癌症犬服用曲美替尼的群体药代动力学、药效学和安全性特性:I 期剂量递增临床试验。

IF 2.3 2区 农林科学 Q1 VETERINARY SCIENCES Veterinary and comparative oncology Pub Date : 2024-09-01 Epub Date: 2024-06-18 DOI:10.1111/vco.12989
Marilia Takada, Keita Kitagawa, Yongzhen Zhang, Jürgen B Bulitta, Steven Moirano, Abigail Jones, Jennifer Borgen, Ashley Onsager, Tuddow Thaiwong, David M Vail
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引用次数: 0

摘要

据报道,MAPK是犬组织细胞肉瘤的一个关键致癌途径,而MEK1/2的一种小型抑制剂曲美替尼可作为药物靶点。初步数据显示,MEK1/2 在体外和体内模型中具有良好的抗肿瘤活性,是将研究成果从实验室转化为临床应用的概念验证。在这项采用 3+3 队列设计的 I 期剂量递增研究中,对 18 只患癌症的狗进行了曲美替尼评估。研究人员根据 VCOG-CTCAE v2 对不良反应进行了分级,并采集了血液样本和肿瘤活检样本用于药代动力学和药效学评估。曲美替尼耐受性良好,最大耐受剂量为0.5毫克/平方米/天,口服。剂量限制性毒性包括全身性高血压、蛋白尿、嗜睡和ALP升高,均为3级。由于曲美替尼的消除是饱和的,因此药物暴露量随剂量的增加而增加,超过了线性关系。在 500 μg Q24h 的剂量下(30 千克犬 0.5 毫克/平方米/天),约 70% 的犬在约 2 周后达到 10 纳克/毫升的平均稳态浓度。这一阈值与人类的临床疗效相关。在第0天和第7天采集的生物样本中未观察到目标参与。总之,在癌症犬中使用曲美替尼是安全的,0.5毫克/平方米/天的剂量是II期研究的推荐剂量。
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Population Pharmacokinetics, Pharmacodynamics and Safety Properties of Trametinib in Dogs With Cancer: A Phase I Dose Escalating Clinical Trial.

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/m2/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/m2/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/m2/day was the recommended dose for phase II studies.

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来源期刊
Veterinary and comparative oncology
Veterinary and comparative oncology 农林科学-兽医学
CiteScore
4.80
自引率
9.50%
发文量
75
审稿时长
>24 weeks
期刊介绍: Veterinary and Comparative Oncology (VCO) is an international, peer-reviewed journal integrating clinical and scientific information from a variety of related disciplines and from worldwide sources for all veterinary oncologists and cancer researchers concerned with aetiology, diagnosis and clinical course of cancer in domestic animals and its prevention. With the ultimate aim of diminishing suffering from cancer, the journal supports the transfer of knowledge in all aspects of veterinary oncology, from the application of new laboratory technology to cancer prevention, early detection, diagnosis and therapy. In addition to original articles, the journal publishes solicited editorials, review articles, commentary, correspondence and abstracts from the published literature. Accordingly, studies describing laboratory work performed exclusively in purpose-bred domestic animals (e.g. dogs, cats, horses) will not be considered.
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