Population Pharmacokinetic (PopPK) Model to Characterize Pharmacokinetics (PK) of Vepdegestrant, a Proteolysis Targeting Chimera (PROTAC) Estrogen Receptor (ER) Degrader, in Healthy Adult Participants
Authors: Drescher Stefanie , Yang Derek Zhiye , Masson Eric , Tan Weiwei 
Published: February 2025

Background: Vepdegestrant (ARV-471) is an investigational, orally administered PROTAC ER degrader. In a first-in-human phase 1/2 study, vepdegestrant monotherapy was well tolerated and showed encouraging clinical activity in participants with ER+/human epidermal growth factor receptor 2- (HER2-) breast cancer (BC). The phase 3 monotherapy dose (200 mg once daily [QD]) is currently under investigation in a randomized phase 3 study (VERITAC-2 [NCT04072952]) in patients with ER+/HER- advanced breast cancer after prior treatment. The aim of this work was to develop PopPK models to characterize the PK of vepdegestrant following oral 200 mg single doses in phase 1 healthy participant clinical pharmacology studies. Method: A total of 610 vepdegestrant plasma concentration observations from 60 healthy participants who received a single dose of vepdegestrant 200 mg alone in four phase 1 clinical pharmacology studies (NCT05673889, NCT05538312, NCT06005688, NCT05652660) were pooled for analysis. Serial PK sampling up to 144 hours were collected in all participants. Non-linear mixed effects modeling was carried out using NONMEM version 7.5.3 using first-order conditional estimation with interaction. Various absorption models, including 0-order, 1st-order, transit, parallel 0- and 1st-order, and sequential 0-order followed by 1st-order models, with and without lag time, were evaluated. Demographic factors were screened for potential covariates. Model performance was assessed by objective function value, parameter estimates, goodness-of-fit, and visual predictive check. Results: The analysis population consisted of 52 male participants and 8 female participants of non-child-bearing potential, with body weight ranging from 55.3 kg to 114.6 kg and age of 22 to 70 years old. The majority of participants were White (73%), followed by Black or African American (18%), Asian (7%) and Others (2%). The measurable plasma vepdegestrant concentrations of the analysis set ranged from 3.46 to 893 ng/mL. An absorption model with sequential zero order followed by first order oral absorption best described the PK profiles of vepdegestrant. The PopPK of vegdegestrant was characterized by a two-compartment model with allometric scaling of body weight incorporated for apparent clearance and volume of distribution parameters raised to a fixed exponent of 0.75 and 1, respectively. No demographic factors (race, sex, and age) in this population showed an overt correlation to any PK parameters. Model evaluation suggested that the developed PopPK model was adequate and robust with good precision. Conclusion: The proposed PopPK model for vepdegestrant adequately described the plasma concentrations of vepdegestrant observed in healthy participants after administration of a single dose of 200 mg vepdegestrant. The developed model will be utilized for the development of PopPK models in vepdegestrant treated patients with ER+/HER2- breast cancer. Citations NA