{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T03:13:21Z","timestamp":1789096401235,"version":"build-2803163510"},"reference-count":41,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2022,11,5]],"date-time":"2022-11-05T00:00:00Z","timestamp":1667606400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Merck &amp; Co., Inc.","award":["EP\/S023054\/1"],"award-info":[{"award-number":["EP\/S023054\/1"]}]},{"name":"Intract Pharma Ltd.","award":["EP\/S023054\/1"],"award-info":[{"award-number":["EP\/S023054\/1"]}]},{"name":"The Engineering and Physical Sciences Research Council","award":["EP\/S023054\/1"],"award-info":[{"award-number":["EP\/S023054\/1"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Janus kinase (JAK) inhibitors, such as tofacitinib (Xeljanz) and filgotinib (Jyseleca), have been approved for treatment of ulcerative colitis with several other JAK inhibitors in late-stage clinical trials for inflammatory bowel disease (IBD). Despite their impressive efficacy, the risk of adverse effects accompanying the use of JAK inhibitors has brought the entire class under scrutiny, leading to them receiving an FDA black box warning. In this study we investigated whether ileocolonic-targeted delivery of a pan-JAK inhibitor, tofacitinib, can lead to increased tissue exposure and reduced systemic exposure compared to untargeted formulations. The stability of tofacitinib in the presence of rat colonic microbiota was first confirmed. Next, in vivo computed tomography imaging was performed in rats to determine the transit time and disintegration site of ileocolonic-targeted capsules compared to gastric release capsules. Pharmacokinetic studies demonstrated that systemic drug exposure was significantly decreased, and colonic tissue exposure increased at 10 mg\/kg tofacitinib dosed in ileocolonic-targeted capsules compared to gastric release capsules and an oral solution. Finally, in a rat model of LPS-induced colonic inflammation, targeted tofacitinib capsules significantly reduced concentrations of proinflammatory interleukin 6 in colonic tissue compared to a vehicle-treated control (p = 0.0408), unlike gastric release tofacitinib capsules and orally administered dexamethasone. Overall, these results support further development of ileocolonic-targeted tofacitinib, and potentially other specific JAK inhibitors in pre-clinical and clinical development, for the treatment of IBD.<\/jats:p>","DOI":"10.3390\/pharmaceutics14112385","type":"journal-article","created":{"date-parts":[[2022,11,7]],"date-time":"2022-11-07T03:02:22Z","timestamp":1667790142000},"page":"2385","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Ileocolonic-Targeted JAK Inhibitor: A Safer and More Effective Treatment for Inflammatory Bowel Disease"],"prefix":"10.3390","volume":"14","author":[{"given":"Vipul","family":"Yadav","sequence":"first","affiliation":[{"name":"Intract Pharma Ltd., London Bioscience Innovation Centre, 2 Royal College Street, London NW1 0NH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aileen","family":"House","sequence":"additional","affiliation":[{"name":"Merck & Co., Inc., 126 East Lincoln Avenue, P.O. Box 2000, Rahway, NJ 07065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Matiz","sequence":"additional","affiliation":[{"name":"Intract Pharma Ltd., London Bioscience Innovation Centre, 2 Royal College Street, London NW1 0NH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura E.","family":"McCoubrey","sequence":"additional","affiliation":[{"name":"UCL School of Pharmacy, University College London, 29-39 Brunswick Square, London WC1N 1AX, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kimberly A.","family":"Bettano","sequence":"additional","affiliation":[{"name":"Merck & Co., Inc., 126 East Lincoln Avenue, P.O. Box 2000, Rahway, NJ 07065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leena","family":"Bhave","sequence":"additional","affiliation":[{"name":"Merck & Co., Inc., 126 East Lincoln Avenue, P.O. Box 2000, Rahway, NJ 07065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meiyao","family":"Wang","sequence":"additional","affiliation":[{"name":"Merck & Co., Inc., 126 East Lincoln Avenue, P.O. Box 2000, Rahway, NJ 07065, USA"},{"name":"Karuna Therapeutics, Inc., 99 High St Floor 26, Boston, MA 02110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Fan","sequence":"additional","affiliation":[{"name":"Merck & Co., Inc., 126 East Lincoln Avenue, P.O. Box 2000, Rahway, NJ 07065, USA"},{"name":"Treeline Biosciences, 500 Arsenal Street, Suite 201, Watertown, MA 02472, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siqun","family":"Zhou","sequence":"additional","affiliation":[{"name":"Merck & Co., Inc., 126 East Lincoln Avenue, P.O. Box 2000, Rahway, NJ 07065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janice D.","family":"Woodhouse","sequence":"additional","affiliation":[{"name":"Merck & Co., Inc., 126 East Lincoln Avenue, P.O. Box 2000, Rahway, NJ 07065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eirini","family":"Poimenidou","sequence":"additional","affiliation":[{"name":"90TEN, Battersea Studios, 80 Silverthorne Road, London SW8 3HE, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liu","family":"Dou","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences (Shenzhen), Sun Yat-Sen University, Guangzhou 510275, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5368-6603","authenticated-orcid":false,"given":"Abdul W.","family":"Basit","sequence":"additional","affiliation":[{"name":"UCL School of Pharmacy, University College London, 29-39 Brunswick Square, London WC1N 1AX, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lily Y.","family":"Moy","sequence":"additional","affiliation":[{"name":"Merck & Co., Inc., 126 East Lincoln Avenue, P.O. Box 2000, Rahway, NJ 07065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4548-3398","authenticated-orcid":false,"given":"Robert","family":"Saklatvala","sequence":"additional","affiliation":[{"name":"Merck & Co., Inc., 126 East Lincoln Avenue, P.O. Box 2000, Rahway, NJ 07065, USA"},{"name":"Kallyope, 430 East 29th Street, 10th Floor, New York, NY 10016, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laxminarayan G.","family":"Hegde","sequence":"additional","affiliation":[{"name":"Merck & Co., Inc., 126 East Lincoln Avenue, P.O. Box 2000, Rahway, NJ 07065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongshi","family":"Yu","sequence":"additional","affiliation":[{"name":"Merck & Co., Inc., 126 East Lincoln Avenue, P.O. Box 2000, Rahway, NJ 07065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,11,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1016\/j.crohns.2013.09.009","article-title":"A tale of two diseases: The history of inflammatory bowel disease","volume":"8","author":"Mulder","year":"2014","journal-title":"J. Crohn\u2019s Colitis"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Yadav, V., Mai, Y., McCoubrey, L.E., Wada, Y., Tomioka, M., Kawata, S., Charde, S., and Basit, A.W. (2021). 5-Aminolevulinic Acid as a Novel Therapeutic for Inflammatory Bowel Disease. Biomedicines, 9.","DOI":"10.3390\/biomedicines9050578"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"651415","DOI":"10.3389\/fphar.2021.651415","article-title":"Novel and Emerging Therapies for Inflammatory Bowel Disease","volume":"12","author":"Shivashankar","year":"2021","journal-title":"Front. 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