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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 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.

Keywords: Population pharmacokinetics; anrikefon; clinical analgesia; exposure-response analysis; κ-opioid receptor.