Abstract C126: Translational pharmacokinetic/pharmacodynamic (PK/PD) modeling of novel covalent Kelch-like ECH-associated protein 1 (KEAP1) activators

Abstract

Introduction: The KEAP1-nuclear factor erythroid 2-related factor 2 (NRF2) signaling axis is a key homeostatic mechanism for cells to maintain redox balance. In oxidative stress, reactive oxygen species (ROS) modify residues on KEAP1, impairing its binding and ubiquitination of NRF2. This leads to an accumulation and translocation of NRF2 to the nucleus where it increases transcription of genes for antioxidant response [Pillai 2022]. The KEAP1-NRF2 pathway is hijacked in cancers through NRF2 gain of function or KEAP1 loss of function mutations leading to aberrant activation of NRF2. We have discovered small molecule covalent KEAP1 activators that increase Keap1 incorporation into productive E3 complexes with CUL3, promoting the degradation of NRF2. Given the covalent nature of binding, the turnover of KEAP1, the resulting regulation of NRF2 protein level, and NRF2 target gene transcription and translation, the relationship between the small molecule KEAP1 activator plasma PK, tumor PK and KEAP1 target engagement (TE), and resulting PD (NRF2 degradation) is complex. A translational PK/PD model is established to quantitatively describe this for a tool molecule VVD-065 [see Roy 2023], investigate parameters which influence PK/PD relationships, and identify potential efficacious doses to guide development.

Methods: The translational PK/PD model includes a physiologically-based PK (PBPK) model to capture available animal PK and predict human plasma PK, a compartmental tumor PK model to describe and predict tumor PK from mouse xenograft experiments, and a mechanistic TE-PD model derived from a published model for binding of KEAP1 and NRF2 and the stabilization and subsequent ubiquitination of the KEAP1-NRF2-drug complex [Liu 2021]. Thus, the translational PK/PD model integrates cumulative available physicochemical properties, in vitro, and preclinical in vivo data of VVD-065 [see Roy 2023]. Model development was undertaken in R software using the mrgsolve package.

Results: The established PBPK model successfully recapitulated animal (mouse, rat, dog) PK from physicochemical properties and in vitro ADME and was used to predict human plasma PK. Mouse plasma and tumor PK collected from xenograft experiments was used to construct a compartmental tumor PK model to subsequently predict human tumor PK from simulated human plasma PK. The mechanistic TE-PD model was qualified based on literature, proteomics, and available in vitro and in vivo (xenograft) KEAP1 TE and NRF2 degradation driven by tumor PK. Physiological variability contributing to human PK was incorporated through creation of a virtual population. Sensitivity analyses from the translational PK/PD model revealed tumor PK and KEAP1 turnover as key parameters influencing PD activity. The translational PK/PD model could be used to predict human dosing regimens which maximize KEAP1 TE and resulting NRF2 degradation.

Conclusion: A translational PK/PD model is established and can be used to predict efficacious dose regimens and guide clinical development for novel KEAP1 activators.

Citation Format: Conrad Housand, Nil Roy, Tine Wyseure, Christie Eissler, Justine Metzger, Michaela Bairlein, Julie O'Brien, Melaminah Williams, Victor Contreras, Marine Garrido, Todd Kinsella, Jenna Goldberg, Matt Patricelli, Peter N. Morcos. Translational pharmacokinetic/pharmacodynamic (PK/PD) modeling of novel covalent Kelch-like ECH-associated protein 1 (KEAP1) activators [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C126.