ageing and persistent pulmonary fibrosis.
CONCLUSION We provided new target genes prediction and proposed blocking TGF-β production as a potential treatment for IPF.
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Affiliation(s)
- Ru Wang
- Henan University of Chinese Medicine, Collaborative Innovation Centre for Chinese Medicine and Respiratory Diseases, Zhengzhou 450046, Henan Province, China
| | - Yan-Mei Yang
- Zhengzhou University, Research Centre of Basic Medicine, Academy of Medical Sciences, Zhengzhou 450000, Henan Province, China
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13
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Factors associated with dose reduction of pirfenidone in patients with idiopathic pulmonary fibrosis: A study based on real-world clinical data. PLoS One 2023; 18:e0281295. [PMID: 36735694 PMCID: PMC9897553 DOI: 10.1371/journal.pone.0281295] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2022] [Accepted: 01/19/2023] [Indexed: 02/04/2023] Open
Abstract
INTRODUCTION Although pirfenidone slows disease progression in patients with idiopathic pulmonary fibrosis (IPF), in clinical practice, patients often cannot tolerate the recommended dose because of several adverse events. This study aimed to investigate adverse events associated with pirfenidone and factors associated with dose reduction. METHODS This single-center retrospective cohort study included 156 consecutive patients with IPF who received pirfenidone. Demographic characteristics, pulmonary function, and pirfenidone-related adverse events were investigated. We compared patients who received standard and reduced doses of pirfenidone. RESULTS The mean patient age was 69.7 years. The median follow-up duration was 243 days. The low-dose group (n = 73) included older patients (71.0 years vs. 67.4 years, p = 0.016), fewer smokers (80.8% vs. 96.4%, p = 0.008), and patients with a lower body mass index (BMI; 24.1 kg/m2 vs. 25.7 kg/m2, p = 0.027) than the standard dose group (n = 57). Multivariate logistic regression analysis revealed that older age (odds ratio = 1.066, p = 0.016) was significantly associated with dose reduction of pirfenidone after adjusting for sex, smoking history, emphysema, and BMI. No significant difference was found in the rates of a reduced forced vital capacity and diffusing capacity for carbon monoxide between the two groups. CONCLUSIONS Although older patients are more likely to undergo dose reduction of pirfenidone, low-dose pirfenidone might be effective for treating patients with IPF. Low-dose pirfenidone could be considered an effective treatment option for older patients with IPF.
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14
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Behr J, Bonella F, Frye BC, Günther A, Hagmeyer L, Henes J, Klemm P, Koschel D, Kreuter M, Leuschner G, Nowak D, Prasse A, Quadder B, Sitter H, Costabel U. [Pharmacological treatment of idiopathic pulmonary fibrosis (update) and progressive pulmonary fibrosis - S2k Guideline of the German Respiratory Society]. Pneumologie 2023; 77:94-119. [PMID: 36791790 DOI: 10.1055/a-1983-6796] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/17/2023]
Affiliation(s)
- Jürgen Behr
- Medizinische Klinik und Polklinik V, LMU Klinikum der Universität München, Mitglied des Deutschen Zentrums für Lungenforschung; Delegierte/r der DGP
| | - Francesco Bonella
- Zentrum für interstitielle und seltene Lungenerkrankungen, Klinik für Pneumologie, Ruhrlandklinik, Universitätsmedizin Essen; Delegierter der DGP
| | - Björn C Frye
- Klinik für Pneumologie, Universitätsklinikum Freiburg, Medizinische Fakultät, Albert-Ludwigs-Universität Freiburg, Deutschland; Delegierter der DGP
| | - Andreas Günther
- Center for Interstitial and Rare Lung Diseases, University Hospital Giessen Marburg, Giessen, Agaplesion Evangelisches Krankenhaus Mittelhessen, Giessen, Germany; Delegierter der DGP
| | - Lars Hagmeyer
- Krankenhaus Bethanien Solingen, Klinik für Pneumologie und Allergologie, Zentrum für Schlaf- und Beatmungsmedizin, Institut für Pneumologie an der Universität zu Köln; Delegierter der DGP
| | - Jörg Henes
- Zentrum für interdisziplinäre Rheumatologie, Immunologie und Autoimmunerkrankungen (INDIRA) und Innere Medizin II; Delegierter DGRh
| | - Philipp Klemm
- Abt. Rheumatologie und klinische Immunologie, Kerckhoff Klinik und Campus Kerckhoff der Justus-Liebig-Universität Gießen, Bad Nauheim; Delegierter der DGRh
| | - Dirk Koschel
- Fachkrankenhaus Coswig, Lungenzentrum und Medizinische Klinik 1, Universitätsklinik Carl Gustav Carus der TU Dresden; Delegierter der DGP
| | - Michael Kreuter
- Zentrum für interstitielle und seltene Lungenerkrankungen & interdisziplinäres Sarkoidosezentrum, Thoraxklinik, Universitätsklinikum Heidelberg, Deutsches Zentrum für Lungenforschung Heidelberg und Klinik für Pneumologie, Interdisziplinäres Lungenzentrum Ludwigsburg, RKH Klinik Ludwigsburg; Delegierter der DGIM
| | - Gabriela Leuschner
- Medizinische Klinik und Polklinik V, LMU Klinikum der Universität München, Mitglied des Deutschen Zentrums für Lungenforschung; Delegierte/r der DGP
| | - Dennis Nowak
- Institut und Poliklinik für Arbeits-, Sozial- und Umweltmedizin, LMU Klinikum der Universität München, Comprehensive Pneumology Center (CPC) München, Mitglied des Deutsches Zentrums für Lungenforschung; Delegierter der DGAUM
| | - Antje Prasse
- Klinik für Pneumologie und Infektiologie, Medizinische Hochschule Hannover, DZL BREATH und Abteilung für Fibroseforschung, Fraunhofer ITEM, Hannover, Delegierte der DGP
| | | | - Helmut Sitter
- Institut für Theoretische Chirurgie, Philipps-Universität Marburg, Moderator
| | - Ulrich Costabel
- Zentrum für interstitielle und seltene Lungenerkrankungen, Klinik für Pneumologie, Ruhrlandklinik, Universitätsmedizin Essen; Delegierter der DGP
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15
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Kang J, Chung MP, Park MS, Oh IJ, Lee HB, Kim YW, Park JS, Uh ST, Kim YS, Jegal Y, Song JW. Clinical outcomes of dose modification during pirfenidone treatment for IPF: A nationwide post-marketing surveillance study. Front Pharmacol 2023; 13:1025947. [PMID: 36703754 PMCID: PMC9871582 DOI: 10.3389/fphar.2022.1025947] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Accepted: 12/26/2022] [Indexed: 01/11/2023] Open
Abstract
Background: Pirfenidone, an antifibrotic medication approved for the treatment of idiopathic pulmonary fibrosis (IPF), often requires dose reduction owing to adverse events. In this study, we evaluated if pirfenidone's reduced dose has any impact on clinical outcomes in patients with IPF. Methods: We used the data of a prospective post-marketing study of pirfenidone conducted at 10 hospitals in South Korea from 2014 to 2017. Dose reduction was defined when the pirfenidone dose was temporarily or permanently reduced to manage adverse events or when the treatment dose failed to reach the standard dose. Study patients were classified based on the most frequently administered dose during 48-week follow-up-1800 mg, 1,200 mg, and <1,200 mg/days. The following clinical outcomes were compared between the groups: death, hospitalization, acute exacerbation, pulmonary function decline, and changes in severity of dyspnea and cough. Results: The median follow-up duration in all 143 patients was 11 months. During the study period, 70.6% experienced at least one dose reduction. Patients treated with standard-dose pirfenidone tended to be young and had the lowest diffusing capacity. Pulmonary function changes did not differ depending on the pirfenidone dose. The three groups were not significantly different in terms of the proportion of death, hospitalization, and acute exacerbation. The symptom changes were also similar between the groups. Conclusion: Reduced doses did not negatively impact clinical outcomes compared with the standard-dose pirfenidone in patients with IPF. Dose reduction may be a useful method to manage adverse events while maintaining therapeutic efficacy.
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Affiliation(s)
- Jieun Kang
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Ilsan Paik Hospital, Goyang-si, South Korea
| | - Man Pyo Chung
- Samsung Medical Center, Department of Pulmonary and Critical Care Medicine, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Moo Suk Park
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea
| | - In Jae Oh
- Department of Internal Medicine, Chonnam National University Medical School and Hwasun Hospital, Hwasun, South Korea
| | - Heung Bum Lee
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Research Center for Pulmonary Disorders, Jeonbuk National University Medical School and Hospital, Jeonju, South Korea
| | - Young Whan Kim
- Division of Respiratory-Allergy and Clinical Immunology, Department of Internal Medicine, Konkuk University Medical Center, Seoul, South Korea
| | - Jong Sun Park
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea
| | - Soo Taek Uh
- Division of Allergy and Respiratory Medicine, Department of Internal Medicine, Soonchunhyang University Seoul Hospital, Seoul, South Korea
| | - Yun Seong Kim
- Department of Internal Medicine, Pusan National University Yangsan Hospital, Yangsan, South Korea
| | - Yangjin Jegal
- Division of Pulmonary Medicine, Department of Internal Medicine, Ulsan University Hospital, Ulsan, South Korea
| | - Jin Woo Song
- Department of Pulmonary and Critical Care Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea,*Correspondence: Jin Woo Song,
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16
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Boshra MS, Abou Warda AE, Sayed MA, Elkomy MH, Alotaibi NH, Mohsen M, Sarhan RM. Effect of Pirfenidone on Risk of Pulmonary Fibrosis in COVID-19 Patients Experiencing Cytokine Storm. Healthcare (Basel) 2022; 10:2387. [PMID: 36553912 PMCID: PMC9777849 DOI: 10.3390/healthcare10122387] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Revised: 11/21/2022] [Accepted: 11/24/2022] [Indexed: 11/29/2022] Open
Abstract
OBJECTIVES Severe stages of COVID-19 infection have been associated with the excessive discharge of pro-inflammatory mediators such as cytokines, resulting in lung deterioration, which progresses rapidly to lung fibrosis leading to acute respiratory distress syndrome. In this investigation, the efficacy and safety of the novel antifibrotic and anti-inflammatory agent, Pirfenidone, were assessed in COVID-19 patients with pulmonary fibrosis secondary to cytokine storm. In this randomized controlled study, we assigned 100 adult COVID-19 patients cytokine storm and admitted to the intensive care isolation unit into either pirfenidone added to the standard therapy (n = 47), or the standard protocol only (n = 53). High-resolution computed tomography of the chest was performed in all patients to evaluate fibrotic lesions and their progression. The results showed that the percentage of patients who developed pulmonary fibrosis during cytokine storm onset in the pirfenidone group relative to the standard group was 29.8% and 35.8%, respectively, with no significant difference between the two groups; while there was a significant increase in the proportion of patients discharged from the isolation unit with pulmonary fibrosis without progression in fibrotic lesions in the pirfenidone group compared to the standard group (21.3% and 5.7%, respectively). Furthermore, there was a significant difference concerning liver enzyme elevation and GIT disturbance incidences in the studied groups (p = 0.006 and 0.01, respectively). Our findings show that Pirfenidone inhibits fibrosis advancement in COVID-19 patients with pulmonary fibrosis and is associated with hepatotoxicity and GI distress. It may be beneficial in patients with mild to moderate COVID-19-induced pulmonary fibrosis; however, additional research is necessary.
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Affiliation(s)
- Marian S. Boshra
- Clinical Pharmacy Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef P.O. Box 62514, Egypt
| | - Ahmed E. Abou Warda
- Clinical Pharmacy Department, Faculty of Pharmacy, October 6 University, Giza P.O. Box 12585, Egypt
| | | | - Mohammed H. Elkomy
- Department of Pharmaceutics, College of Pharmacy, Jouf University, Sakaka 72341, Saudi Arabia
| | - Nasser H. Alotaibi
- Department of Clinical Pharmacy, College of Pharmacy, Jouf University, Sakaka 72341, Saudi Arabia
| | - Marwa Mohsen
- Clinical Pharmacy Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef P.O. Box 62514, Egypt
| | - Rania M. Sarhan
- Clinical Pharmacy Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef P.O. Box 62514, Egypt
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17
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Cottin V, Bonniaud P, Cadranel J, Crestani B, Jouneau S, Marchand-Adam S, Nunes H, Wémeau-Stervinou L, Bergot E, Blanchard E, Borie R, Bourdin A, Chenivesse C, Clément A, Gomez E, Gondouin A, Hirschi S, Lebargy F, Marquette CH, Montani D, Prévot G, Quetant S, Reynaud-Gaubert M, Salaun M, Sanchez O, Trumbic B, Berkani K, Brillet PY, Campana M, Chalabreysse L, Chatté G, Debieuvre D, Ferretti G, Fourrier JM, Just N, Kambouchner M, Legrand B, Le Guillou F, Lhuillier JP, Mehdaoui A, Naccache JM, Paganon C, Rémy-Jardin M, Si-Mohamed S, Terrioux P. [French practical guidelines for the diagnosis and management of IPF - 2021 update, full version]. Rev Mal Respir 2022; 39:e35-e106. [PMID: 35752506 DOI: 10.1016/j.rmr.2022.01.014] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/17/2022]
Abstract
BACKGROUND Since the previous French guidelines were published in 2017, substantial additional knowledge about idiopathic pulmonary fibrosis has accumulated. METHODS Under the auspices of the French-speaking Learned Society of Pulmonology and at the initiative of the coordinating reference center, practical guidelines for treatment of rare pulmonary diseases have been established. They were elaborated by groups of writers, reviewers and coordinators with the help of the OrphaLung network, as well as pulmonologists with varying practice modalities, radiologists, pathologists, a general practitioner, a head nurse, and a patients' association. The method was developed according to rules entitled "Good clinical practice" in the overall framework of the "Guidelines for clinical practice" of the official French health authority (HAS), taking into account the results of an online vote using a Likert scale. RESULTS After analysis of the literature, 54 recommendations were formulated, improved, and validated by the working groups. The recommendations covered a wide-ranging aspects of the disease and its treatment: epidemiology, diagnostic modalities, quality criteria and interpretation of chest CT, indication and modalities of lung biopsy, etiologic workup, approach to familial disease entailing indications and modalities of genetic testing, evaluation of possible functional impairments and prognosis, indications for and use of antifibrotic therapy, lung transplantation, symptom management, comorbidities and complications, treatment of chronic respiratory failure, diagnosis and management of acute exacerbations of fibrosis. CONCLUSION These evidence-based guidelines are aimed at guiding the diagnosis and the management in clinical practice of idiopathic pulmonary fibrosis.
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Affiliation(s)
- V Cottin
- Centre national coordonnateur de référence des maladies pulmonaires rares, service de pneumologie, hôpital Louis-Pradel, Hospices Civils de Lyon (HCL), Lyon, France; UMR 754, IVPC, INRAE, Université de Lyon, Université Claude-Bernard Lyon 1, Lyon, France; Membre d'OrphaLung, RespiFil, Radico-ILD2, et ERN-LUNG, Lyon, France.
| | - P Bonniaud
- Centre de référence constitutif des maladies pulmonaires rares, service de pneumologie et soins intensifs respiratoires, centre hospitalo-universitaire de Bourgogne et faculté de médecine et pharmacie, université de Bourgogne-Franche Comté, Dijon ; Inserm U123-1, Dijon, France
| | - J Cadranel
- Centre de référence constitutif des maladies pulmonaires rares, service de pneumologie et oncologie thoracique, Assistance publique-Hôpitaux de Paris (AP-HP), hôpital Tenon, Paris ; Sorbonne université GRC 04 Theranoscan, Paris, France
| | - B Crestani
- Centre de référence constitutif des maladies pulmonaires rares, service de pneumologie A, AP-HP, hôpital Bichat, Paris, France
| | - S Jouneau
- Centre de compétence pour les maladies pulmonaires rares de l'adulte, service de pneumologie, hôpital Pontchaillou, Rennes ; IRSET UMR1085, université de Rennes 1, Rennes, France
| | - S Marchand-Adam
- Centre de compétence pour les maladies pulmonaires rares de l'adulte, hôpital Bretonneau, service de pneumologie, CHRU, Tours, France
| | - H Nunes
- Centre de référence constitutif des maladies pulmonaires rares, service de pneumologie, AP-HP, hôpital Avicenne, Bobigny ; université Sorbonne Paris Nord, Bobigny, France
| | - L Wémeau-Stervinou
- Centre de référence constitutif des maladies pulmonaires rares, Institut Cœur-Poumon, service de pneumologie et immuno-allergologie, CHRU de Lille, Lille, France
| | - E Bergot
- Centre de compétence pour les maladies pulmonaires rares de l'adulte, service de pneumologie et oncologie thoracique, hôpital Côte de Nacre, CHU de Caen, Caen, France
| | - E Blanchard
- Centre de compétence pour les maladies pulmonaires rares de l'adulte, service de pneumologie, hôpital Haut Levêque, CHU de Bordeaux, Pessac, France
| | - R Borie
- Centre de référence constitutif des maladies pulmonaires rares, service de pneumologie A, AP-HP, hôpital Bichat, Paris, France
| | - A Bourdin
- Centre de compétence pour les maladies pulmonaires rares de l'adulte, département de pneumologie et addictologie, hôpital Arnaud-de-Villeneuve, CHU de Montpellier, Montpellier ; Inserm U1046, CNRS UMR 921, Montpellier, France
| | - C Chenivesse
- Centre de référence constitutif des maladies pulmonaires rares, service de pneumologie et d'immuno-allergologie, hôpital Albert Calmette ; CHRU de Lille, Lille ; centre d'infection et d'immunité de Lille U1019 - UMR 9017, Université de Lille, CHU Lille, CNRS, Inserm, Institut Pasteur de Lille, Lille, France
| | - A Clément
- Centre de ressources et de compétence de la mucoviscidose pédiatrique, centre de référence des maladies respiratoires rares (RespiRare), service de pneumologie pédiatrique, hôpital d'enfants Armand-Trousseau, CHU Paris Est, Paris ; Sorbonne université, Paris, France
| | - E Gomez
- Centre de compétence pour les maladies pulmonaires rares, département de pneumologie, hôpitaux de Brabois, CHRU de Nancy, Vandoeuvre-les Nancy, France
| | - A Gondouin
- Centre de compétence pour les maladies pulmonaires rares, service de pneumologie, CHU Jean-Minjoz, Besançon, France
| | - S Hirschi
- Centre de compétence pour les maladies pulmonaires rares, service de pneumologie, Nouvel Hôpital civil, Strasbourg, France
| | - F Lebargy
- Centre de compétence pour les maladies pulmonaires rares, service de pneumologie, CHU Maison Blanche, Reims, France
| | - C-H Marquette
- Centre de compétence pour les maladies pulmonaires rares, FHU OncoAge, département de pneumologie et oncologie thoracique, hôpital Pasteur, CHU de Nice, Nice cedex 1 ; Université Côte d'Azur, CNRS, Inserm, Institute of Research on Cancer and Aging (IRCAN), Nice, France
| | - D Montani
- Centre de compétence pour les maladies pulmonaires rares, centre national coordonnateur de référence de l'hypertension pulmonaire, service de pneumologie et soins intensifs pneumologiques, AP-HP, DMU 5 Thorinno, Inserm UMR S999, CHU Paris-Sud, hôpital de Bicêtre, Le Kremlin-Bicêtre ; Université Paris-Saclay, Faculté de médecine, Le Kremlin-Bicêtre, France
| | - G Prévot
- Centre de compétence pour les maladies pulmonaires rares, service de pneumologie, CHU Larrey, Toulouse, France
| | - S Quetant
- Centre de compétence pour les maladies pulmonaires rares, service de pneumologie et physiologie, CHU Grenoble Alpes, Grenoble, France
| | - M Reynaud-Gaubert
- Centre de compétence pour les maladies pulmonaires rares, service de pneumologie, AP-HM, CHU Nord, Marseille ; Aix Marseille Université, IRD, APHM, MEPHI, IHU-Méditerranée Infection, Marseille, France
| | - M Salaun
- Centre de compétence pour les maladies pulmonaires rares, service de pneumologie, oncologie thoracique et soins intensifs respiratoires & CIC 1404, hôpital Charles Nicole, CHU de Rouen, Rouen ; IRIB, laboratoire QuantiIF-LITIS, EA 4108, université de Rouen, Rouen, France
| | - O Sanchez
- Centre de compétence pour les maladies pulmonaires rares, service de pneumologie et soins intensifs, hôpital européen Georges-Pompidou, AP-HP, Paris, France
| | | | - K Berkani
- Clinique Pierre de Soleil, Vetraz Monthoux, France
| | - P-Y Brillet
- Université Paris 13, UPRES EA 2363, Bobigny ; service de radiologie, AP-HP, hôpital Avicenne, Bobigny, France
| | - M Campana
- Service de pneumologie et oncologie thoracique, CHR Orléans, Orléans, France
| | - L Chalabreysse
- Service d'anatomie-pathologique, groupement hospitalier est, HCL, Bron, France
| | - G Chatté
- Cabinet de pneumologie et infirmerie protestante, Caluire, France
| | - D Debieuvre
- Service de pneumologie, GHRMSA, hôpital Emile-Muller, Mulhouse, France
| | - G Ferretti
- Université Grenoble Alpes, Grenoble ; service de radiologie diagnostique et interventionnelle, CHU Grenoble Alpes, Grenoble, France
| | - J-M Fourrier
- Association Pierre-Enjalran Fibrose Pulmonaire Idiopathique (APEFPI), Meyzieu, France
| | - N Just
- Service de pneumologie, CH Victor-Provo, Roubaix, France
| | - M Kambouchner
- Service de pathologie, AP-HP, hôpital Avicenne, Bobigny, France
| | - B Legrand
- Cabinet médical de la Bourgogne, Tourcoing ; Université de Lille, CHU Lille, ULR 2694 METRICS, CERIM, Lille, France
| | - F Le Guillou
- Cabinet de pneumologie, pôle santé de l'Esquirol, Le Pradet, France
| | - J-P Lhuillier
- Cabinet de pneumologie, La Varenne Saint-Hilaire, France
| | - A Mehdaoui
- Service de pneumologie et oncologie thoracique, CH Eure-Seine, Évreux, France
| | - J-M Naccache
- Service de pneumologie, allergologie et oncologie thoracique, GH Paris Saint-Joseph, Paris, France
| | - C Paganon
- Centre national coordonnateur de référence des maladies pulmonaires rares, service de pneumologie, hôpital Louis-Pradel, Hospices Civils de Lyon (HCL), Lyon, France
| | - M Rémy-Jardin
- Institut Cœur-Poumon, service de radiologie et d'imagerie thoracique, CHRU de Lille, Lille, France
| | - S Si-Mohamed
- Département d'imagerie cardiovasculaire et thoracique, hôpital Louis-Pradel, HCL, Bron ; Université de Lyon, INSA-Lyon, Université Claude-Bernard Lyon 1, UJM-Saint Etienne, CNRS, Inserm, CREATIS UMR 5220, U1206, Villeurbanne, France
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French practical guidelines for the diagnosis and management of idiopathic pulmonary fibrosis - 2021 update. Full-length version. Respir Med Res 2022; 83:100948. [PMID: 36630775 DOI: 10.1016/j.resmer.2022.100948] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
BACKGROUND Since the latest 2017 French guidelines, knowledge about idiopathic pulmonary fibrosis has evolved considerably. METHODS Practical guidelines were drafted on the initiative of the Coordinating Reference Center for Rare Pulmonary Diseases, led by the French Language Pulmonology Society (SPLF), by a coordinating group, a writing group, and a review group, with the involvement of the entire OrphaLung network, pulmonologists practicing in various settings, radiologists, pathologists, a general practitioner, a health manager, and a patient association. The method followed the "Clinical Practice Guidelines" process of the French National Authority for Health (HAS), including an online vote using a Likert scale. RESULTS After a literature review, 54 guidelines were formulated, improved, and then validated by the working groups. These guidelines addressed multiple aspects of the disease: epidemiology, diagnostic procedures, quality criteria and interpretation of chest CT scans, lung biopsy indication and procedures, etiological workup, methods and indications for family screening and genetic testing, assessment of the functional impairment and prognosis, indication and use of antifibrotic agents, lung transplantation, management of symptoms, comorbidities and complications, treatment of chronic respiratory failure, diagnosis and management of acute exacerbations of fibrosis. CONCLUSION These evidence-based guidelines are intended to guide the diagnosis and practical management of idiopathic pulmonary fibrosis.
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Fournier D, Jouneau S, Bouzille G, Polard E, Osmont MN, Scailteux LM. Real-world safety profiles of pirfenidone and nintedanib in idiopathic pulmonary fibrosis patients. Pulm Pharmacol Ther 2022; 76:102149. [PMID: 35918026 DOI: 10.1016/j.pupt.2022.102149] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Revised: 07/08/2022] [Accepted: 07/14/2022] [Indexed: 11/17/2022]
Abstract
INTRODUCTION While pirfenidone and nintedanib have greatly influenced the treatment of idiopathic pulmonary fibrosis (IPF), both drugs have significant early adverse drug reactions (ADRs) and almost nothing is known of their rare and delayed ADRs. We collected and analyzed pirfenidone- or nintedanib-related ADRs identified in a French rare lung disease center, recorded their profiles and identified potential safety signals. METHODS We analyzed the medical records of IPF patients treated with pirfenidone or nintedanib between January, 2011 and January, 2020 at the Rennes University Hospital to estimate the incidence of serious and non-serious ADRs cases due to each drug and the incidence of ADRs involving the cardiovascular, hepatobiliary, gastro-intestinal, dermatological, and metabolic/nutritional systems. RESULTS The 176 patients included 115 (65%) initially treated with pirfenidone and 61 (35%) given nintedanib. ADRs occurred in 78.3% of those given pirfenidone and in 70.5% of those given nintedanib. The incidence of first serious ADRs cases was about 33 per 100 person-years (100 PY) for both drugs; first non-serious pirfenidone ADRs cases were 102 per 100 PY and 130 per 100 PY for nintedanib. The incidence involving each organ system were quite similar, except for the gastro-intestinal and skin disorders. Cardiovascular disorders occurred in about 10 cases per 100 PY in both pirfenidone and nintedanib patients. DISCUSSION Most ADRs were consistent with the expected antifibrotic drug safety profiles. As arterial and venous thromboembolic events are rare, it is important to assess the risk associated with using antifibrotics by a dedicated pharmacoepidemiological study.
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Affiliation(s)
- Dorine Fournier
- Pharmacovigilance, Pharmacoepidemiology and Drug Information Center, Department of Clinical Pharmacology, Rennes University Hospital, 35033, Rennes, France
| | - Stéphane Jouneau
- Dept of Respiratory Medicine, Competence Center for Rare Pulmonary Diseases, CHU Rennes, University of Rennes, Rennes, France; Univ Rennes, CHU Rennes, INSERM, EHESP, IRSET (Institut de recherche en santé, environnement et travail), UMR_S, 1085, Rennes, France
| | | | - Elisabeth Polard
- Pharmacovigilance, Pharmacoepidemiology and Drug Information Center, Department of Clinical Pharmacology, Rennes University Hospital, 35033, Rennes, France; Univ Rennes, CHU Rennes, INSERM, EHESP, IRSET (Institut de recherche en santé, environnement et travail), UMR_S, 1085, Rennes, France
| | - Marie-Noëlle Osmont
- Pharmacovigilance, Pharmacoepidemiology and Drug Information Center, Department of Clinical Pharmacology, Rennes University Hospital, 35033, Rennes, France
| | - Lucie-Marie Scailteux
- Pharmacovigilance, Pharmacoepidemiology and Drug Information Center, Department of Clinical Pharmacology, Rennes University Hospital, 35033, Rennes, France; Univ Rennes, CHU Rennes, INSERM, EHESP, IRSET (Institut de recherche en santé, environnement et travail), UMR_S, 1085, Rennes, France.
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20
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Lee EG, Lee TH, Hong Y, Ryoo J, Heo JW, Gil BM, Kang HS, Kwon SS, Kim YH. Effects of low-dose pirfenidone on survival and lung function decline in patients with idiopathic pulmonary fibrosis (IPF): Results from a real-world study. PLoS One 2021; 16:e0261684. [PMID: 34941933 PMCID: PMC8699661 DOI: 10.1371/journal.pone.0261684] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Accepted: 12/07/2021] [Indexed: 11/18/2022] Open
Abstract
BACKGROUND Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrosing interstitial pneumonia of unknown etiology. In several randomized clinical trials, and in the clinical practice, pirfenidone is used to effectively and safely treat IPF. However, sometimes it is difficult to use the dose of pirfenidone used in clinical trials. This study evaluated the effects of low-dose pirfenidone on IPF disease progression and patient survival in the real-world. METHODS This retrospective, observational study enrolled IPF patients seen at the time of diagnosis at a single center from 2008 to 2018. Longitudinal clinical and laboratory data were prospectively collected. We compared the clinical characteristics, survival, and pulmonary function decline between patients treated and untreated with various dose of pirfenidone. RESULTS Of 295 IPF patients, 100 (33.9%) received pirfenidone and 195 (66.1%) received no antifibrotic agent. Of the 100 patients who received pirfenidone, 24 (24%), 50 (50%), and 26 (26%), respectively, were given 600, 1200, and 1800 mg pirfenidone daily. The mean survival time was 57.03 ± 3.90 months in the no-antifibrotic drug group and 73.26 ± 7.87 months in the pirfenidone-treated group (p = 0.027). In the unadjusted analysis, the survival of the patients given pirfenidone was significantly better (hazard ratio [HR] = 0.69, 95% confidence interval [CI]: 0.48-0.99, p = 0.04). After adjusting for age, gender, body mass index, and the GAP score [based on gender (G), age (A), and two physiological lung parameters (P)], survival remained better in the patients given pirfenidone (HR = 0.56, 95% CI: 0.37-0.85, p = 0.006). In terms of pulmonary function, the decreases in forced vital capacity (%), forced expiratory volume in 1 s (%) and the diffusing capacity of lung for carbon monoxide (%) were significantly smaller (p = 0.000, p = 0.001, and p = 0.007, respectively) in patients given pirfenidone. CONCLUSIONS Low-dose pirfenidone provided beneficial effects on survival and pulmonary function decline in the real-world practice.
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Affiliation(s)
- Eung Gu Lee
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, Bucheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Tae-Hee Lee
- Department of Statistics and Data Science, Yonsei University, Seoul, South Korea
| | - Yujin Hong
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, Bucheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Jiwon Ryoo
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, Bucheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Jung Won Heo
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, Eunpyeong St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Bo Mi Gil
- Department of Radiology, Bucheon St. Mary’s Hospital, College of Medicine, The Catholic university of Korea, Seoul, Republic of Korea
| | - Hye Seon Kang
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, Bucheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Soon Seog Kwon
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, Bucheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Yong Hyun Kim
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, Bucheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
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21
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Role of pirfenidone in TGF-β pathways and other inflammatory pathways in acute respiratory syndrome coronavirus 2 (SARS-Cov-2) infection: a theoretical perspective. Pharmacol Rep 2021; 73:712-727. [PMID: 33880743 PMCID: PMC8057922 DOI: 10.1007/s43440-021-00255-x] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Revised: 03/14/2021] [Accepted: 03/23/2021] [Indexed: 12/13/2022]
Abstract
Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes pulmonary injury or multiple-organ injury by various pathological pathways. Transforming growth factor-beta (TGF-β) is a key factor that is released during SARS-CoV-2 infection. TGF-β, by internalization of the epithelial sodium channel (ENaC), suppresses the anti-oxidant system, downregulates the cystic fibrosis transmembrane conductance regulator (CFTR), and activates the plasminogen activator inhibitor 1 (PAI-1) and nuclear factor-kappa-light-chain-enhancer of activated B cells (NF-kB). These changes cause inflammation and lung injury along with coagulopathy. Moreover, reactive oxygen species play a significant role in lung injury, which levels up during SARS-CoV-2 infection. Drug Suggestion Pirfenidone is an anti-fibrotic drug with an anti-oxidant activity that can prevent lung injury during SARS-CoV-2 infection by blocking the maturation process of transforming growth factor-beta (TGF-β) and enhancing the protective role of peroxisome proliferator-activated receptors (PPARs). Pirfenidone is a safe drug for patients with hypertension or diabetes and its side effect tolerated well. Conclusion The drug as a theoretical perspective may be an effective and safe choice for suppressing the inflammatory response during COVID-19. The recommendation would be a combination of pirfenidone and N-acetylcysteine to achieve maximum benefit during SARS-CoV-2 treatment.
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Yao Y, Yuan Y, Lu Z, Ma Y, Xie Y, Wang M, Liu F, Zhu C, Lin C. Effects of Nervilia fordii Extract on Pulmonary Fibrosis Through TGF-β/Smad Signaling Pathway. Front Pharmacol 2021; 12:659627. [PMID: 33953686 PMCID: PMC8090936 DOI: 10.3389/fphar.2021.659627] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Accepted: 03/22/2021] [Indexed: 12/20/2022] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) is a progressive and irreversible interstitial pulmonary disease with a poor prognosis. The extract of Nervilia fordii (NFE) has shown remarkable benefit in the treatment of acute lung injury, lung cancer, and severe acute respiratory syndrome (SARS). However, the potential mechanism and efficacy of NFE in the treatment of IPF remain unknown. In this study, a systematic network pharmacology analysis was used to predict the mechanism and efficacy of NFE in the treatment of IPF, based on the major components of NFE elucidated by UPLC-TOF-MS/MS. The potential molecular interactions between the compounds and potential targets were predicted using molecular docking. In vivo, rats with pulmonary fibrosis induced by a single intratracheal injection of bleomycin (BLM) were orally administered NFE for 14 days. Lung index and biochemical levels were determined, and histopathological analysis using hematoxylin and eosin (H&E) and Masson staining was performed. The effects of NFE on fibroblast proliferation in Lipopolysaccharide (LPS) and TGF-β1-induced mouse 3T6 fibroblasts were evaluated in vitro. In total, 20 components were identified in NFE, and 102 potential targets for IPF treatment were predicted. These targets potentially participate in processes regulated by transmembrane receptor protein tyrosine kinase, ERBB2, and et al. Molecular docking results predicted high affinity interactions between three components (rhamnazin, rhamnetin, and rhamnocitrin) and the potential targets, suggesting that TGF-β is the most important potential target of NFE in the treatment of pulmonary fibrosis. NFE significantly decreased the lung index and alleviated BLM-induced pulmonary fibrosis in rats. Histopathological observation of lung tissues showed that NFE alleviated inflammation and collagen deposition in BLM-induced rats. NFE inhibited the migration of LPS- and TGF-β1-induced 3T6 fibroblasts, reduced the contents of hydroxyproline and collagen, and contributed to anti-inflammation and anti-oxidation. With the intervention of NFE, the protein and RNA expression of TGF-β1, a-SMA, Smad3/4, p-Smad3/4, CTGF, and p-ERK1/2 were significantly downregulated, while Smad7 and ERK1/2 were upregulated significantly in vivo and in vitro. These findings indicated that NFE may exert therapeutic effects on pulmonary fibrosis by alleviating inflammation, oxidation, and collagen deposition. The mechanism related to the inhibition of the TGF-β/Smad signaling pathway.
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Affiliation(s)
- Yufeng Yao
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yue Yuan
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Zenghui Lu
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yunxia Ma
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yuanyuan Xie
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Meiqi Wang
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Fangle Liu
- School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Chenchen Zhu
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Chaozhan Lin
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
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Pastre J, Barnett S, Ksovreli I, Taylor J, Brown AW, Shlobin OA, Ahmad K, Khangoora V, Aryal S, King CS, Nathan SD. Idiopathic pulmonary fibrosis patients with severe physiologic impairment: characteristics and outcomes. Respir Res 2021; 22:5. [PMID: 33407450 PMCID: PMC7788925 DOI: 10.1186/s12931-020-01600-z] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Accepted: 12/10/2020] [Indexed: 01/01/2023] Open
Abstract
RESEARCH QUESTION There is no widely accepted grading system for IPF disease severity, although physiologic impairment based on pulmonary function testing is frequently employed. We sought to describe clinical and functional characteristics as well as outcomes of patients with severe physiologic impairment. PATIENTS AND METHODS IPF patients with severe physiologic impairment defined by FVC ≤ 50% and/or DLco ≤ 30% predicted evaluated in the Inova Advanced Lung Disease Program between 2011 and 2019 were included. Demographic, physiologic, functional treatment and outcome data were collated. RESULTS There were 531 patients with IPF evaluated of whom 242 (46%) had severe physiologic impairment. Mean age was 72 ± 8 years; baseline FVC was 53 ± 17% and DLCO 28 ± 9% of predicted. The mean 6 min walks test (6MWT) distance was 304 ± 121 m with 59% of the patients requiring supplemental oxygen ([Formula: see text] group). There was a poor correlation between the 6MWT distance and both FVC% and DLco%. Patients in the 6MWTRA group had a better transplant-free survival than the [Formula: see text] group (p = 0.002). Patients managed before October 2014 and not receiving antifibrotic therapy had worse outcomes with reduced transplant-free survival compared with patients presenting after this date who did receive antifibrotic therapy (n = 113) (log rank p < 0.0001). CONCLUSION IPF patients often present with severe physiologic impairment which may be poorly correlated with their functional status. Assessment of IPF disease severity should not be based on physiologic impairment alone, but should also encompass functional status as well as need for supplemental oxygen. Antifibrotic therapy in patients with severe physiologic impairment is associated with improved outcomes.
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Affiliation(s)
- Jean Pastre
- Inova Advanced Lung Disease and Transplant Program, Inova Fairfax Hospital, 3300 Gallows Road, Falls Church, VA, 22042, USA. .,Service de Pneumologie Et Soins Intensifs, Hôpital Européen Georges Pompidou, APHP, Paris, France.
| | - Scott Barnett
- Inova Advanced Lung Disease and Transplant Program, Inova Fairfax Hospital, 3300 Gallows Road, Falls Church, VA, 22042, USA
| | - Inga Ksovreli
- Inova Advanced Lung Disease and Transplant Program, Inova Fairfax Hospital, 3300 Gallows Road, Falls Church, VA, 22042, USA
| | - Jeannie Taylor
- Inova Advanced Lung Disease and Transplant Program, Inova Fairfax Hospital, 3300 Gallows Road, Falls Church, VA, 22042, USA
| | - A Whitney Brown
- Inova Advanced Lung Disease and Transplant Program, Inova Fairfax Hospital, 3300 Gallows Road, Falls Church, VA, 22042, USA
| | - Oksana A Shlobin
- Inova Advanced Lung Disease and Transplant Program, Inova Fairfax Hospital, 3300 Gallows Road, Falls Church, VA, 22042, USA
| | - Kareem Ahmad
- Inova Advanced Lung Disease and Transplant Program, Inova Fairfax Hospital, 3300 Gallows Road, Falls Church, VA, 22042, USA
| | - Vikramjit Khangoora
- Inova Advanced Lung Disease and Transplant Program, Inova Fairfax Hospital, 3300 Gallows Road, Falls Church, VA, 22042, USA
| | - Shambhu Aryal
- Inova Advanced Lung Disease and Transplant Program, Inova Fairfax Hospital, 3300 Gallows Road, Falls Church, VA, 22042, USA
| | - Christopher S King
- Inova Advanced Lung Disease and Transplant Program, Inova Fairfax Hospital, 3300 Gallows Road, Falls Church, VA, 22042, USA
| | - Steven D Nathan
- Inova Advanced Lung Disease and Transplant Program, Inova Fairfax Hospital, 3300 Gallows Road, Falls Church, VA, 22042, USA
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Yasmin H, Saha S, Butt MT, Modi RK, George AJT, Kishore U. SARS-CoV-2: Pathogenic Mechanisms and Host Immune Response. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1313:99-134. [PMID: 34661893 DOI: 10.1007/978-3-030-67452-6_6] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an enveloped, positive-sense RNA coronavirus responsible for the COVID-19 pandemic. Since December 2019, coronavirus disease 2019 (COVID-19) has affected more than 127 million people, 2.7 million deaths globally (as per WHO dashboard, dated 31 March, 2020), the virus is capable of transmitting from human to human via inhalation of infected respiratory droplets or aerosols or contact with infected fomites. Clinically, patients with COVID-19 present with severe respiratory distress syndrome, which is very similar to the presentation of other respiratory viral infections. A huge variation in the host response exists, with the resulting symptoms varying from mild to moderate. Comorbidities such as cardiovascular disease, hypertension, diabetes, coagulation dysfunction, stroke, malignant tumor and multiple organ dysfunction syndrome, as well as age and sex, are associated with severe COVID-19 cases. So far, no targeted therapies have been developed to treat this disease and existing drugs are being investigated for repurposing. This chapter discusses the epidemiology, clinical features of COVID-19, pathogenesis and the innate and adaptive immune response mounted by the host to the SARS-CoV-2 infection. A deeper understanding of the host-pathogen interaction is fundamental to the development of a vaccine.
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Affiliation(s)
- Hadida Yasmin
- Immunology and Cell Biology Laboratory, Department of Zoology, Cooch Behar Panchanan Barma University, Cooch Behar, West Bengal, India
| | - Sudipta Saha
- Amity Institute of Physiology and Allied Sciences, Amity University Campus, Noida, Uttar Pradesh, India
| | - Mariam Tariq Butt
- Biosciences, College of Health, Medicine and Life Sciences, Brunel University London, Uxbridge, UK
| | - Rishab Kumar Modi
- Immunology and Cell Biology Laboratory, Department of Zoology, Cooch Behar Panchanan Barma University, Cooch Behar, West Bengal, India
| | - Andrew J T George
- Department of Surgery and Cancer, Imperial College London, London, UK
| | - Uday Kishore
- Biosciences, College of Health, Medicine and Life Sciences, Brunel University London, Uxbridge, UK.
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Yogaratnam D, Carey KM, Coppenrath V, Dawson A, Harris M, LaMothe AB, Pourhosseini P, Lynch AM. Drugs that act on the respiratory tract. SIDE EFFECTS OF DRUGS ANNUAL 2021. [PMCID: PMC8526131 DOI: 10.1016/bs.seda.2021.09.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
Abstract
No published data from this past year provide new insight on the safety and tolerability of corticosteroids, β2-adrenoreceptor agonists, or phosphodiesterase inhibitors as they pertain to respiratory diseases. While systemic corticosteroids have become a valuable therapeutic agent in treating Covid-19 pneumonia, there have been no new or unexpected adverse events reported within this context. Reports evaluating the psychiatric and vascular side effect profile of the leukotriene modifier, montelukast, are described below. For inhaled anticholinergic drugs, meta-analyses describe the cardiovascular safety of these agents, as well as the safety of tiotropium in pediatric patients. A case of mydriasis associated with ipratropium therapy is described. In addition, the safety of umeclidinium as part of a triple-drug inhaler was evaluated in a large randomized clinical trial. For the antifibrotic drugs nintedanib and pirfenidone, there are a number of reports describing the safety of these drugs in specific populations, and there are a number of case reports describing unique side effects. Lastly, there are new reports describing the safety of monoclonal antibody therapy for moderate to severe asthma, as well as a few case reports describing rare adverse events associated with benralizumab, dupilumab, mepolizumab, omalizumab, and reslizumab.
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COVID-19 Patients with Pulmonary Fibrotic Tissue: Clinical Pharmacological Rational of Antifibrotic Therapy. ACTA ACUST UNITED AC 2020; 2:1709-1712. [PMID: 32875276 PMCID: PMC7452615 DOI: 10.1007/s42399-020-00487-7] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/24/2020] [Indexed: 02/07/2023]
Abstract
In December 2019, the first data emerged from Wuhan, China, of a serious acute respiratory disease caused by a new coronavirus, SARS-CoV-2 (COVID-19). In a short time, the health emergency became a global pandemic. To date, there are about 18.8 million infected people and about 700,000 deaths. There are currently no effective vaccines, and treatments are mostly experimental. The symptoms associated with COVID-19 are different, ranging from mild upper respiratory tract symptoms to severe acute respiratory distress syndrome (SARS). Data from previous coronavirus outbreaks such as SARS-CoV (2003 outbreak) and emerging epidemiological data from the current global COVID-19 pandemic suggest that there could be substantial tissue fibrotic consequences following SARS-CoV-2 infection, responsible for severe and in some cases fatal lung lesions. Some data show that even patients cured of viral infection have lung fibrotic tissue residues responsible for incorrect respiratory function even after healing. The role of antifibrotic drug therapy in patients with ongoing SARS-CoV-2 infection or in patients cured of residual pulmonary fibrosis is still to be defined and unclear; the scientific rationale for initiating, continuing, or discontinuing therapy is poorly defined. In this article, we describe the advantages of antifibrotic therapy in patients with ongoing SARS-CoV-2 viral infection to prevent the worsening and aggravation of the clinical situation, and the advantages it could have in the role of preventing pulmonary fibrosis after SARS-CoV-2 infection, and in accelerating the complete healing process.
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The added value of pirfenidone to fight inflammation and fibrotic state induced by SARS-CoV-2 : Anti-inflammatory and anti-fibrotic therapy could solve the lung complications of the infection? Eur J Clin Pharmacol 2020; 76:1615-1618. [PMID: 32594204 PMCID: PMC7320911 DOI: 10.1007/s00228-020-02947-4] [Citation(s) in RCA: 60] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2020] [Accepted: 06/23/2020] [Indexed: 01/08/2023]
Abstract
Aim SARS-CoV-2 infection has been divided by scientific opinion into three phases: the first as asymptomatic or slightly symptomatic and the second and the third with greater severity, characterized by a hyperinflammatory and fibrotic state, responsible for lung lesions, in some cases fatal. The development of antiviral drugs directed against SARS-CoV-2 and effective vaccines is progressing; meanwhile, the best pharmacological objective is related to the management of all the complications caused by this viral infection, mainly controlling the inflammatory and fibrotic state and preventing the infection from moving into the most serious phases. Subject and method Describe the scientific rationale related to the use of an antifibrotic therapy with pirfenidone, as monotherapy and/or in combination with anti-inflammatory drugs to manage and control complications of SARS-CoV-2 infection. Results Based on the scientific literature and epidemiological results and considering the pathophysiological, biological, and molecular characteristics of SARS-CoV-2, an antifibrotic drug such as pirfenidone as monotherapy or in combination with anti-inflammatory drugs can be (acting early, at the right doses and at the right time) therapeutically effective to avoid serious complications during viral infection. The same approach can also be effective as postinfection therapy in patients with residual pulmonary fibrotic damage. Management of inflammation and fibrotic status with a combination therapy of pirfenidone and IL-6 or IL-1 inhibitors could represent a pharmacological synergy with added value. Conclusion In this article, we consider the role of antifibrotic therapy with pirfenidone in patients with SARS-CoV-2 infection on going or in the stage of postinfection with pulmonary fibrotic consequences. The scientific rationale for its use is also described.
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