Evaluation of the Carcinogenic Potential of Enarodustat (JTZ-951), a Hypoxia-Inducible Factor-Prolyl Hydroxylase Inhibitor, in 26-Week Tg.rasH2 Mouse Study and 2-Year Sprague-Dawley Rat Study.

IF 1.2 4区医学 Q4 PHARMACOLOGY & PHARMACY

International Journal of Toxicology Pub Date : 2023-12-01 Epub Date: 2023-07-22 DOI:10.1177/10915818231190550

Yusuke Kemmochi, Kaoru Toyoda, Tomio Ishida, Yuzo Yasui, Toshiyuki Shoda

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Abstract

Enarodustat (JTZ-951) is an oral hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitor for the treatment of anemia with chronic kidney disease. Carcinogenicity of enarodustat was evaluated in a 26-week repeated oral dose study in Transgenic rasH2 (Tg.rasH2) mice and a 2-year repeated oral dose study in Sprague-Dawley (SD) rats. The highest dose levels were set at 6 mg/kg in the Tg.rasH2 mouse study and at 1 mg/kg in the SD rat study based on the maximum tolerated doses in the 3-month and 6-month dose-range finding studies, respectively. Enarodustat did not increase the incidence of any tumors or affect survival in these carcinogenicity studies. Pharmacology-related findings including increases in blood RBC parameters were observed at the highest dose levels for each study. The AUC-based exposure margins as protein-unbound drug base are 16.3-/26.0-fold multiple (males/females) for Tg.rasH2 mice and 1.6-/1.1-fold multiple for SD rats when compared with the estimated exposure in human with chronic kidney disease at 8 mg/day (maximum recommended human dose). In conclusion, enarodustat was considered to have no carcinogenic potential at the clinical dose.

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缺氧诱导因子-丙氨酸羟化酶抑制剂Enarodustat (JTZ-951)在26周Tg中的致癌潜力评估。rasH2小鼠研究和2年Sprague-Dawley大鼠研究。

Enarodustat（JTZ-951）是一种口服缺氧诱导因子脯氨酰羟化酶（HIF-PH）抑制剂，用于治疗贫血伴慢性肾脏疾病。在转基因rasH2（Tg.rasH2）小鼠中进行的26周重复口服剂量研究和在Sprague-Dawley（SD）大鼠中进行的2年重复口服剂量的研究中，评估了埃纳杜斯塔的致癌性。在Tg.rasH2小鼠研究中，根据3个月和6个月剂量范围发现研究中的最大耐受剂量，最高剂量水平分别设定为6 mg/kg，在SD大鼠研究中设定为1 mg/kg。在这些致癌性研究中，埃纳杜斯塔没有增加任何肿瘤的发生率或影响生存率。在每项研究的最高剂量水平下，观察到包括血液RBC参数增加在内的药理学相关结果。与患有慢性肾脏疾病的人类在8 mg/天（人类最大推荐剂量）下的估计暴露量相比，Tg.rasH2小鼠的基于AUC的暴露裕度（作为蛋白质非结合药物基础）是16.3/26.0倍（雄性/雌性），SD大鼠是1.6-1/1.1倍。总之，依那罗达司他被认为在临床剂量下没有致癌潜力。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

International Journal of Toxicology 医学-毒理学

CiteScore

3.40

自引率

4.50%

发文量

审稿时长

4.5 months

期刊介绍： The International Journal of Toxicology publishes timely, peer-reviewed papers on current topics important to toxicologists. Six bi-monthly issues cover a wide range of topics, including contemporary issues in toxicology, safety assessments, novel approaches to toxicological testing, mechanisms of toxicity, biomarkers, and risk assessment. The Journal also publishes invited reviews on contemporary topics, and features articles based on symposia. In addition, supplemental issues are routinely published on various special topics, including three supplements devoted to contributions from the Cosmetic Review Expert Panel.