Physiologically‐based pharmacokinetic/pharmacodynamic modeling to predict tumor growth inhibition and the efficacious dose of selective estrogen receptor degraders in humans

Abstract

GDC‐9545 (giredestrant) is a highly potent, nonsteroidal, oral selective estrogen receptor antagonist and degrader that is being developed as a best‐in‐class drug candidate for early‐stage and advanced drug‐resistant breast cancer. GDC‐9545 was designed to improve the poor absorption and metabolism of its predecessor GDC‐0927, for which development was halted due to a high pill burden. This study aimed to develop physiologically‐based pharmacokinetic/pharmacodynamic (PBPK‐PD) models to characterize the relationships between oral exposure of GDC‐9545 and GDC‐0927 and tumor regression in HCI‐013 tumor‐bearing mice, and to translate these PK‐PD relationships to a projected human efficacious dose by integrating clinical PK data. PBPK and Simeoni tumor growth inhibition (TGI) models were developed using the animal and human Simcyp V20 Simulator (Certara) and adequately described each compound's systemic drug concentrations and antitumor activity in the dose‐ranging xenograft experiments in mice. The established PK‐PD relationship was translated to a human efficacious dose by substituting mouse PK for human PK. PBPK input values for human clearance were predicted using allometry and in vitro in vivo extrapolation approaches and human volume of distribution was predicted from simple allometry or tissue composition equations. The integrated human PBPK‐PD model was used to simulate TGI at clinically relevant doses. Translating the murine PBPK‐PD relationship to a human efficacious dose projected a much lower efficacious dose for GDC‐9545 than GDC‐0927. Additional sensitivity analysis of key parameters in the PK‐PD model demonstrated that the lower efficacious dose of GDC‐9545 is a result of improvements in clearance and absorption. The presented PBPK‐PD methodology can be applied to support lead optimization and clinical development of many drug candidates in discovery or early development programs.

Can 3D Printed Tablets Be Bioequivalent and How to Test It: A PBPK Model Based Virtual Bioequivalence Study for Ropinirole Modified Release Tablets

“…In addition to patient-related parameters, it can also estimate the influence of formulation differences on the endpoints of interest. There are a number of examples when PBPK was used in supporting the regulatory decisions, including dose selection and optimization for the newly approved drug, dose adjustment in special populations, and drug–drug interaction studies [ 11 , 12 , 13 ]. The number of studies where PBPK was used for biopharmaceutical purposes and VBE studies has also grown recently [ 14 , 15 , 16 ].…”

Linking in vitro–in vivo extrapolations with physiologically based modeling to inform drug and formulation development

“…Probably, the most common integration is between PBPK and pharmacodynamics (PD) models to assess the time course of drug effect. In this special issue, a PBPK model was linked to a tumor growth inhibition model to identify the optimal dose of selective estrogen receptor degraders in humans (Ganti et al., 2023). Furthermore, real world evidence (RWE) analysis can be used to verify PBPK‐based predictions, leveraging the predict–learn–confirm paradigm (Grillo et al., 2023).…”

“…Probably, the most common integration is between PBPK and pharmacodynamics (PD) models to assess the time course of drug effect. In this special issue, a PBPK model was linked to a tumor growth inhibition model to identify the optimal dose of selective estrogen receptor degraders in humans (Ganti et al, 2023).…”