{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T21:56:55Z","timestamp":1779141415721,"version":"3.51.4"},"reference-count":47,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2024,6,18]],"date-time":"2024-06-18T00:00:00Z","timestamp":1718668800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100001250","name":"Morris Animal Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100001250","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Vet Comparative Oncology"],"published-print":{"date-parts":[[2024,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>MAPK has been reported as a key oncogenic pathway for canine histiocytic sarcoma, which can be pharmacologically targeted with trametinib, a small inhibitor of MEK1\/2. Preliminary data showed promising antitumor activity in in vitro and in vivo models and represented a proof of concept to translate the findings from bench to bedside. In this phase I, dose escalating study using a 3\u2009+\u20093 cohort design, trametinib was evaluated in 18 dogs with cancer. Adverse events were graded according to VCOG\u2010CTCAE v2. Blood samples and tumour biopsies were collected for pharmacokinetic and pharmacodynamic assessment. Trametinib was well tolerated with a maximum tolerated dose of 0.5\u2009mg\/m<jats:sup>2<\/jats:sup>\/day, PO. Dose\u2010limiting toxicities included systemic hypertension, proteinuria, lethargy and elevated ALP, and were all Grade 3. The drug exposures increased more than linearly with dose since the elimination of trametinib was saturable. At a dose of 500\u2009\u03bcg Q24h (0.5\u2009mg\/m<jats:sup>2<\/jats:sup>\/day in a 30\u2009kg dog), approximately 70% of dogs had an average steady\u2010state concentration of 10\u2009ng\/mL, achieved after approximately 2\u2009weeks. This threshold was associated with clinical efficacy in humans. Target engagement was not observed in biospecimens collected on Days 0 and 7. In conclusion, trametinib was considered safe in dogs with cancer, and the dose of 0.5\u2009mg\/m<jats:sup>2<\/jats:sup>\/day was the recommended dose for phase II studies.<\/jats:p>","DOI":"10.1111\/vco.12989","type":"journal-article","created":{"date-parts":[[2024,6,18]],"date-time":"2024-06-18T23:28:25Z","timestamp":1718753305000},"page":"410-421","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Population Pharmacokinetics, Pharmacodynamics and Safety Properties of Trametinib in Dogs With Cancer: A Phase I Dose Escalating Clinical Trial"],"prefix":"10.1111","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9509-0528","authenticated-orcid":false,"given":"Marilia","family":"Takada","sequence":"first","affiliation":[{"name":"Department of Surgical Sciences, School of Veterinary Medicine University of Wisconsin\u2010Madison  Madison Wisconsin USA"},{"name":"Department of Small Animal Clinical 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