{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T18:30:59Z","timestamp":1787164259191,"version":"build-2736575974"},"reference-count":39,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2025,12,11]],"date-time":"2025-12-11T00:00:00Z","timestamp":1765411200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Faes Farma S.A.","award":["CLEU-0321\/FAST"],"award-info":[{"award-number":["CLEU-0321\/FAST"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background\/Objectives: Ulcerative colitis (UC), a chronic inflammatory bowel disease, affects approximately 5 million individuals worldwide, exerting a considerable influence on global health and economic systems. Among the challenges in UC management, treatment non-adherence stands out as a critical issue, often compromising therapeutic efficacy. One strategy to address this challenge is by reducing pill burden, which may improve patient compliance and optimize treatment outcomes. Methods: This randomized, two-sequence, four-period, crossover replicate study evaluated the pharmacokinetic profiles, bioequivalence, and safety of a newly developed 1500 mg mesalazine gastro-resistant tablet compared to three of the reference 500 mg Claversal\u00ae gastro-resistant tablets (total dose 1500 mg) in 80 healthy participants under fasted conditions. Results: Bioequivalence between mesalazine formulations was observed in both the rate and extent of systemic bioavailability. The geometric mean ratios and their 90% CI were 102.51% (95.85\u2013109.63) for AUC0\u2013\u221e, 103.36% (96.40\u2013110.83) for AUC0\u2013t, 84.49% (78.24\u201391.24) for AUC8\u201348h, and 114.24% (100.15\u2013130.32) for Cmax. All within the accepted bioequivalence ranges, confirming comparable pharmacokinetic performance. Secondary pharmacokinetic parameters such as tmax, t1\/2, Ke, Cl, and MRT were also consistent across both formulations. The incidence of adverse events was comparable between the two mesalazine formulations, with only flatulence and mild self-limited rash considered possibly related to test treatment. Conclusions: Overall, the 1500 mg formulation demonstrated a pharmacokinetic profile and tolerability comparable to the reference formulation, offering a higher-strength option to reduce daily pill burden. This strategy is of clinical relevance, particularly for improving treatment adherence among UC patients who need to take multiple pills daily to achieve their required dosage. While adherence is influenced by various factors, reducing pill burden may facilitate compliance and optimize therapeutic efficacy.<\/jats:p>","DOI":"10.3390\/ph18121876","type":"journal-article","created":{"date-parts":[[2025,12,11]],"date-time":"2025-12-11T08:39:18Z","timestamp":1765442358000},"page":"1876","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Safety, Pharmacokinetics, and Bioequivalence Characterization of Two Different Strengths of Mesalazine Gastro-Resistant Tablets"],"prefix":"10.3390","volume":"18","author":[{"given":"Dolores","family":"Ochoa Mazarro","sequence":"first","affiliation":[{"name":"Clinical Pharmacology Department, Hospital Universitario de La Princesa, 28006 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7562-9845","authenticated-orcid":false,"given":"Manuel","family":"Rom\u00e1n Mart\u00ednez","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology Department, Hospital Universitario de La Princesa, 28006 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel","family":"Mart\u00edn V\u00edlchez","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology Department, Hospital Universitario de La Princesa, 28006 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4517-4082","authenticated-orcid":false,"given":"Sergio","family":"Luquero-Bueno","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology Department, Hospital Universitario de La Princesa, 28006 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-4694-2923","authenticated-orcid":false,"given":"Paola","family":"Camargo-Mamani","sequence":"additional","affiliation":[{"name":"Clinical Research Department, Faes Farma S.A., 48940 Leioa, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariana","family":"Frau Usoz","sequence":"additional","affiliation":[{"name":"Clinical Research Department, Faes Farma S.A., 48940 Leioa, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Mart\u00ednez Ostal\u00e9","sequence":"additional","affiliation":[{"name":"Clinical Research Department, Faes Farma S.A., 48940 Leioa, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paula","family":"Arranz","sequence":"additional","affiliation":[{"name":"Clinical Research Department, Faes Farma S.A., 48940 Leioa, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Inmaculada","family":"Gilaberte","sequence":"additional","affiliation":[{"name":"Clinical Research Department, Faes Farma S.A., 48940 Leioa, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1093\/ecco-jcc\/jjab178","article-title":"ECCO Guidelines on Therapeutics in Ulcerative Colitis: Medical Treatment","volume":"16","author":"Raine","year":"2022","journal-title":"J. Crohn\u2019s Colitis"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1016\/S0140-6736(23)00966-2","article-title":"Ulcerative Colitis","volume":"402","author":"Honap","year":"2023","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1093\/ecco-jcc\/jjx008","article-title":"Third European Evidence-Based Consensus on Diagnosis and Management of Ulcerative Colitis. Part 1: Definitions, Diagnosis, Extra-Intestinal Manifestations, Pregnancy, Cancer Surveillance, Surgery, and Ileo-Anal Pouch Disorders","volume":"11","author":"Magro","year":"2017","journal-title":"J. Crohn\u2019s Colitis"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1097\/MIB.0000000000000582","article-title":"Mortality and Causes of Death in Ulcerative Colitis: Results from 20 Years of Follow-up in the IBSEN Study","volume":"22","author":"Hovde","year":"2016","journal-title":"Inflamm. Bowel Dis."},{"key":"ref_5","first-page":"2001","article-title":"A Review of Mortality and Surgery in Ulcerative Colitis: Milestones of the Seriousness of the Disease","volume":"19","author":"Bernstein","year":"2013","journal-title":"Inflamm. Bowel Dis."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"114","DOI":"10.17235\/reed.2016.4620\/2016","article-title":"What Is the Real-Life Maintenance Mesalazine Dose in Ulcerative Colitis?","volume":"109","author":"Algaba","year":"2016","journal-title":"Rev. Esp. Enferm. Dig."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Paridaens, K., Freddi, M.J., and Travis, S.P.L. (2024). The Continuing Value of Mesalazine as First-Line Therapy for Patients with Moderately Active Ulcerative Colitis. Front. Gastroenterol., 3.","DOI":"10.3389\/fgstr.2024.1335380"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"638","DOI":"10.1016\/S0016-5085(19)31672-5","article-title":"Role of Prostaglandins in Ulcerative Colitis. Enhanced Production during Active Disease and Inhibition by Sulfasalazine","volume":"75","author":"Sharon","year":"1978","journal-title":"Gastroenterology"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1016\/j.gtc.2010.08.011","article-title":"Clinical Pharmacology of 5-ASA Compounds in Inflammatory Bowel Disease","volume":"39","author":"Sonu","year":"2010","journal-title":"Gastroenterol. Clin. N. Am."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1205","DOI":"10.1084\/jem.20041948","article-title":"Intestinal Antiinflammatory Effect of 5-Aminosalicylic Acid Is Dependent on Peroxisome Proliferator\u2013Activated Receptor-\u03b3","volume":"201","author":"Rousseaux","year":"2005","journal-title":"J. Exp. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1341","DOI":"10.1136\/gut.2006.093484","article-title":"PPAR as a New Therapeutic Target in Inflammatory Bowel Diseases","volume":"55","author":"Dubuquoy","year":"2006","journal-title":"Gut"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1016\/j.jcol.2016.03.003","article-title":"Antioxidant Effect of Mesalazine in the Experimental Colitis Model Induced by Acetic Acid","volume":"36","author":"Moura","year":"2016","journal-title":"J. Coloproctology"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2929","DOI":"10.1111\/j.1572-0241.2001.04683.x","article-title":"Prevalence of Nonadherence with Maintenance Mesalamine in Quiescent Ulcerative Colitis","volume":"96","author":"Kane","year":"2001","journal-title":"Am. J. Gastroenterol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1118","DOI":"10.1111\/j.1365-2036.2009.04152.x","article-title":"An Investigation of Medication Adherence to 5-aminosalicylic Acid Therapy in Patients with Ulcerative Colitis, Using Self-report and Urinary Drug Excretion Measurements","volume":"30","author":"Moshkovska","year":"2009","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1111\/j.1365-2036.2008.03865.x","article-title":"Systematic Review: Impact of Non-adherence to 5-aminosalicylic Acid Products on the Frequency and Cost of Ulcerative Colitis Flares","volume":"29","author":"Higgins","year":"2009","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1020","DOI":"10.1007\/s10620-007-9968-0","article-title":"Medication Non-Adherence Is Associated with Increased Medical Health Care Costs","volume":"53","author":"Kane","year":"2008","journal-title":"Dig. Dis. Sci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"748","DOI":"10.1053\/j.gastro.2018.12.009","article-title":"AGA Clinical Practice Guidelines on the Management of Mild-to-Moderate Ulcerative Colitis","volume":"156","author":"Ko","year":"2019","journal-title":"Gastroenterology"},{"key":"ref_18","first-page":"e1","article-title":"The GETECCU Clinical Guideline for the Treatment of Ulcerative Colitis: A Guideline Created Using GRADE Methodology","volume":"36","author":"Sicilia","year":"2013","journal-title":"Gastroenterol. Y Hepatol."},{"key":"ref_19","first-page":"1","article-title":"Guidelines for the Management of Ulcerative Colitis. Recommendations of the Polish Society of Gastroenterology and the Polish National Consultant in Gastroenterology","volume":"18","author":"Eder","year":"2023","journal-title":"Przegl\u0105d Gastroenterol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1934","DOI":"10.1053\/j.gastro.2009.08.069","article-title":"Delayed-Release Oral Mesalamine 4.8 g\/Day (800-Mg Tablet) Is Effective for Patients With Moderately Active Ulcerative Colitis","volume":"137","author":"Sandborn","year":"2009","journal-title":"Gastroenterology"},{"key":"ref_21","first-page":"CD000543","article-title":"Oral 5-Aminosalicylic Acid for Induction of Remission in Ulcerative Colitis","volume":"8","author":"Murray","year":"2020","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1111\/apt.12266","article-title":"Randomised Clinical Trial: Once- vs. Twice-daily Prolonged-release Mesalazine for Active Ulcerative Colitis","volume":"37","author":"Tucat","year":"2013","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1016\/j.crohns.2011.10.006","article-title":"Mesalazine in Left-Sided Ulcerative Colitis: Efficacy Analyses from the PODIUM Trial on Maintenance of Remission and Mucosal Healing","volume":"6","author":"Bokemeyer","year":"2012","journal-title":"J. Crohn\u2019s Colitis"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1186\/s43094-020-00057-7","article-title":"Recent Advances in Mesalamine Colonic Delivery Systems","volume":"6","author":"Bayan","year":"2020","journal-title":"Future J. Pharm. Sci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1016\/j.jconrel.2022.04.024","article-title":"Population Pharmacokinetics and IVIVC for Mesalazine Enteric-Coated Tablets","volume":"346","author":"Zhang","year":"2022","journal-title":"J. Control. Release"},{"key":"ref_26","first-page":"1","article-title":"5-ASA Dose-Response: Maximizing Efficacy and Adherence","volume":"6","author":"Katz","year":"2010","journal-title":"Gastroenterol. Hepatol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1053\/j.gastro.2007.05.051","article-title":"Mucosal Healing in Inflammatory Bowel Disease: Results From a Norwegian Population-Based Cohort","volume":"133","author":"Jahnsen","year":"2007","journal-title":"Gastroenterology"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1511","DOI":"10.1053\/j.gastro.2010.07.039","article-title":"Prevalence of Colorectal Cancer Surveillance for Ulcerative Colitis in an Integrated Health Care Delivery System","volume":"139","author":"Velayos","year":"2010","journal-title":"Gastroenterology"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1080\/17474124.2024.2397650","article-title":"Practical Management of Mild-to-Moderate Ulcerative Colitis: An International Expert Consensus","volume":"18","author":"Magro","year":"2024","journal-title":"Expert Rev. Gastroenterol. Hepatol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1111\/j.1365-2036.1991.tb00030.x","article-title":"Steady-state Pharmacokinetics of Enteric Coated 5-amino-salicylic Acid Tablets in Healthy Volunteers and in Patients with Crohn\u2019s Disease or Ulcerative Colitis","volume":"5","author":"Norlander","year":"1991","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1111\/j.1365-2036.1994.tb00290.x","article-title":"Comparative Bioavailability of 5-aminosalicylic Acid from a Controlled Release Preparation and an Azo-bond Preparation","volume":"8","author":"Christensen","year":"1994","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1046\/j.1365-2036.2003.01408.x","article-title":"The Pharmacokinetic Profiles of Oral Mesalazine Formulations and Mesalazine Pro-drugs Used in the Management of Ulcerative Colitis","volume":"17","author":"Sandborn","year":"2003","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1597","DOI":"10.1111\/apt.14688","article-title":"Systematic Review: Safety of Mesalazine in Ulcerative Colitis","volume":"47","author":"Sehgal","year":"2018","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_34","unstructured":"European Medicines Agency C for MP for HU (CHMP) (2025, September 25). Guideline on the Investigation of Bioequivalence. Doc. Ref.: CPMP\/EWP\/QWP\/1401\/98 Rev. 1\/ Corr ** [Internet]; European Medicines Agency C for MP for HU (CHMP): Amsterdam The Netherlands, 2010. Available online: https:\/\/www.Ema.Europa.Eu\/En\/Documents\/Scientific-Guideline\/Guideline-Investigation-Bioequivalence-Rev1_en.Pdf."},{"key":"ref_35","unstructured":"U.S. Food and Drug Administratio (2012). Draft Guidance on Mesalamine. Strength 800 Mg DR_RLD 21830_RC06-16 (Revised Jun 2016), U.S. Food and Drug Administratio."},{"key":"ref_36","unstructured":"U.S. Food and Drug Administratio (2012). Draft Guidance on Mesalamine. Strength 1200 Mg RLD 22000_RC06-16 (Revised Jun 2016), U.S. Food and Drug Administratio."},{"key":"ref_37","unstructured":"European Medicines Agency C for MP for HU (CHMP) (2025, September 15). Guideline on the Pharmacokinetic and Clinical Evaluation of Modified Release Dosage Forms. Doc. Ref. EMA-CHMP-EWP-280-96 Rev1; European Medicines Agency C for MP for HU (CHMP): Amsterdam The Netherlands, 2014. Available online: https:\/\/www.Ema.Europa.Eu\/En\/Pharmacokinetic-Clinical-Evaluation-Modified-Release-Dosage-Forms-Scientific-Guideline."},{"key":"#cr-split#-ref_38.1","unstructured":"European Union (2014). Regulation"},{"key":"#cr-split#-ref_38.2","unstructured":"(EU) No 536\/2014 of the European Parliament and of the Council of 16 April 2014 on Clinical Trials on Medicinal Products for Human Use, and Repealing Directive 2001\/20\/EC, European Union."}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/18\/12\/1876\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,11]],"date-time":"2025-12-11T08:47:29Z","timestamp":1765442849000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/18\/12\/1876"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,11]]},"references-count":39,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["ph18121876"],"URL":"https:\/\/doi.org\/10.3390\/ph18121876","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,11]]}}}