A Mechanistic Pharmacokinetics and Pharmacodynamics (PK/PD) Platform Model for Induced proximity-based therapeutics - PROTACs

Objectives: Induced proximity-based therapeutics offer an innovative approach to reach undruggable targets. It is the central mechanisms of PROTACs (Proteolysis-Targeting Chimeras) that leverage natural ubiquitin-proteasome systems to tag and degrade targeted proteins. Pharmaceutical development of PROTACs can greatly benefit from utilization of a mechanistic PK/PD model to help support decision making in the areas such as FIH dose selection, dose optimizations throughout clinical development, and evaluation of clinical liabilities. The objective of this work is to develop a mechanistic and multiscale platform model of PROTACs to predict whole-body PK and PD of PROTACs and to evaluate the utility of the developed model with a case study on ARV-110, a PROTAC protein degrader targeting the Androgen Receptor (AR). Methods: We have developed a mechanistic platform model that captures the PK/PD of PROTACs at the cellular, tissue, and physiological levels to predict proximity-induced targeted protein degradation using a published model[ 1]. To capture the unique features of PROTACs, the model included the following cellular mechanisms: target turnover kinetics, binary and ternary complex formation, step-wise ubiquitination, UPS-mediated target protein degradation, and recycling. ARV-110, a PROTAC protein degrader with publicly available data, was chosen as a case study molecule to predict the targeted degradation of the Androgen Receptor (AR). Published in vitro and in vivo PK and PD data for ARV-110 were used for respective model components development [ 2, 3]. Cellular distribution kinetics and dynamics components of the model were parameterized and target degradation kinetics was estimated using available in vitro data. In vitro to in vivo extrapolation (IVIVE) was applied to scale the PD model to predict ARV-110 dynamics in castrated mouse model with VCaP tumors. In vivo PK parameters were estimated using mouse data following 5 mg/kg ARV-110 oral administration. Results: The calibrated model well predicted the PD Exposure-Response for ARV-110 mediated AR degradation kinetics in VCaP and LNCaP cell lines at 8 hours across a range of doses (0.01-3000 nM). Anticipated Hook-Effect at higher concentrations where dimerization is favored was well captured. Applying in vitro to in vivo extrapolation (IVIVE) concepts the model was successfully scaled to in vivo to predict the whole-body PK and PD of ARV-110 in castrated mouse model with VCaP tumors across three dose groups, 0.3, 1, and 3 mg/kg, where 70 hour AR degradation predictions were compared to the in vivo data. Conclusions: A mechanistic and multiscale PK/PD model has been successfully developed for first-in-class oral PROTAC, ARV-110, a selective degrader of Androgen Receptor (AR) currently evaluated for the treatment of metastatic castration-resistant prostate cancer (mCRPC). The model can be further developed for clinical translation to predict clinical PK/PD of PROTACs and help evaluate key patient factors and clinical liabilities.