Kun Wang, Meixia Chen, Fengyan Xu, Fengyi Zhang, Lu Liu, Xiao Liu, Zhongyi Sun, Wanyun Zhao, Yongrui Wang, Jing Yang
{"title":"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。","authors":"Kun Wang, Meixia Chen, Fengyan Xu, Fengyi Zhang, Lu Liu, Xiao Liu, Zhongyi Sun, Wanyun Zhao, Yongrui Wang, Jing Yang","doi":"10.1080/17512433.2025.2449983","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Anrikefon (HSK21542), a potent and selective peripheral kappa opioid receptor (KOR) agonist developed by Haisco, effectively blocks pain and itch signals.</p><p><strong>Aim: </strong>To develop a population pharmacokinetic (PK) model for anrikefon and conduct exposure-response (E-R) analysis for safety and efficacy in postoperative pain patients.</p><p><strong>Method: </strong>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<sub>max</sub> models.</p><p><strong>Results: </strong>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<sub>max</sub> model indicated that most of subjects achieved over 90% of the maximum effect for SPID<sub>0-24 h</sub> at 1.0 μg/kg. Safety analysis confirmed this dose was well tolerated with no safety issues.</p><p><strong>Conclusion: </strong>This study provides valuable insights into dose selection, PK variability, and safety and efficacy endpoints.</p>","PeriodicalId":12207,"journal":{"name":"Expert Review of Clinical Pharmacology","volume":" ","pages":"1-12"},"PeriodicalIF":3.6000,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Population pharmacokinetic modeling and exposure-response analysis of anrikefon: insights and implications in clinical analgesia.\",\"authors\":\"Kun Wang, Meixia Chen, Fengyan Xu, Fengyi Zhang, Lu Liu, Xiao Liu, Zhongyi Sun, Wanyun Zhao, Yongrui Wang, Jing Yang\",\"doi\":\"10.1080/17512433.2025.2449983\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Anrikefon (HSK21542), a potent and selective peripheral kappa opioid receptor (KOR) agonist developed by Haisco, effectively blocks pain and itch signals.</p><p><strong>Aim: </strong>To develop a population pharmacokinetic (PK) model for anrikefon and conduct exposure-response (E-R) analysis for safety and efficacy in postoperative pain patients.</p><p><strong>Method: </strong>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<sub>max</sub> models.</p><p><strong>Results: </strong>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<sub>max</sub> model indicated that most of subjects achieved over 90% of the maximum effect for SPID<sub>0-24 h</sub> at 1.0 μg/kg. Safety analysis confirmed this dose was well tolerated with no safety issues.</p><p><strong>Conclusion: </strong>This study provides valuable insights into dose selection, PK variability, and safety and efficacy endpoints.</p>\",\"PeriodicalId\":12207,\"journal\":{\"name\":\"Expert Review of Clinical Pharmacology\",\"volume\":\" \",\"pages\":\"1-12\"},\"PeriodicalIF\":3.6000,\"publicationDate\":\"2025-01-23\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Expert Review of Clinical Pharmacology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1080/17512433.2025.2449983\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"PHARMACOLOGY & PHARMACY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Expert Review of Clinical Pharmacology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1080/17512433.2025.2449983","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
Population pharmacokinetic modeling and exposure-response analysis of anrikefon: insights and implications in clinical analgesia.
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 Emax 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 Emax model indicated that most of subjects achieved over 90% of the maximum effect for SPID0-24 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.
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.
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