Oral nintedanib is marketed for the treatment of idiopathic pulmonary fibrosis (IPF), Systemic Sclerosis-Associated Interstitial Lung Disease and Chronic Fibrosing Interstitial Lung Diseases with a ...Progressive Phenotype. While effective at slowing fibrosis progression, as an oral medicine nintedanib has limitations. To reduce side effects and maximize efficacy, nintedanib was reformulated as a solution for nebulization and inhaled administration. To predict effectiveness treating IPF, inhalation was used as a tool to dissect the pharmacokinetic components required for nintedanib pulmonary anti-fibrotic activity. Following oral administration, nintedanib extensively partitioned into tissue and exhibited flip-flop pharmacokinetics, whereby resulting lung Cmax and AUC were substantially higher than plasma. By comparison, inhaled nintedanib was capable of delivering an oral-equivalent lung Cmax with lower local and systemic AUC. Using a multi-challenge bleomycin rat model, this distinct inhaled pharmacokinetic profile was dose responsive (0.05, 0.25 and 0.375 mg/kg), delivering oral-superior pulmonary anti-fibrotic activity with an equivalent delivered lung Cmax (QD inhaled 0.375 mg/kg versus BID oral 60 mg/kg). Possibly assisting this improvement, the infrequent high inhaled dose also improved bleomycin-challenged animal weight gain to levels equivalent to sham. By comparison, BID oral weight gain was substantially less than controls, suggesting a negative health impact on oral administered animals combating fibrosis. Both oral and inhaled administration exhibited anti-inflammatory activity, with oral achieving significance. In summary, inhalation (short-duration nintedanib lung Cmax without high local or systemic AUC) was well-tolerated and was effective reducing bleomycin-induced pulmonary fibrosis.
Although pulmonary fibrosis secondary to COVID-19 infection is uncommon, it can lead to problems if not treated effectively in the early period. This study aimed to compare the effects of treatment ...with nintedanib and pirfenidone in patients with COVID-19-related fibrosis.
Thirty patients who presented to the post-COVID outpatient clinic between May 2021 and April 2022 with a history of COVID-19 pneumonia and exhibited persistent cough, dyspnea, exertional dyspnea, and low oxygen saturation at least 12 weeks after diagnosis were included. The patients were randomized to receive off-label treatment with nintedanib or pirfenidone and were followed up for 12 weeks.
After 12 weeks of treatment, all pulmonary function test (PFT) parameters, 6MWT distance, and oxygen saturation were increased compared to baseline in both the pirfenidone group and nintedanib groups, while heart rate and radiological score levels were decreased (p<0.05 for all). The changes in 6MWT distance and oxygen saturation were significantly greater in the nintedanib group than in the pirfenidone group (p=0.02 and 0.005, respectively). Adverse drug effects were more frequent with nintedanib than pirfenidone, with the most common being diarrhea, nausea, and vomiting.
In patients with interstitial fibrosis after COVID-19 pneumonia, both nintedanib and pirfenidone were observed to be effective in improving radiological score and PFT parameters. Nintedanib was more effective than pirfenidone in increasing exercise capacity and saturation values but caused more adverse drug effects.
Aunque la fibrosis pulmonar secundaria a la infección por COVID-19 es poco común, puede generar problemas si no se trata de manera efectiva en el período inicial. Este estudio tuvo como objetivo comparar los efectos del tratamiento con nintedanib y pirfenidona en pacientes con fibrosis relacionada con COVID-19.
Se incluyeron 30 pacientes que acudieron a la consulta externa post-COVID entre mayo de 2021 y abril de 2022 con antecedentes de neumonía por COVID-19 y presentaron tos persistente, disnea, disnea de esfuerzo y baja saturación de oxígeno al menos 12semanas después del diagnóstico. Los pacientes fueron aleatorizados para recibir un tratamiento no aprobado con nintedanib o pirfenidona y fueron seguidos durante 12semanas.
Después de 12semanas de tratamiento, todos los parámetros de la prueba de función pulmonar (PFT), la distancia de la PM6M y la saturación de oxígeno aumentaron en comparación con los valores basales tanto en el grupo de pirfenidona como en el de nintedanib, mientras que la frecuencia cardíaca y los niveles de puntuación radiológica disminuyeron (p<0,05 para todos). Los cambios en la distancia de la PM6M y la saturación de oxígeno fueron significativamente mayores en el grupo de nintedanib que en el grupo de pirfenidona (p=0,02 y p=0,005, respectivamente). Los efectos adversos del fármaco fueron más frecuentes con nintedanib que con pirfenidona, siendo los más comunes diarrea, náuseas y vómitos.
En pacientes con fibrosis intersticial después de neumonía por COVID-19 se observó que tanto nintedanib como pirfenidona son efectivos para mejorar la puntuación radiológica y los parámetros de la PFT. Nintedanib fue más eficaz que pirfenidona para aumentar la capacidad de ejercicio y los valores de saturación, pero provocó más efectos adversos del fármaco.
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive disease characterized by the aberrant accumulation of fibrotic tissue in the lungs parenchyma, associated with significant morbidity and ...poor prognosis. This review will present the substantial advances achieved in the understanding of IPF pathogenesis and in the therapeutic options that can be offered to patients, and will address the issues regarding diagnosis and management that are still open.
Over the last two decades much has been clarified about the pathogenic pathways underlying the development and progression of the lung scarring in IPF. Sustained alveolar epithelial micro-injury and activation has been recognised as the trigger of several biological events of disordered repair occurring in genetically susceptible ageing individuals. Despite multidisciplinary team discussion has demonstrated to increase diagnostic accuracy, patients can still remain unclassified when the current diagnostic criteria are strictly applied, requiring the identification of a Usual Interstitial Pattern either on high-resolution computed tomography scan or lung biopsy. Outstanding achievements have been made in the management of these patients, as nintedanib and pirfenidone consistently proved to reduce the rate of progression of the fibrotic process. However, many uncertainties still lie in the correct use of these drugs, ranging from the initial choice of the drug, the appropriate timing for treatment and the benefit-risk ratio of a combined treatment regimen. Several novel compounds are being developed in the perspective of a more targeted therapeutic approach; in the meantime, the supportive care of these patients and their carers should be appropriately prioritized, and greater efforts should be made toward the prompt identification and management of relevant comorbidities.
Building on the advances in the understanding of IPF pathobiology, the further investigation of the role of gene variants, epigenetic alterations and other molecular biomarkers reflecting disease activity and behaviour will hopefully enable earlier and more confident diagnosis, improve disease phenotyping and support the development of novel agents for personalized treatment of IPF.
Idiopathic pulmonary fibrosis (IPF) is a progressive fibrosing interstitial lung disease associated with significant morbidity and mortality. Nintedanib and pirfenidone are two antifibrotic ...medications currently approved for slowing the rate of lung function decline in IPF, but data on treatment effect on mortality and risk of acute exacerbation (AE) remains limited or unknown.
Does antifibrotic treatment decrease risk of mortality and AE?
A comprehensive search of several databases, including Ovid MEDLINE(R), Ovid Embase, Ovid Cochrane Central Register of Controlled Trials, Ovid Cochrane Database of Systematic Reviews, and Scopus, was conducted. Studies were included if they were original articles comparing mortality or AE events in IPF patients with and without antifibrotic treatment. Relative risk (RR) with 95%CI was pooled using random-effects meta-analyses with inverse variance method, assessing two primary outcomes of all-cause mortality and AE risk.
A total of 12,956 patients across 26 studies (eight randomized controlled trials and 18 cohort studies) were included in the meta-analysis. Antifibrotic treatment was associated with decreased risk of all-cause mortality with a pooled RR of 0.55 (95% CI, 0.45-0.66) and I2 of 82%. This effect was consistent across additional subgroup analyses, including stratification by study type, risk of bias, duration of follow-up, and antifibrotic subtype. Antifibrotic treatment also reduced the risk of AE, with a pooled RR of 0.63 (95% CI, 0.53-0.76), and I2 of 0%. Effect on AE risk was consistent across subgroup analyses by study type and for nintedanib but not for pirfenidone.
Antifibrotic treatment appears to reduce the risk of all-cause mortality and AE in IPF. Despite greater heterogeneity with pooled analysis, its effect was robust in subgroup analyses by study type, duration of follow-up, and antifibrotic subtype.
In December 2020, Indonesia was introduced to the long Coronavirus disease 2019 (COVID-19) phenomenon. The Centers for Disease Control and Prevention (CDC) introduced the term "post-COVID condition" ...as a health problem that persists after four weeks from the first exposure to COVID-19. The National Institute for Healthcare and Care Excellence (NICE) classifies COVID-19 infections into three categories based on disease duration: (1) acute infection for up to 4 weeks; (2) ongoing infection within 4-12 weeks; and (3) post-COVID-19 syndrome for more than 12 weeks and not associated with an alternative diagnosis. One of these phenomena is lung fibrosis. About 80% of COVID-19 survivors had mild to severe chest X-rays in 6 months of follow-up with decreasing lung function. COVID-19-related lung fibrosis is still not widely researched. COVID-19 survivors who develop lung fibrosis usually recover independently, but some develop persistent lung fibrosis. The use of antifibrotic agents, such as nintedanib, has long been approved for idiopathic pulmonary fibrosis (IPF). However, its use in the cases of lung fibrosis due to COVID-19 has not been widely studied. Nintedanib is a tyrosine kinase inhibitor. It inhibits receptor activity of vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and fibroblast growth factor (FGF). Those actions will eventually inhibit the proliferation, migration, and transformation of fibroblasts into myofibroblasts in lung fibrogenesis. Therefore, an antifibrotic agent is potentially needed to inhibit COVID-19-related lung fibrosis to improve quality of life and prevent further lung damage.
To investigate the rate of decline in forced vital capacity (FVC) in patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD) with and without cough or dyspnoea in the SENSCIS ...trial.
Patients in the SENSCIS trial were randomized to receive nintedanib or placebo. Subgroups with and without cough or dyspnoea at baseline were defined by responses to the St. George's Respiratory Questionnaire.
At baseline, 114/575 patients (19.8%) did not have cough and 172/574 patients (30.0%) did not have dyspnoea. In the placebo group, the rate of FVC decline over 52 weeks was similar in patients with and without cough (-95.6 and -83.4 ml/year, respectively) or dyspnoea (-95.8 and -87.7 ml/year, respectively). The effect of nintedanib vs placebo on reducing the rate of FVC decline was numerically more pronounced in patients without than with cough (difference: 74.4 95% CI -11.1, 159.8 vs 31.5 -11.1, 74.1) and without than with dyspnoea (79.8 9.8, 149.7 vs 25.7 -19.9, 71.3), but interaction p-values did not indicate heterogeneity in the treatment effect between these subgroups (p= 0.38 and p= 0.20, respectively).
In the placebo group of the SENSCIS trial, the rate of FVC decline was similar irrespective of the presence of cough or dyspnoea at baseline. The effect of nintedanib on reducing the rate of FVC decline was numerically more pronounced in patients without than with cough or dyspnoea at baseline, but no statistically significant heterogeneity was observed between the subgroups.
ClinicalTrials.gov, https://clinicaltrials.gov, NCT02597933.
Radiation induced pneumonitis is a common side effect of thoracic radiotherapy. We report a case of a patient diagnosed with symptomatic radiation pneumonitis and a serious contra-indication for ...corticosteroids. For that reason, the patient was treated with nintedanib instead. After several weeks of treatment her symptoms and chest CT improved significantly. This case shows that nintedanib might be an effective treatment of radiation pneumonitis if corticosteroids are contra-indicated.
Pulmonary fibrosis (PF) in children is a rare complication of specific forms of childhood interstitial lung diseases (chILD) with extremely limited scientific evidence to guide optimal management. ...Whilst there continues to be significant progress in PF management for adult populations, paediatric guidelines have stagnated. New anti-fibrotic medications (nintedanib and pirfenidone) are finding regular use amongst adult PF patients but remain largely unstudied and untested in children. Although there are major differences between the two age-group populations, it is useful to learn from the evolution of adult PF management, especially in the absence of dedicated paediatric studies. Whilst there have been recent trials aimed at assessing the safety and efficacy of drugs such as nintedanib and hydroxychloroquine, there is still a dire need for more research aimed at further assessing current treatment practices and evaluating the safety and efficacy of new emerging treatments in the paediatric population.
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