Reproductive and developmental toxicity assessment of HSK21542, a novel peripherally-restricted kappa opioid receptor agonist in rats and rabbits

IF 3 4区医学 Q1 MEDICINE, LEGAL

Regulatory Toxicology and Pharmacology Pub Date : 2025-03-18 DOI:10.1016/j.yrtph.2025.105811

Xiaoli Gou , Qidi Ye , Bo Chen , Yu Zheng , Hongyu Chen , Litong Fan , Qingyuan Meng , Chen Zhang , Yao Lu , Ju Wang

{"title":"Reproductive and developmental toxicity assessment of HSK21542, a novel peripherally-restricted kappa opioid receptor agonist in rats and rabbits","authors":"Xiaoli Gou , Qidi Ye , Bo Chen , Yu Zheng , Hongyu Chen , Litong Fan , Qingyuan Meng , Chen Zhang , Yao Lu , Ju Wang","doi":"10.1016/j.yrtph.2025.105811","DOIUrl":null,"url":null,"abstract":"<div><div>HSK21542, a potent and peripherally-restricted kappa opioid receptor (KOR) agonist, is currently being developed to treat postoperative pain and pruritus. Given that conventional opioids (MOR agonists) are widely recognized for their toxicological impacts on the reproductive system and embryonic development, we evaluated the effects of HSK21542 accordingly. The results showed that HSK21542 did not influence male and female fertility or early embryonic development in rats. HSK21542 also did not show significant manifestations of pre- and post-natal development toxicity in rats. In the embryo-fetal developmental study, even though there was a 3.5 % increase in incidence of fetuses with incomplete ossification of thoracic vertebral centrum in the 4 mg/kg/day group, the plasma exposure of HSK21542 in rats at the no observed adverse effect level (NOAEL) was 82.3 times higher than that of human exposure at 1 μg/kg. On the other hand, exposure to HSK21542 during pregnancy in rabbits did not show any teratogenic risk, only causing a minor impact on bone ossification in fetuses. In conclusion, HSK21542 has a favorable safety profile with only minor effects on the embryo-fetal developmental outcomes.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"159 ","pages":"Article 105811"},"PeriodicalIF":3.0000,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Regulatory Toxicology and Pharmacology","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0273230025000418","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"MEDICINE, LEGAL","Score":null,"Total":0}

引用次数: 0

Abstract

HSK21542, a potent and peripherally-restricted kappa opioid receptor (KOR) agonist, is currently being developed to treat postoperative pain and pruritus. Given that conventional opioids (MOR agonists) are widely recognized for their toxicological impacts on the reproductive system and embryonic development, we evaluated the effects of HSK21542 accordingly. The results showed that HSK21542 did not influence male and female fertility or early embryonic development in rats. HSK21542 also did not show significant manifestations of pre- and post-natal development toxicity in rats. In the embryo-fetal developmental study, even though there was a 3.5 % increase in incidence of fetuses with incomplete ossification of thoracic vertebral centrum in the 4 mg/kg/day group, the plasma exposure of HSK21542 in rats at the no observed adverse effect level (NOAEL) was 82.3 times higher than that of human exposure at 1 μg/kg. On the other hand, exposure to HSK21542 during pregnancy in rabbits did not show any teratogenic risk, only causing a minor impact on bone ossification in fetuses. In conclusion, HSK21542 has a favorable safety profile with only minor effects on the embryo-fetal developmental outcomes.

查看原文本刊更多论文

新型外周限制性kappa阿片受体激动剂HSK21542对大鼠和家兔的生殖和发育毒性评价

HSK21542是一种有效的外周限制性kappa阿片受体（KOR）激动剂，目前正在开发用于治疗术后疼痛和瘙痒。鉴于传统阿片类药物（MOR激动剂）因其对生殖系统和胚胎发育的毒理学影响而被广泛认可，我们相应地评估了HSK21542的作用。结果表明，HSK21542不影响大鼠雌雄生殖能力和早期胚胎发育。HSK21542在大鼠中也未表现出明显的产前和产后发育毒性。在胚胎-胎儿发育研究中，尽管在4 mg/kg/天组中，胸椎椎体不完全骨化的胎儿发生率增加了3.5%，但未观察到不良反应水平（NOAEL）的大鼠血浆暴露HSK21542是1 μg/kg时人类暴露HSK21542的82.3倍。另一方面，兔怀孕期间暴露于HSK21542没有显示出任何致畸风险，仅对胎儿骨骨化产生轻微影响。总之，HSK21542具有良好的安全性，仅对胚胎-胎儿发育结局有轻微影响。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Regulatory Toxicology and Pharmacology 医学-毒理学

CiteScore

6.70

自引率

8.80%

发文量

147

审稿时长

58 days

期刊介绍： Regulatory Toxicology and Pharmacology publishes peer reviewed articles that involve the generation, evaluation, and interpretation of experimental animal and human data that are of direct importance and relevance for regulatory authorities with respect to toxicological and pharmacological regulations in society. All peer-reviewed articles that are published should be devoted to improve the protection of human health and environment. Reviews and discussions are welcomed that address legal and/or regulatory decisions with respect to risk assessment and management of toxicological and pharmacological compounds on a scientific basis. It addresses an international readership of scientists, risk assessors and managers, and other professionals active in the field of human and environmental health. Types of peer-reviewed articles published: -Original research articles of relevance for regulatory aspects covering aspects including, but not limited to: 1.Factors influencing human sensitivity 2.Exposure science related to risk assessment 3.Alternative toxicological test methods 4.Frameworks for evaluation and integration of data in regulatory evaluations 5.Harmonization across regulatory agencies 6.Read-across methods and evaluations -Contemporary Reviews on policy related Research issues -Letters to the Editor -Guest Editorials (by Invitation)