Inhalation: A means to explore and optimize nintedanib's pharmacokinetic/pharmacodynamic relationship

Shochet, Gali Epstein; Pham, Scott; Beck, Steven; Naiel, Safaa; Mekhael, Olivia; Revill, Spencer; Hayat, Aaron; Vierhout, Megan; Bardestein-Wald, Becky; Shitrit, David; Ask, Kjetil; Montgomery, A. Bruce; Kolb, Martin; Surber, Mark W.

doi:10.1016/j.pupt.2020.101933

Cited by 13 publications

(21 citation statements)

References 33 publications

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“…For this aim, an inhaled version of nintedanib was recently described. Using two animal models [12,13], it was shown that oral-equivalent to superior effects could be obtained administering substantially reduced inhaled doses, with less adverse effects on general health. Moreover, the activity of inhaled pharmacokinetics were further supported using the in-vitro IPF-CM system wherein only short-duration nintedanib exposure was required to achieve similar effects [13].…”

Section: Introductionmentioning

confidence: 99%

Hypoxia Inducible Factor 1A Supports a Pro-Fibrotic Phenotype Loop in Idiopathic Pulmonary Fibrosis

Shochet

Bardenstein-Wald

McElroy

et al. 2021

IJMS

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Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with poor prognosis. The IPF-conditioned matrix (IPF-CM) system enables the study of matrix–fibroblast interplay. While effective at slowing fibrosis, nintedanib has limitations and the mechanism is not fully elucidated. In the current work, we explored the underlying signaling pathways and characterized nintedanib involvement in the IPF-CM fibrotic process. Results were validated using IPF patient samples and bleomycin-treated animals with/without oral and inhaled nintedanib. IPF-derived primary human lung fibroblasts (HLFs) were cultured on Matrigel and then cleared using NH4OH, creating the IPF-CM. Normal HLF-CM served as control. RNA-sequencing, PCR and western-blots were performed. HIF1α targets were evaluated by immunohistochemistry in bleomycin-treated rats with/without nintedanib and in patient samples with IPF. HLFs cultured on IPF-CM showed over-expression of ‘HIF1α signaling pathway’ (KEGG, p < 0.0001), with emphasis on SERPINE1 (PAI-1), VEGFA and TIMP1. IPF patient samples showed high HIF1α staining, especially in established fibrous tissue. PAI-1 was overexpressed, mainly in alveolar macrophages. Nintedanib completely reduced HIF1α upregulation in the IPF-CM and rat-bleomycin models. IPF-HLFs alter the extracellular matrix, thus creating a matrix that further propagates an IPF-like phenotype in normal HLFs. This pro-fibrotic loop includes the HIF1α pathway, which can be blocked by nintedanib.

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Section: Introductionmentioning

confidence: 99%

Hypoxia Inducible Factor 1A Supports a Pro-Fibrotic Phenotype Loop in Idiopathic Pulmonary Fibrosis

Shochet

Bardenstein-Wald

McElroy

et al. 2021

IJMS

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“…Although nintedanib is standardly given orally, inhalation was also tested in silica-exposed animals to promote the local effect of the drug. The authors have demonstrated that small-dose inhalation might be comparable with oral treatment [91].…”

Section: Anti-fibrotic Drugsmentioning

confidence: 99%

New Insights into Pathomechanisms and Treatment Possibilities for Lung Silicosis

Adamcakova

Mokrá

2021

IJMS

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Inhalation of silica particles is an environmental and occupational cause of silicosis, a type of pneumoconiosis. Development of the lung silicosis is a unique process in which the vicious cycle of ingestion of inhaled silica particles by alveolar macrophages and their release triggers inflammation, generation of nodular lesions, and irreversible fibrosis. The pathophysiology of silicosis is complex, and interactions between the pathomechanisms have not been completely understood. However, elucidation of silica-induced inflammation cascades and inflammation-fibrosis relations has uncovered several novel possibilities of therapeutic targeting. This article reviews new information on the pathophysiology of silicosis and points out several promising treatment approaches targeting silicosis-related pathways.

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“…In vivo silica mouse model Mouse studies were performed in collaboration with McMaster University using established protocols, as previously described. 21 Briefly, IPF was induced on day 1 in 20-22 g female C57BL/6 mice by a single intratracheal intubation of silica (2.5 mg/kg) or phosphate-buffered saline (PBS) control while animals were under isoflurane anesthesia. Nintedanib was delivered using intranasal (IN) administration of 50 µl formulation directly to the lung.…”

Section: Biomarker Analysismentioning

confidence: 99%

“…Nintedanib was delivered using intranasal (IN) administration of 50 µl formulation directly to the lung. 21,22 After acclimation, animals were randomized based upon body weight. On days 10-29, animals were lightly anesthetized with isoflurane and dosed once a day with 0.021, 0.21, or 2.1 mg/kg nintedanib (35 µl per dose) or inhaled vehicle.…”

Section: Biomarker Analysismentioning

confidence: 99%

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Galectin-3 levels are elevated following nintedanib treatment

Shochet

Pomerantz

Shitrit

et al. 2020

Therapeutic Advances in Chronic Disease

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Background and Aims: Idiopathic pulmonary fibrosis (IPF) is a common and severe form of pulmonary fibrosis. Nintedanib, a triple angiokinase inhibitor, is approved for treating IPF. Galectin 3 (Gal-3) activates a variety of profibrotic processes. Currently, the Gal-3 inhibitor TD139 is being tested in phase II clinical trials. Since this treatment is given ‘on top’ of nintedanib, it is important to estimate its effect on Gal-3 levels. Therefore, we evaluated the impact of nintedanib on Gal-3 expression using both in vitro and in vivo models, in addition to serum samples from patients with IPF. Methods: Gal-3 levels were evaluated in IPF and control tissue samples, primary human lung fibroblasts (HLFs) following nintedanib treatment (10–100 nM, quantitative polymerase chain reaction), and in a silica-induced fibrosis mouse model with/without nintedanib (0.021–0.21 mg/kg) by immunohistochemistry. In addition, Gal-3 levels were analyzed in serum samples from 41 patients with interstitial lung disease patients with/without nintedanib treatment by ELISA. Results: Nintedanib addition to HLFs resulted in significant elevations in Gal-3, phospho-signal transducer and activator of transcription 3 (pSTAT3), as well as IL-8 mRNA levels ( p < 0.05). Gal-3 expression was higher in samples from IPF patients compared with non-IPF controls at the protein and mRNA levels ( p < 0.05). In the in vivo mouse model, Gal-3 levels were increased following fibrosis induction and even further increased with the addition of nintedanib, mostly in macrophages ( p < 0.05). Patients receiving nintedanib presented with higher Gal-3 serum levels compared with those who did not receive nintedanib ( p < 0.05). Conclusion: Nintedanib elevates Gal-3 levels in both experimental models, along with patient samples. These findings highlight the possibility of using combined inhibition therapy for patients with IPF.

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Inhalation: A means to explore and optimize nintedanib's pharmacokinetic/pharmacodynamic relationship

Cited by 13 publications

References 33 publications

Hypoxia Inducible Factor 1A Supports a Pro-Fibrotic Phenotype Loop in Idiopathic Pulmonary Fibrosis

Hypoxia Inducible Factor 1A Supports a Pro-Fibrotic Phenotype Loop in Idiopathic Pulmonary Fibrosis

New Insights into Pathomechanisms and Treatment Possibilities for Lung Silicosis

Galectin-3 levels are elevated following nintedanib treatment

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