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

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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.

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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)