Characterization of preclinical radio ADME properties of ARV-471 for predicting human PK using PBPK modeling
10.1016/j.jpha.2024.101175
- Author:
Yifei HE
1
;
Chenggu ZHU
;
Peng LEI
;
Chen YANG
;
Yifan ZHANG
;
Yuandong ZHENG
;
Xingxing DIAO
Author Information
1. Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai,201203,China;University of Chinese Academy of Sciences,Beijing,100049,China
- Publication Type:Journal Article
- Keywords:
PROTAC;
Vepdegestrant(ARV-471);
Radiolabeling;
In vitro-in vivo extrapolation(IVIVE);
Physiologically based pharmacokinetic(PBPK)model
- From:
Journal of Pharmaceutical Analysis
2025;15(5):1145-1159
- CountryChina
- Language:English
-
Abstract:
Proteolysis-targeting chimeras(PROTACs)represent a promising class of drugs that can target disease-causing proteins more effectively than traditional small molecule inhibitors can,potentially revolu-tionizing drug discovery and treatment strategies.However,the links between in vitro and in vivo data are poorly understood,hindering a comprehensive understanding of the absorption,distribution,metabolism,and excretion(ADME)of PROTACs.In this work,14C-labeled vepdegestrant(ARV-471),which is currently in phase Ⅲ clinical trials for breast cancer,was synthesized as a model PROTAC to characterize its preclinical ADME properties and simulate its clinical pharmacokinetics(PK)by estab-lishing a physiologically based pharmacokinetics(PBPK)model.For in vitro-in vivo extrapolation(IVIVE),hepatocyte clearance correlated more closely with in vivo rat PK data than liver microsomal clearance did.PBPK models,which were initially developed and validated in rats,accurately simulate ARV-471's PK across fed and fasted states,with parameters within 1.75-fold of the observed values.Human models,informed by in vitro ADME data,closely mirrored postoral dose plasma profiles at 30 mg.Furthermore,no human-specific metabolites were identified in vitro and the metabolic profile of rats could overlap that of humans.This work presents a roadmap for developing future PROTAC medications by elucidating the correlation between in vitro and in vivo characteristics.
