{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T13:04:38Z","timestamp":1789391078067,"version":"build-2803163510"},"reference-count":25,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2026,9,13]],"date-time":"2026-09-13T00:00:00Z","timestamp":1789257600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Idiopathic pulmonary fibrosis (IPF) remains a progressive and fatal disease despite major advances in antifibrotic therapy. Pirfenidone and nintedanib slow lung function decline, and the PDE4B inhibitor nerandomilast and treprostinil have recently shown promise as next-generation treatments. However, current therapies neither halt nor reverse disease progression, and tolerability issues often limit adherence. We compared the antifibrotic activity and plasma levels of nintedanib administered by either oral gavage or dietary supplementation in a rat model of pulmonary fibrosis. Male Sprague-Dawley rats received intratracheal bleomycin (1 U\/kg) on days 0 and 4. From day 7 to day 28, animals were treated with nintedanib (100 mg\/kg\/day) by either oral gavage or medicated chow. Lung weight, fibrosis biomarkers (procollagen-I, metalloproteinase-7 or MMP7, WNT1-inducible signaling pathway protein or WISP-1), epithelial injury marker KL-6, target engagement biomarkers (Fibroblast Growth Factor 2 or FGF-2, Vascular Endothelial Growth Factor or VEGF), plasma drug levels, and histological fibrosis scores were evaluated. Both administration regimens significantly reduced procollagen-I, WISP-1 and KL-6, and histological fibrosis scores. Oral gavage produced approximately fourfold-higher peak plasma concentrations of nintedanib 30 min after dosing, whereas dietary administration resulted in lower, more stable plasma levels with reduced variability while resulting in comparable antifibrotic efficacy. In conclusion, nintedanib retained robust antifibrotic activity when administered via dietary supplementation despite lower, but continuous, active plasma concentrations. Collectively, these findings indicate that optimizing drug delivery and absorption kinetics may achieve sustained therapeutic efficacy while reducing unnecessary exposure to supratherapeutic concentrations, thereby potentially improving tolerability.<\/jats:p>","DOI":"10.3390\/ijms27188158","type":"journal-article","created":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T12:09:51Z","timestamp":1789387791000},"page":"8158","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Comparative Assessment of the Antifibrotic Effect of Nintedanib Administered via a Medicated Diet or Oral Gavage in a Rat Model of Bleomycin-Induced Pulmonary Fibrosis"],"prefix":"10.3390","volume":"27","author":[{"given":"Vanessa","family":"Pitozzi","sequence":"first","affiliation":[{"name":"Chiesi Farmaceutici S.p.A., Global Research and Preclinical Development, Largo Belloli, 11\/A, 43122 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paola","family":"Caruso","sequence":"additional","affiliation":[{"name":"Chiesi Farmaceutici S.p.A., Global Research and Preclinical Development, Largo Belloli, 11\/A, 43122 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Pontis","sequence":"additional","affiliation":[{"name":"Chiesi Farmaceutici S.p.A., Global Research and Preclinical Development, Largo Belloli, 11\/A, 43122 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Ruscitti","sequence":"additional","affiliation":[{"name":"Chiesi Farmaceutici S.p.A., Global Research and Preclinical Development, Largo Belloli, 11\/A, 43122 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4851-699X","authenticated-orcid":false,"given":"Maria Gloria","family":"Pittelli","sequence":"additional","affiliation":[{"name":"Chiesi Farmaceutici S.p.A., Global Research and Preclinical Development, Largo Belloli, 11\/A, 43122 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giancarlo","family":"Aquino","sequence":"additional","affiliation":[{"name":"Chiesi Farmaceutici S.p.A., Global Research and Preclinical Development, Largo Belloli, 11\/A, 43122 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberta","family":"Volta","sequence":"additional","affiliation":[{"name":"Chiesi Farmaceutici S.p.A., Global Research and Preclinical Development, Largo Belloli, 11\/A, 43122 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alice","family":"Pappani","sequence":"additional","affiliation":[{"name":"Chiesi Farmaceutici S.p.A., Global Research and Preclinical Development, Largo Belloli, 11\/A, 43122 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariarosaria","family":"Barrea","sequence":"additional","affiliation":[{"name":"Chiesi Farmaceutici S.p.A., Global Research and Preclinical Development, Largo Belloli, 11\/A, 43122 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2377-4810","authenticated-orcid":false,"given":"Federico","family":"Quaini","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0552-9205","authenticated-orcid":false,"given":"Costanza Anna Maria","family":"Lagrasta","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2719-7272","authenticated-orcid":false,"given":"Antonella Maria","family":"Nogara","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1096-0596","authenticated-orcid":false,"given":"Paolo","family":"Spagnolo","sequence":"additional","affiliation":[{"name":"Respiratory Disease Unit, Department of Cardiac Thoracic, Vascular Sciences and Public Health, University of Padova, 35128 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-4384-6545","authenticated-orcid":false,"given":"Marcello","family":"Trevisani","sequence":"additional","affiliation":[{"name":"Chiesi Farmaceutici S.p.A., Global Research and Preclinical Development, Largo Belloli, 11\/A, 43122 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"788","DOI":"10.1164\/rccm.2009-040GL","article-title":"An Official ATS\/ERS\/JRS\/ALAT Statement: Idiopathic Pulmonary Fibrosis: Evidence-Based Guidelines for Diagnosis and Management","volume":"183","author":"Raghu","year":"2011","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1016\/S2213-2600(25)00129-8","article-title":"Global Epidemiology and Burden of Interstitial Lung Disease","volume":"13","author":"Spagnolo","year":"2025","journal-title":"Lancet Respir. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2083","DOI":"10.1056\/NEJMoa1402582","article-title":"A Phase 3 Trial of Pirfenidone in Patients with Idiopathic Pulmonary Fibrosis","volume":"370","author":"King","year":"2014","journal-title":"N. Engl. J. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2071","DOI":"10.1056\/NEJMoa1402584","article-title":"Efficacy and Safety of Nintedanib in Idiopathic Pulmonary Fibrosis","volume":"370","author":"Richeldi","year":"2014","journal-title":"N. Engl. J. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2193","DOI":"10.1056\/NEJMoa2414108","article-title":"Nerandomilast in Patients with Idiopathic Pulmonary Fibrosis","volume":"392","author":"Richeldi","year":"2025","journal-title":"N. Engl. J. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1056\/NEJMoa2512911","article-title":"Inhaled Treprostinil for Idiopathic Pulmonary Fibrosis","volume":"395","author":"Nathan","year":"2026","journal-title":"N. Engl. J. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1056\/NEJMoa2501488","article-title":"Phase 3 Trials of Inhaled Treprostinil for Idiopathic Pulmonary Fibrosis","volume":"395","author":"Nathan","year":"2026","journal-title":"N. Engl. J. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1007\/s40265-026-02288-z","article-title":"Nerandomilast: First Approval","volume":"86","author":"Brown","year":"2026","journal-title":"Drugs"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Chianese, M., Screm, G., Salton, F., Confalonieri, P., Trotta, L., Barbieri, M., Ruggero, L., Mari, M., Reccardini, N., and Geri, P. (2024). Pirfenidone and Nintedanib in Pulmonary Fibrosis: Lights and Shadows. Pharmaceuticals, 17.","DOI":"10.3390\/ph17060709"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"170057","DOI":"10.1183\/16000617.0057-2017","article-title":"Pirfenidone Safety and Adverse Event Management in Idiopathic Pulmonary Fibrosis","volume":"26","author":"Lancaster","year":"2017","journal-title":"Eur. Respir. Rev."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"e70181","DOI":"10.1111\/crj.70181","article-title":"Safety and Efficacy of Nerandomilast in Patients with Pulmonary Fibrosis: A Systematic Review and Meta-Analysis of Randomized Controlled Trials","volume":"20","author":"Shahzad","year":"2026","journal-title":"Clin. Respir. J."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Pitozzi, V., Caruso, P.L., Pontis, S., Pioselli, B., Ruscitti, F., Pittelli, M.G., Lagrasta, C.A.M., Quaini, F., Nogara, A.M., and Aquino, G. (2026). In Vivo Target Engagement Assessment of Nintedanib in a Double-Hit Bleomycin Lung Fibrosis Rat Model. Int. J. Mol. Sci., 27.","DOI":"10.3390\/ijms27010064"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1007\/s41030-026-00349-y","article-title":"Emerging Therapies in Pulmonary Fibrosis","volume":"12","author":"Temizel","year":"2026","journal-title":"Pulm. Ther."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1007\/s12325-014-0112-1","article-title":"Pirfenidone in Idiopathic Pulmonary Fibrosis: Expert Panel Discussion on the Management of Drug-Related Adverse Events","volume":"31","author":"Costabel","year":"2014","journal-title":"Adv. Ther."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2038","DOI":"10.1007\/s12325-023-02454-9","article-title":"A Narrative Review of Real-World Data on the Safety of Nintedanib in Patients with Idiopathic Pulmonary Fibrosis","volume":"40","author":"Podolanczuk","year":"2023","journal-title":"Adv. Ther."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Majewski, S., G\u00f3rska, K., Lewandowska, K.B., Martusewicz-Boros, M.M., Sobiecka, M., and Piotrowski, W.J. (2025). Real-World Treatment Persistence and Predictive Factors for Discontinuation of Antifibrotic Therapies in Patients with Idiopathic Pulmonary Fibrosis: A Post-Hoc Analysis of Two Multicenter Observational Cohort Studies in Poland. Front. Pharmacol., 16.","DOI":"10.3389\/fphar.2025.1586197"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1513\/AnnalsATS.202404-430RL","article-title":"Persistence of Antifibrotic Therapy in Patients with Idiopathic Pulmonary Fibrosis: A Pulmonary Fibrosis Foundation Patient Registry Study","volume":"22","author":"Kulkarni","year":"2025","journal-title":"Ann. Am. Thorac. Soc."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e001687","DOI":"10.1136\/bmjresp-2023-001687","article-title":"Antifibrotic Treatment Adherence, Efficacy and Outcomes for Patients with Idiopathic Pulmonary Fibrosis in Spain: A Real-World Evidence Study","volume":"11","year":"2024","journal-title":"BMJ Open Respir. Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2178","DOI":"10.1056\/NEJMoa2201737","article-title":"Trial of a Preferential Phosphodiesterase 4B Inhibitor for Idiopathic Pulmonary Fibrosis","volume":"386","author":"Richeldi","year":"2022","journal-title":"N. Engl. J. Med."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Bocchi, E., Pitozzi, V., Pontis, S., Caruso, P.L., Beghi, S., Caputi, M., and Trevisani, M. (2024). Ruscitti, Investigation of Aberrant Basaloid Cells in a Rat Model of Lung Fibrosis. Front. Biosci., 29.","DOI":"10.31083\/j.fbl2908305"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"200149","DOI":"10.1183\/16000617.0149-2020","article-title":"The Role of Mucin 1 in Respiratory Diseases","volume":"30","author":"Ballester","year":"2021","journal-title":"Eur. Respir. Rev."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1131","DOI":"10.1007\/s40262-019-00766-0","article-title":"Clinical Pharmacokinetics and Pharmacodynamics of Nintedanib","volume":"58","author":"Wind","year":"2019","journal-title":"Clin. Pharmacokinet."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Vasanthi, S.S., Massey, N., Nair, S.N., Mochel, J.P., Showman, L., and Thippeswamy, T. (2023). Exploring the Benefits of In-Diet versus Repeated Oral Dosing of Saracatinib (AZD0530) in Chronic Studies: Insights into Pharmacokinetics and Animal Welfare. Front. Vet. Sci., 9.","DOI":"10.3389\/fvets.2023.1297221"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1136\/jcp.41.4.467","article-title":"Simple Method of Estimating Severity of Pulmonary Fibrosis on a Numerical Scale","volume":"41","author":"Ashcroft","year":"1988","journal-title":"J. Clin. Pathol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"507","DOI":"10.2144\/000112729","article-title":"Standardized Quantification of Pulmonary Fibrosis in Histological Samples","volume":"44","author":"Gitter","year":"2008","journal-title":"BioTechniques"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/18\/8158\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T12:26:21Z","timestamp":1789388781000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/18\/8158"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,13]]},"references-count":25,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["ijms27188158"],"URL":"https:\/\/doi.org\/10.3390\/ijms27188158","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,13]]}}}