Population pharmacokinetic modeling and exposure-response analysis of anrikefon: insights and implications in clinical analgesia.

IF 3.6 3区医学 Q2 PHARMACOLOGY & PHARMACY

Expert Review of Clinical Pharmacology Pub Date : 2025-01-23 DOI:10.1080/17512433.2025.2449983

Kun Wang, Meixia Chen, Fengyan Xu, Fengyi Zhang, Lu Liu, Xiao Liu, Zhongyi Sun, Wanyun Zhao, Yongrui Wang, Jing Yang

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引用次数: 0

Abstract

Background: Anrikefon (HSK21542), a potent and selective peripheral kappa opioid receptor (KOR) agonist developed by Haisco, effectively blocks pain and itch signals.

Aim: To develop a population pharmacokinetic (PK) model for anrikefon and conduct exposure-response (E-R) analysis for safety and efficacy in postoperative pain patients.

Method: The Population PK analysis uses NONMEM software with data from six trials. E-R relationships were assessed using safety and efficacy data from three trials. Covariate screening and Bayesian post-hoc simulations identified relevant factors and compared exposure metrics. The fixed dosing regimen was evaluated by simulation. Safety and efficacy endpoints were evaluated using logistic regression and E_max models.

Results: A three-compartment model with linear elimination accurately described anrikefon's PK, incorporating weight through allometric scaling. Significant covariates affecting clearance included creatinine clearance, total bilirubin, albumin, aspartate transaminase, and age. Fixed and weight-based dosing showed similar exposures. No apparent E-R trend was observed for safety endpoints. The E_max model indicated that most of subjects achieved over 90% of the maximum effect for SPID_0-24 h at 1.0 μg/kg. Safety analysis confirmed this dose was well tolerated with no safety issues.

Conclusion: This study provides valuable insights into dose selection, PK variability, and safety and efficacy endpoints.

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Anrikefon的人群药代动力学建模和暴露-反应分析：在临床镇痛中的见解和意义。

背景：Anrikefon （HSK21542）是海斯科公司开发的一种强效、选择性外周kappa阿片受体（KOR）激动剂，可有效阻断疼痛和瘙痒信号。目的：建立anrikefon的群体药代动力学（PK）模型，并对其在术后疼痛患者中的安全性和有效性进行暴露反应（E-R）分析。方法：采用NONMEM软件对6个试验数据进行群体PK分析。E-R关系使用来自三个试验的安全性和有效性数据进行评估。协变量筛选和贝叶斯事后模拟确定了相关因素并比较了暴露指标。对固定给药方案进行模拟评价。安全性和有效性终点采用logistic回归和Emax模型进行评估。结果：线性消除的三室模型准确地描述了anrikefon的PK，通过异速缩放纳入了重量。影响清除率的重要协变量包括肌酐清除率、总胆红素、白蛋白、天冬氨酸转氨酶和年龄。固定剂量和基于体重的剂量显示出相似的暴露。安全终点未观察到明显的E-R趋势。Emax模型显示，在1.0 μg/kg的剂量下，大多数受试者在0-24 h内达到90%以上的最大效果。安全性分析证实该剂量耐受性良好，无安全性问题。结论：该研究为剂量选择、PK变异性以及安全性和有效性终点提供了有价值的见解。

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

Expert Review of Clinical Pharmacology PHARMACOLOGY & PHARMACY-

CiteScore

7.30

自引率

2.30%

发文量

127

期刊介绍： Advances in drug development technologies are yielding innovative new therapies, from potentially lifesaving medicines to lifestyle products. In recent years, however, the cost of developing new drugs has soared, and concerns over drug resistance and pharmacoeconomics have come to the fore. Adverse reactions experienced at the clinical trial level serve as a constant reminder of the importance of rigorous safety and toxicity testing. Furthermore the advent of pharmacogenomics and ‘individualized’ approaches to therapy will demand a fresh approach to drug evaluation and healthcare delivery. Clinical Pharmacology provides an essential role in integrating the expertise of all of the specialists and players who are active in meeting such challenges in modern biomedical practice.