当前位置: X-MOL 学术Regul. Toxicol. Pharmacol. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Evaluation of preclinical safety profile of SPH3127, a direct renin inhibitor, after 28-day repeated oral administration in Sprague-Dawley rats and cynomolgus monkeys.
Regulatory Toxicology and Pharmacology ( IF 3.4 ) Pub Date : 2019-10-01 , DOI: 10.1016/j.yrtph.2019.104484
Yu Mao 1 , Leduo Zhang 1 , Hua Li 2 , Xin Li 3 , Yanjun Liu 1 , Guangxin Xia 1
Affiliation  

SPH3127, a newly developed oral nonpeptide direct renin inhibitor with good tolerance and favorable ADME (absorption distribution metabolism excretion) properties in preclinical species, is now being evaluated in phase Ι clinical trial. In this work, the subchronic toxicity of SPH3127 in Sprague-Dawley rats and cynomolgus monkeys has been characterized. Rats and monkeys received SPH3127 orally (30, 300, 900 and 20, 100, 450 mg/kg/day, respectively) on a consecutive daily dosing schedule for 28 days followed by a 28-days recovery period for one third of the animals. The adverse effects of SPH3127 on rats and monkeys mainly included kidney and cardiovascular toxicity, which were consistent with pharmacologic perturbations of physiologic processes associated with the intended molecular targets for this class of renin signaling inhibitors. Moderate liver weight increases accompanied by CYP3A induction were seen in 300 and 900 mg/kg/day rats but not in monkeys or in vitro human hepatocytes. One 450 mg/kg/day monkey died early at day 23 with apparent myelosuppression characterized by atrophy of thymus and spleen, and the relevance to the action of SPH3127 remained unclear. Most of the treatment-induced effects were reversible upon discontinuation of treatment. The no-observed-adverse-effect level (NOAEL) of SPH3127 was determined to be 30 mg/kg/day for Sprague-Dawley rats and 20 mg/kg/day for cynomolgus monkeys based on the kidney and cardiovascular changes found at mid- and high-dose animals.

中文翻译:

在Sprague-Dawley大鼠和食蟹猴重复口服28天后,对直接肾素抑制剂SPH3127的临床前安全性进行评估。

SPH3127是一种新开发的口服非肽直接肾素抑制剂,在临床前物种中具有良好的耐受性和良好的ADME(吸收分布代谢排泄)特性,目前正在I期临床试验中进行评估。在这项工作中,已对SPH3127在Sprague-Dawley大鼠和食蟹猴中的亚慢性毒性进行了表征。大鼠和猴子以连续28天的每日给药方案口服SPH3127(分别为30、300、900和20、100、450、450 mg / kg /天),随后有三分之一的动物接受了28天的恢复期。SPH3127对大鼠和猴子的不利影响主要包括肾脏和心血管毒性,这与与这类肾素信号转导抑制剂的预期分子靶标相关的生理过程的药理学扰动一致。在300和900 mg / kg / day的大鼠中观察到中度肝重增加并伴有CYP3A诱导作用,但在猴子或体外人肝细胞中未见到此现象。一只450 mg / kg / day的猴子在第23天早期死亡,表现出明显的骨髓抑制,其特征在于胸腺和脾脏萎缩,与SPH3127作用的相关性仍不清楚。大多数治疗诱导的作用在治疗中断后是可逆的。根据中途发现的肾脏和心血管变化,对Sprague-Dawley大鼠,SPH3127的未观察到的不良反应水平(NOAEL)确定为30 mg / kg /天,对于食蟹猴则确定为20 mg / kg / day。和大剂量的动物。一只450 mg / kg / day的猴子在第23天早期死亡,表现出明显的骨髓抑制,其特征在于胸腺和脾脏萎缩,与SPH3127作用的相关性仍不清楚。大多数治疗诱导的作用在治疗中断后是可逆的。根据中途发现的肾脏和心血管变化,对Sprague-Dawley大鼠,SPH3127的未观察到的不良反应水平(NOAEL)确定为30 mg / kg /天,对于食蟹猴则确定为20 mg / kg / day。和大剂量的动物。一只450 mg / kg / day的猴子在第23天早期死亡,表现出明显的骨髓抑制,其特征在于胸腺和脾脏萎缩,与SPH3127作用的相关性仍不清楚。大多数治疗诱导的作用在治疗中断后是可逆的。根据中途发现的肾脏和心血管变化,对Sprague-Dawley大鼠,SPH3127的未观察到的不良反应水平(NOAEL)确定为30 mg / kg /天,对于食蟹猴则确定为20 mg / kg / day。和大剂量的动物。
更新日期:2019-10-01
down
wechat
bug