Expert opinion on drug metabolism & toxicology · 2026
Vepdegestrant (ARV-471): pharmacokinetics, drug metabolism and clinical translation of an oral ERα-targeting PROTAC.
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Rana Nidhi, Patel Ashish
Аннотация
INTRODUCTION: Vepdegestrant (VEPPANU) is an orally administered proteolysis-targeting chimera (PROTAC) that targets estrogen receptor-α (ERα), a main transcription regulator of estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) breast cancer.
AREAS COVERED: The molecule consists of a lasofoxifene-based ER-binding part and a rigid, nitrogen-containing linker with a glutarimide-based CRBN (cereblon)-binding part related to lenalidomide. Preclinical studies show extensive degradation of both wild-type and mutant ERα, while clinical pharmacology studies demonstrate clinically relevant oral exposure despite the molecule's beyond-Rule-of-5 (bRo5) physicochemical properties. The review integrates the absorption, distribution, metabolism and excretion of vepdegestrant with its event-driven pharmacology, CYP3A4-, P-glycoprotein- and BCRP (Breast Cancer Resistance Protein)-mediated drug-drug interactions, and the translational implications of oral PROTAC design. The literature was identified through a search of Scopus from database inception through 31 August 2026, supplemented by screening of relevant reference lists and appropriate regulatory and clinical-trial information.
EXPERT OPINION: Vepdegestrant is a paradigm shift in the field of targeted protein degradation in endocrine oncology, yet its huge molecular size, metabolic problems, drug-drug interactions, development of resistance and persistent toxicological profile are all relevant matters of concern.
AREAS COVERED: The molecule consists of a lasofoxifene-based ER-binding part and a rigid, nitrogen-containing linker with a glutarimide-based CRBN (cereblon)-binding part related to lenalidomide. Preclinical studies show extensive degradation of both wild-type and mutant ERα, while clinical pharmacology studies demonstrate clinically relevant oral exposure despite the molecule's beyond-Rule-of-5 (bRo5) physicochemical properties. The review integrates the absorption, distribution, metabolism and excretion of vepdegestrant with its event-driven pharmacology, CYP3A4-, P-glycoprotein- and BCRP (Breast Cancer Resistance Protein)-mediated drug-drug interactions, and the translational implications of oral PROTAC design. The literature was identified through a search of Scopus from database inception through 31 August 2026, supplemented by screening of relevant reference lists and appropriate regulatory and clinical-trial information.
EXPERT OPINION: Vepdegestrant is a paradigm shift in the field of targeted protein degradation in endocrine oncology, yet its huge molecular size, metabolic problems, drug-drug interactions, development of resistance and persistent toxicological profile are all relevant matters of concern.