Peer-reviewed veterinary case report
Trametinib drug safety and dosing in dogs with cancer
By Takada, Marilia et al.·Published in Veterinary and comparative oncology·2024·Department of Surgical Sciences, United States·View original on PubMed →
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Original publication title: Population Pharmacokinetics, Pharmacodynamics and Safety Properties of Trametinib in Dogs With Cancer: A Phase I Dose Escalating Clinical Trial.
- Species:
- dog
Plain-English summary
Eighteen dogs with cancer participated in a study to test a new drug called trametinib, which targets a specific cancer pathway. The dogs were given trametinib at a dose of 0.5 mg/m² per day, and it was generally well tolerated, although some experienced side effects like high blood pressure, protein in the urine, and lethargy. After about two weeks, around 70% of the dogs reached a drug concentration that is known to be effective in humans. Overall, trametinib was found to be safe for dogs with cancer, and this dosage is recommended for further studies.
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Abstract
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 + 3 cohort design, trametinib was evaluated in 18 dogs with cancer. Adverse events were graded according to VCOG-CTCAE 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 mg/m/day, PO. Dose-limiting 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 μg Q24h (0.5 mg/m/day in a 30 kg dog), approximately 70% of dogs had an average steady-state concentration of 10 ng/mL, achieved after approximately 2 weeks. 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 mg/m/day was the recommended dose for phase II studies.
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Search related cases →Original publication on PubMed: https://pubmed.ncbi.nlm.nih.gov/38889903/